Dr. Napolioni received his Ph.D in Genetics in 2011, from the University of Camerino, Italy, working on complex trait genetics, focusing both on human longevity and Autism. His interest in neuropsychiatric traits led him to continue working on Autism genetics, first as post-doc at the Laboratory of Molecular Psychiatry, University Campus Bio-Medico, Rome, and then as visiting researcher at the Neurogenomics Division, TGen, Phoenix, AZ. In 2013 he became the technical director of the Next-Gen Sequencing Core at University of Perugia, Italy. In 2015 he joined the FIND lab where he is pursuing his strong research interest in the genetics of neuropsychiatric and behavioral human traits.
Boards, Advisory Committees, Professional Organizations
Associate Editor, BMC Medical Genetics (2016 - Present)
Member, American Society of Human Genetics (2016 - Present)
Member, European Society of Human Genetics (2009 - Present)
Doctor of Philosophy, Universita Degli Stud di Camerino (2011)
Doctor of Philosophy, University of Camerino, Genetics (2011)
Master of Science, University of Camerino, Biomolecular and Biofunctional Sciences (2007)
Bachelor of Science, University of Camerino, Biology (2005)
Michael Greicius, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
My research is focused on the genetic underpinnings of common complex neuropsychiatric disorders with an emphasis on evolutionary/adaptive effects of gene variants. Given the incredible complexity underlying human neurobehavioral traits, I strongly believe in the necessity of applying a multidisciplinary approach that may involve genetics, neuropsychiatry, ecology, immunology and sociology. Currently I’m working on X-chromosome wide association studies, aiming to get a better understanding of sex-specific differences in the susceptibility to neuropsychiatric conditions.
A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis.
2017; 8: 14017
T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25(+) type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.
View details for DOI 10.1038/ncomms14017
View details for PubMedID 28090087
IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis.
2016; 7: 10791
Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.
View details for DOI 10.1038/ncomms10791
View details for PubMedID 26972847
GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability.
American journal of human genetics
GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
View details for DOI 10.1016/j.ajhg.2016.06.025
View details for PubMedID 27523599
Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1.
Cell host & microbe
Defects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-β/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ.
View details for DOI 10.1016/j.chom.2016.10.012
View details for PubMedID 27889463
A New Homozygous IGF1R Variant Defines a Clinically Recognizable Incomplete Dominant form of SHORT Syndrome.
2015; 36 (11): 1043–47
Here, we describe a child, born from consanguineous parents, with clinical features of SHORT syndrome, high IGF1 levels, developmental delay, CNS defects, and marked progeroid appearance. By exome sequencing, we identified a new homozygous c.2201G>T missense mutation in the IGF1R gene. Proband's parents and other relatives, all heterozygous carriers of the mutation, presented with milder phenotype including high IGFI levels, short stature, and type 2 diabetes. Functional studies using patient's cell lines showed a lower IGF1R expression that leads to the alteration of IGF1R-mediated PI3K/AKT/mTOR downstream pathways, including autophagy. This study defines a clinically recognizable incomplete dominant form of SHORT syndrome, and provides relevant insights into the pathophysiological and phenotypical consequences of IGF1R mutations.
View details for DOI 10.1002/humu.22853
View details for PubMedID 26252249
Infectious diseases, IL6 -174G>C polymorphism, and human development.
Brain, behavior, and immunity
Interleukin-6 (IL6) is a pro-inflammatory cytokine that is required for resistance against many pathogens. However, sustained IL6 activity can cause tissue damage in the periphery and brain. Previous studies have shown that populations in disease-endemic regions adapt by selecting the high-producing G-allele at the -174G>C (rs1800795) polymorphism, while others have linked increased IL6 to cognitive impairments. The present study sought to determine whether up-regulation of IL6 by the G-allele at rs1800795 polymorphism in disease-endemic regions was associated with increased cognitive deficits and corollary reductions in social, economic, and political development. We tested these hypotheses in a global sample of 189 nations with World Health Organization ratings for infectious diseases. We also included the Historical Pathogen Prevalence index, a measure of national average intelligence (IQ), and the United Nation Human Development Index (HDI) including per capita income, life expectancy, child mortality, and fertility rate. IL6 -174G>C allele frequencies were obtained from 171,168 individuals spanning 84 nations. The high-producing G-allele frequency was positively correlated with infectious disease ranking (r=0.745, P<0.001) and negatively with IQ (r=-0.524, P<0.001) and HDI (r=-0.671, P<0.001). These robust findings suggest that in regions with a high pathogen burden the need for a strong IL6 response is accompanied by cognitive deficits and reduced HDI ranking.
View details for DOI 10.1016/j.bbi.2015.08.016
View details for PubMedID 26291404
Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder
JOURNAL OF NEUROINFLAMMATION
Converging lines of evidence point to the existence of immune dysfunction in autism spectrum disorder (ASD), which could directly affect several key neurodevelopmental processes. Previous studies have shown higher cytokine levels in patients with autism compared with matched controls or subjects with other developmental disorders. In the current study, we used plasma-cytokine profiling for 25 discordant sibling pairs to evaluate whether these alterations occur within families with ASD.Plasma-cytokine profiling was conducted using an array-based multiplex sandwich ELISA for simultaneous quantitative measurement of 40 unique targets. We also analyzed the correlations between cytokine levels and clinically relevant quantitative traits (Vineland Adaptive Behavior Scale in Autism (VABS) composite score, Social Responsiveness Scale (SRS) total T score, head circumference, and full intelligence quotient (IQ)). In addition, because of the high phenotypic heterogeneity of ASD, we defined four subgroups of subjects (those who were non-verbal, those with gastrointestinal issues, those with regressive autism, and those with a history of allergies), which encompass common and/or recurrent endophenotypes in ASD, and tested the cytokine levels in each group.None of the measured parameters showed significant differences between children with ASD and their related typically developing siblings. However, specific target levels did correlate with quantitative clinical traits, and these were significantly different when the ASD subgroups were analyzed. It is notable that these differences seem to be attributable to a predisposing immunogenetic background, as no other significant differences were noticed between discordant sibling pairs. Interleukin-1β appears to be the cytokine most involved in quantitative traits and clinical subgroups of ASD.In the present study, we found a lack of significant differences in plasma-cytokine levels between children with ASD and in their related non-autistic siblings. Thus, our results support the evidence that the immune profiles of children with autism do not differ from their typically developing siblings. However, the significant association of cytokine levels with the quantitative traits and the clinical subgroups analyzed suggests that altered immune responses may affect core feature of ASD.
View details for DOI 10.1186/1742-2094-10-38
View details for Web of Science ID 000317239800001
View details for PubMedID 23497090
The gene-immune-behavioral pathway: Gamma-interferon (IFN-γ) simultaneously coordinates susceptibility to infectious disease and harm avoidance behaviors.
Brain, behavior, and immunity
Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma-interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It is a functional SNP, regulating IFNG mRNA expression; it is known to modulate serotonergic activity and is therefore capable of modifying behavior; and it has previously been associated with increased susceptibility to malaria, tuberculosis, leprosy and Chagas disease. We hypothesized that the infectious disease-high-risk IFNG +874 A-allele would be associated with four personality traits previously reported as behavioral defenses against infection: Harm Avoidance (HA), Extraversion (E), Exploratory Excitability (Exp E), and Openness to Experience (O). We tested this hypothesis in a sample of 168 healthy university students from Southern California genotyped for IFNG +874 T>A and evaluated by the Temperament and Character Inventory-Revised (TCI-R) and the NEO Five-Factor Inventory (NEO-FFI). We found that the infectious disease-high-risk IFNG +874 A-allele was associated with increased HA (P=0.001) and decreased E (P=0.030) and Exp E (P=0.030). These findings suggest that the IFNG +874 A gene variant is linked both to infectious disease susceptibility and to proactive behavioral defenses that reduce infection risk in healthy subjects.
View details for DOI 10.1016/j.bbi.2013.09.012
View details for PubMedID 24075848
The Mitochondrial Aspartate/Glutamate Carrier AGC1 and Calcium Homeostasis: Physiological Links and Abnormalities in Autism
2011; 44 (1): 83-92
Autism spectrum disorder (ASD) is a severe, complex neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped patterns of interests and behaviors. Recent evidence has unveiled an important role for calcium (Ca(2+)) signaling in the pathogenesis of ASD. Post-mortem studies of autistic brains have pointed toward abnormalities in mitochondrial function as possible downstream consequences of altered Ca(2+) signaling, abnormal synapse formation, and dysreactive immunity. SLC25A12, an ASD susceptibility gene, encodes the Ca(2+)-regulated mitochondrial aspartate-glutamate carrier, isoform 1 (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate (ATP) production. Here, we review the physiological roles of AGC1, its links to calcium homeostasis, and its involvement in autism pathogenesis.
View details for DOI 10.1007/s12035-011-8192-2
View details for Web of Science ID 000295282500008
View details for PubMedID 21691713
Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes
EUROPEAN JOURNAL OF HUMAN GENETICS
2011; 19 (3): 353-359
The integrin-β 3 gene (ITGB3), located on human chromosome 17q21.3, was previously identified as a quantitative trait locus (QTL) for 5-HT blood levels and has been implicated as a candidate gene for autism spectrum disorder (ASD). We performed a family-based association study in 281 simplex and 12 multiplex Caucasian families. ITGB3 haplotypes are significantly associated with autism (HBAT, global P=0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P=0.005; odds ratio (OR)=2.000), at the expense of haplotype H1, which is under-transmitted (HBAT P=0.018; OR=0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P-value of 0.072 in single-marker FBAT analyses. Interestingly, rs12603582 is strongly associated with pre-term delivery in our ASD patients (P=0.008). On the other hand, it is SNP rs2317385, located at the 5' end of the gene, that significantly affects 5-HT blood levels (Mann-Whitney U-test, P=0.001; multiple regression analysis, P=0.010). No gene-gene interaction between ITGB3 and SLC6A4 has been detected. In conclusion, we identify a significant association between a common ITGB3 haplotype and ASD. Distinct markers, located toward the 5' and 3' ends of the gene, seemingly modulate 5-HT blood levels and autism liability, respectively. Our results also raise interest into ITGB3 influences on feto-maternal immune interactions in autism.
View details for DOI 10.1038/ejhg.2010.180
View details for Web of Science ID 000287445600023
View details for PubMedID 21102624
Angiotensin-Converting Enzyme Ins/Del Polymorphism and Body Composition: The Intermediary Role of Hydration Status.
Journal of nutrigenetics and nutrigenomics
2017; 10 (1-2): 1–8
The well-known insertion/deletion polymorphism (rs4646994) of the angiotensin-converting enzyme (ACE) gene has been previously associated with obesity, blood flow, muscular strength, and ACE enzyme activity. Despite the relevant role of ACE in homeostasis, few data are currently available on the relationship between rs4646994 and hydration status. Thus, we tested the association between the ACE Ins/Del polymorphism, body composition, and hydration status in a young Italian population.A total of 306 healthy children and adolescents who regularly practice sports were recruited. Anthropometric, bioimpedentiometric parameters, and urine samples were collected, while ACE rs4646994 genotyping was performed on DNA from buccal swabs. General linear models were used for association testing.The ACE Ins/Del polymorphism was associated with body composition. Ins/Ins individuals had higher phase angle (PhA) and body cellular mass index (BCMI) values. A significant influence of the ACE rs4646994 according to hydration status on body composition was also identified. In particular, Ins/Ins individuals displayed higher PhA and BCMI values only if norm-hydrated, while they showed values similar to Del carriers if dehydrated.Our results confirm the relationship between the ACE Ins/Del polymorphism and body composition and suggest a role for hydration status in modulating this relationship. These interesting preliminary results warrant further investigation to disentangle the genetic role of ACE on hydration homeostasis.
View details for DOI 10.1159/000458154
View details for PubMedID 28315876
Obesity-related genetic polymorphisms and adiposity indices in a young Italian population.
Pediatric obesity develops when a complex biological predisposition collides with an obesogenic environment. To further elucidate the role of genetics in obesity onset, we performed a candidate-gene association study in a young and sportive Italian population by testing the association of functional polymorphisms in ACE (rs4646994), FTO (rs9939609), MC4R (rs17782313) and PPARG (rs1801282) genes with body mass index (BMI) and waist-to-height ratio (WHtR). We also tested the combinations of identified risk genotypes and epistatic interactions among them to determine the existence of cumulative effects in predicting the predisposition to gain weight. Our results confirm a significant direct influence of MC4R rs17782313 and PPARG rs1801282 on body composition, that is, minor allele homozygotes showed significantly higher BMI (rs17782313, β = 1.258, P = 0.031; rs1801282, β = 6.689, P = 1.2 × 10(-4) ) and WHtR (rs17782313, β = 0.021, P = 0.005; rs1801282, β = 0.069, P = 0.003) values. Moreover, by leveraging multifactor dimensionality reduction and general linear model (GLM) approaches we identified an epistatic interaction between ACE and MC4R, where heterozygosity at ACE rs4646994 seems to protect from the unfavorable predisposition to gain weight given by C/C genotype at MC4R rs17782313 (GLM, P = 0.004). In conclusion, to clarify the role of genetics in multifactorial diseases remains a difficult goal, even for the most investigated polymorphisms and in controlled populations. Further studies on epistasis and gene-gene interaction will help to elucidate this complex scenario. © 2017 IUBMB Life, 2017.
View details for DOI 10.1002/iub.1596
View details for PubMedID 28090739
Human Genetic Variability Contributes to Post-operative Morphine Consumption.
The journal of pain : official journal of the American Pain Society
High inter-individual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain and single nucleotide polymorphisms (SNPs) within OPRM1, COMT, UGT2B7, and ESR1 gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients undergone abdominal surgery receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex covariates. A haplotype of seven SNPs in OPRM1 showed significant additive effect on opioid consumption (P=0.007); a linear regression model including age and nine SNPs in ESR1, OPRM1 and COMT explained the highest proportion of variance of morphine consumption (10.7%) (P=0.001). The minimal model including three SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P=0.007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P=0.007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variant. Our results contribute to develop genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy. Number of registration on ClinicalTrial.gov: NCT01233752 PERSPECTIVE: This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administrated by patients by a PCA pump, after major surgery. The clinical effect is expressed in terms of both morphine consumption and pain scores.
View details for DOI 10.1016/j.jpain.2016.02.003
View details for PubMedID 26902643
Changes in total plasma and serum N-glycome composition and patient-controlled analgesia after major abdominal surgery.
2016; 6: 31234
Systemic inflammation participates to the complex healing process occurring after major surgery, thus directly affecting the surgical outcome and patient recovery. Total plasma N-glycome might be an indicator of inflammation after major surgery, as well as an anti-inflammatory therapy response marker, since protein glycosylation plays an essential role in the inflammatory cascade. Therefore, we assessed the effects of surgery on the total plasma N-glycome and the association with self-administration of postoperative morphine in two cohorts of patients that underwent major abdominal surgery. We found that plasma N-glycome undergoes significant changes one day after surgery and intensifies one day later, thus indicating a systemic physiological response. In particular, we observed the increase of bisialylated biantennary glycan, A2G2S[3,6]2, 12 hours after surgery, which progressively increased until 48 postoperative hours. Most changes occurred 24 hours after surgery with the decrease of most core-fucosylated biantennary structures, as well as the increase in sialylated tetraantennary and FA3G3S[3,3,3]3 structures. Moreover, we observed a progressive increase of sialylated triantennary and tetraantennary structures two days after surgery, with a concomitant decrease of the structures containing bisecting N-acetylglucosamine along with bi- and trisialylated triantennary glycans. We did not find any statistically significant association between morphine consumption and plasma N-glycome.
View details for DOI 10.1038/srep31234
View details for PubMedID 27501865
Fine-tuning of Th17 Cytokines in Periodontal Disease by IL-10
JOURNAL OF DENTAL RESEARCH
2015; 94 (9): 1267-1275
Periodontitis (PD) is a chronic disease caused by the host inflammatory response to bacteria colonizing the oral cavity. In addition to tolerance to oral microbiome, a fine-tuned balance of IL-10 levels is critical to efficiently mount antimicrobial resistance without causing immunopathology. Clinical and animal studies support that adaptive T-helper (Th) cytokines are involved in the pathogenesis of alveolar bone destruction in PD. However, it remains unclear what type of Th response is related to human PD progression and what role IL-10 has on this process. We addressed the contribution of IL-10 in limiting Th1 and Th17 inflammatory response in murine and human PD. Through a combination of basic and translational approaches involving selected cytokine-deficient mice as well as human genetic epidemiology, our results demonstrate the requirement for IL-10 in fine-tuning the levels of Th17 (IL-17A and IL-17F) cytokines in experimental and human PD. Of novelty, we found that IL-17F correlated with protection in murine and human PD and was positively regulated by IL-10. To our knowledge, this is the first demonstration of the protective role for IL-17F in PD, its positive regulation by IL-10, and the potential differential role for IL-17A and IL-17F in periodontal disease.
View details for DOI 10.1177/0022034515591790
View details for Web of Science ID 000360188900012
View details for PubMedID 26092379
A draft genome sequence of an invasive mosquito: an Italian Aedes albopictus.
Pathogens and global health
2015; 109 (5): 207-220
The draft genome sequence of Italian specimens of the Asian tiger mosquito Aedes (Stegomyia) albopictus (Diptera: Culicidae) was determined using a standard NGS (next generation sequencing) approach. The size of the assembled genome is comparable to that of Aedes aegypti; the two mosquitoes are also similar as far as the high content of repetitive DNA is concerned, most of which is made up of transposable elements. Although, based on BUSCO (Benchmarking Universal Single-Copy Orthologues) analysis, the genome assembly reported here contains more than 99% of protein-coding genes, several of those are expected to be represented in the assembly in a fragmented state. We also present here the annotation of several families of genes (tRNA genes, miRNA genes, the sialome, genes involved in chromatin condensation, sex determination genes, odorant binding proteins and odorant receptors). These analyses confirm that the assembly can be used for the study of the biology of this invasive vector of disease.
View details for DOI 10.1179/2047773215Y.0000000031
View details for PubMedID 26369436
The functional polymorphism rs73598374:G>A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length.
European journal of human genetics
2015; 23 (2): 267-270
Recent evidence demonstrated a relevant role of adenosine deaminase (ADA) in replicative senescence of T cells through its capacity to modulate telomerase activity (TA). Herein, we tested the impact of the functional polymorphism ADA rs73598374:G>A (c.22G>A, p.Asp8Asn) on telomere biology, by measuring TA and leukocyte telomere length (LTL) in healthy subjects selected according to rs73598374 genotype. rs73598374-A carriers showed lower TA (P=0.019) and shorter LTL (P=0.003), respectively, compared to G/G carriers. rs73598374-A carriers showed a stronger cross-sectional age reduction of LTL (r=-0.314, P=0.005) compared to G/G carriers (r=-0.243, P=0.022). The reduced ADA activity associated to rs73598374-A variant predisposes those carriers to display higher levels of adenosine compared to G/G carriers. Consequently, it may lead to an accelerated process of replicative senescence, causing a stronger reduction of TA and in turn shorter LTL. In conclusion, the crucial role played by replicative senescence of the immune system in several human diseases and in the aging process underscores the relevance of the present findings and also spurs interest into the possible involvement of rs73598374 in shaping the susceptibility to several age-related diseases.
View details for DOI 10.1038/ejhg.2014.102
View details for PubMedID 24896148
A genetic-demographic approach reveals a gender-specific association of SLC6A3/DAT1 40 bp-VNTR with life-expectancy.
Several recent lines of evidence are proving an important role for dopamine in the aging process and in the determination of life span. Components of the dopaminergic system may represent good candidates for longevity studies. Herein, we tested the possible association of the functional SLC6A3/DAT1 40-bp VNTR with life-expectancy in a healthy population of Central Italy (N = 993) by applying a genetic-demographic approach that takes into account the demographic information and different survival rates between sexes for modeling the survival of specific allele carriers in the population. Male carriers of S*/S* genotype showed a lower survival chance across most of the lifespan respect to the survival of DAT1*L-carriers (P = 0.021). The same analyses gave non-significant results in females. Several studies already reported significant sex differences in dopamine metabolism and its related biological pathways. Thus, we can hypothesize that the SLC6A3/DAT1 40 bp-VNTR may affect life expectancy in a sex-specific way. Moreover, it is conceivable that DAT1 S*/S* carriers, who are prone to assume "risk" type behaviors, may be dropped out of the "healthy" population by a sort of "demographic selection".
View details for DOI 10.1007/s10522-015-9552-5
View details for PubMedID 25617181
Salmonella enterica Serovar Typhimurium Exploits Inflammation to Modify Swine Intestinal Microbiota.
Frontiers in cellular and infection microbiology
2015; 5: 106
Salmonella enterica serovar Typhimurium is an important zoonotic gastrointestinal pathogen responsible for foodborne disease worldwide. It is a successful enteric pathogen because it has developed virulence strategies allowing it to survive in a highly inflamed intestinal environment exploiting inflammation to overcome colonization resistance provided by intestinal microbiota. In this study, we used piglets featuring an intact microbiota, which naturally develop gastroenteritis, as model for salmonellosis. We compared the effects on the intestinal microbiota induced by a wild type and an attenuated S. Typhimurium in order to evaluate whether the modifications are correlated with the virulence of the strain. This study showed that Salmonella alters microbiota in a virulence-dependent manner. We found that the wild type S. Typhimurium induced inflammation and a reduction of specific protecting microbiota species (SCFA-producing bacteria) normally involved in providing a barrier against pathogens. Both these effects could contribute to impair colonization resistance, increasing the host susceptibility to wild type S. Typhimurium colonization. In contrast, the attenuated S. Typhimurium, which is characterized by a reduced ability to colonize the intestine, and by a very mild inflammatory response, was unable to successfully sustain competition with the microbiota.
View details for DOI 10.3389/fcimb.2015.00106
View details for PubMedID 26835435
- Reply to Larcombe and Orr: Still seeing the big picture. Brain, behavior, and immunity 2015
- Beyond the lack of association between IFNG +874T>A polymorphism and personality traits in healthy Japanese subjects: Possible ethnic-specific effects. Brain, behavior, and immunity 2015
The GLO1 C332 (Ala111) allele confers autism vulnerability: Family-based genetic association and functional correlates
JOURNAL OF PSYCHIATRIC RESEARCH
2014; 59: 108-116
Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
View details for DOI 10.1016/j.jpsychires.2014.07.021
View details for Web of Science ID 000344205700015
View details for PubMedID 25201284
The functional VNTR of IGH enhancer HS1.2 associates with human longevity and interacts with TNFA promoter diplotype in a population of Central Italy
2014; 551 (2): 201-205
The dysregulation of both immune and inflammatory responses occurring with aging is believed to substantially contribute to morbidity and mortality in humans. We have already reported the association of the functional Variable Number of Tandem Repeat (VNTR) at the Immunoglobulin heavy chain (IGH) enhancer HS1.2 with Immunoglobulin levels and with several autoimmune diseases. Herein we tested the association of the VNTR at the HS1.2 enhancer with human longevity, also evaluating the possible modulatory effect of TNFA promoter diplotype (rs361525/rs1800629). HS1.2 enhancer genotypes have been determined for 193 unrelated healthy individuals from Central Italy divided into two groups: Group 1 (18-84 yrs, mean age 56.8 ± 19.4) and Group 2 (85-100 yrs, mean age 93.0 ± 3.5). Homozygous subjects for 2 allele were significantly disadvantaged in reaching higher life-expectancy (OR=0.457, p=0.021). A significant interaction between TNFA promoter diplotype status, HS1.2 2/2 genotype and the two Groups was found (p=0.014). Of note, TNFA -308A allele seems to exert a protective effect in HS1.2 2/2 carriers. These results support the hypothesis of an important role of HS1.2 VNTR in the puzzle of the immune-system regulation, evidenced also by the potential interaction with TNFA. Moreover, the previous results showing the association of HS1.2 2 allele with inflammatory phenomena are consistent with the hypothesis that this allele is a detrimental factor in reaching advanced age.
View details for DOI 10.1016/j.gene.2014.08.057
View details for Web of Science ID 000343624800011
View details for PubMedID 25175451
- The relevance of checking population allele frequencies and Hardy-Weinberg Equilibrium in genetic association studies: the case of SLC6A4 5-HTTLPR polymorphism in a Chinese Han Irritable Bowel Syndrome association study. Immunology letters 2014; 162 (1): 276-278
DPP6 gene disruption in a family with Gilles de la Tourette syndrome
2014; 15 (4): 237-242
Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the DPP6 gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The DPP6 gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo DPP6 exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the DPP6 gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.
View details for DOI 10.1007/s10048-014-0418-9
View details for Web of Science ID 000343221800003
View details for PubMedID 25129042
Brief Report: Functional MRI of a Patient with 7q11.23 Duplication Syndrome and Autism Spectrum Disorder
JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS
2014; 44 (10): 2608-2613
The duplication of the Williams-Beuren syndrome (WBS) region (7q11.23) is a copy number variant associated with autism spectrum disorder (ASD). One of the most intriguing aspects is that the reciprocal microdeletion causes WBS, characterized by hypersociability, marked empathy, and a relative capacity in verbal short-term memory and language. Herein, we studied, by using functional morphological and volumetric magnetic resonance, a 17-year-old male patient who displays a de novo 7q11.23 duplication and ASD. The limbic system of the patient appeared hypo-functional, while the total brain volume was increased, thus contrasting, in an opposite and intriguing manner, with the global brain volume reduction reported in WBS. Even if these findings come from the analysis of a single patient and, therefore, have to be considered preliminary results, they encourage carrying on further functional and volumetric studies in patients with 7q11.23 duplication, to fully elucidate the role of this gene-dosage alteration on brain development and limbic system function.
View details for DOI 10.1007/s10803-014-2117-7
View details for Web of Science ID 000342211800022
View details for PubMedID 24722762
Interaction between infectious diseases and personality traits: ACP1*C as a potential mediator
INFECTION GENETICS AND EVOLUTION
2014; 26: 267-273
In geographical regions characterized by high pathogen prevalence, it has been shown that human populations tend to be characterized by lower levels of extraversion (E) and openness to experience (OtE). According to the "behavioral immune system" hypothesis, the reduction of extraversion and openness levels represents a behavioral defense against infections. Like the 'classical' immune system, the "behavioral immune system" could also be shaped by its underlying genetic background. Previous studies have shown that the *C allele of the ACP1 gene confers increased susceptibility to infectious/parasitic diseases. We hypothesized that carriers of the ACP1*C allele should likewise be associated with reduced E and OtE. We tested this hypothesis using two samples comprised of 153 students from Southern California (Group 1), and 162 female subjects recruited from an executive health program (Group 2), genotyped for ACP1 polymorphism and evaluated by the NEO Five-Factor Inventory (NEO-FFI). ACP1 was significantly associated with E: we found that carriers of ACP1*C showed reduced scores for E (Group 1: β=-4.263, P=0.027; Group 2: β=-8.315, P=0.003; Group 1+Group 2: β=-5.366, P=0.001). Across groups, ACP1 was only marginally associated with OtE. In conclusion, the present study found that the ACP1*C allele, previously associated with an increased vulnerability to infectious/parasitic diseases may also be able to shape behavioral immune defenses by interaction with the level of E.
View details for DOI 10.1016/j.meegid.2014.06.002
View details for Web of Science ID 000339954500034
View details for PubMedID 24933463
Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder
BRAIN BEHAVIOR AND IMMUNITY
2014; 38: 91-99
Circulating 45 and 62kDa antibodies targeting the cerebellum were previously associated with Autism Spectrum Disorder (ASD), lower adaptive/cognitive function and aberrant behaviors. Moreover, 37, 39 and 73kDa maternal antibodies (mAb) targeting the fetal brain were previously correlated with broad autism spectrum, irritability, abnormal brain enlargement and impaired expressive language. The present study aims towards clinically characterizing individuals with brain-targeted IgG and/or exposed to maternal antibrain antibodies in a large sample of Italian autistic children (N=355), their unaffected siblings (N=142) and mothers (N=333). The presence of patient- and mother-produced anti-brain antibodies does not confer increased risk of autism within the same sibship. However, the 45 and 62kDa antibodies are correlated with autism severity: the 45kDa Ab is associated with cognitive impairment and lower scores at the Vineland Adaptive Behavior Scales, the 62kDa Ab with motor stereotypies, while both correlate with larger head circumference (all P<0.05). On the other hand, maternal 37, 39 and 73kDa antibrain antibodies, either alone or in combination, are correlated with impaired verbal and non-verbal language development, neurodevelopmental delay and sleep/wake cycle disturbances in their autistic children (P<0.05). Presence of the 62kDa autoAb in the child is significantly associated with presence of the 39 and/or 73kDa antibodies in his/her mother. Our results confirm and extend previous observations in an ethnically distinct sample, providing further evidence of a pathomorphic role for anti-brain antibodies in autism while demonstrating their familial clustering.
View details for DOI 10.1016/j.bbi.2013.12.020
View details for Web of Science ID 000334984100010
View details for PubMedID 24389156
The cross-talk between opportunistic fungi and the mammalian host via microbiota's metabolism.
Seminars in immunopathology
An increased understanding of the importance of microbiota in shaping the host's immune and metabolic activities has rendered fungal interactions with their hosts more complex than previously appreciated. It is now clear that a three-way interaction between host, fungi, and microbiota dictates the types of host-fungus relationship. Indeed, microbial dysbiosis predisposes to a variety of chronic fungal infections and diseases at local and distant sites. By correlating changes in metabolite profiles with microbiota metagenomic composition, we have defined a functional node whereby certain bacteria species contribute to host-fungal symbiosis and mucosal homeostasis. A tryptophan catabolic pathway is exploited by commensal lactobacilli and the mammalian host to increase fitness in response to Candida albicans by inducing resistance and tolerance mechanisms of antifungal immunity. Much like lactobacilli in the gut, Firmicutes change significantly in the airways during aspergillosis. The aryl hydrocarbon receptor has a pivotal role in connecting tryptophan catabolism by microbial communities and the host's own pathway of tryptophan degradation through the enzyme indoleamine 2,3-dioxygenase 1. These data suggest that the study of the human microbiota in the trans-omics era, with a focus on metagenomics and metabonomics, is providing novel insights into the regulation of host immune responsiveness to fungi.
View details for DOI 10.1007/s00281-014-0464-2
View details for PubMedID 25404119
- The ARES Project: Cloud Services for Medical Genomics IEEE 3rd Symposium on Network Cloud Computing and Applications (NCCA) IEEE. 2014: 15–22
BEHAVIOURAL BRAIN RESEARCH
2013; 251: 95-112
Autism spectrum disorder (ASD) is a severe neuropsychiatric disease with strong genetic underpinnings. However, genetic contributions to autism are extremely heterogeneous, with many different loci underlying the disease to a different extent in different individuals. Moreover, the phenotypic expression (i.e., "penetrance") of these genetic components is also highly variable, ranging from fully penetrant point mutations to polygenic forms with multiple gene-gene and gene-environment interactions. Furthermore, many genes involved in ASD are also involved in intellectual disability, further underscoring their lack of specificity in phenotypic expression. We shall hereby review current knowledge on the genetic basis of ASD, spanning genetic/genomic syndromes associated with autism, monogenic forms due to copy number variants (CNVs) or rare point mutations, mitochondrial forms, and polygenic autisms. Finally, the recent contributions of genome-wide association and whole exome sequencing studies will be highlighted.
View details for DOI 10.1016/j.bbr.2013.06.012
View details for Web of Science ID 000322927700011
View details for PubMedID 23769996
The functional VNTR MNS16A of the TERT gene is associated with human longevity in a population of Central Italy
2013; 48 (6): 587-592
Telomerase, encoded by TERT, is the ribonucleoprotein polymerase that maintains telomere ends and it plays a crucial role in cellular senescence. TERT single nucleotide polymorphisms (SNPs) have been associated both with various malignancies and telomere length (TL). The association of TERT SNPs with longevity remains uncertain and varies with ethnicity. The aim of this study was to investigate whether the functional variable number of tandem repeat (VNTR) MNS16A of TERT is associated with longevity.MNS16A genotypes have been determined for 1072 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals <66 years old (<73 years old), the second class of individuals 66-88 years old (73-91 years old), and the third class of individuals >88 years old (>91 years old). TL was assessed using genomic DNA from whole blood of 72 selected individuals by a multiplex real-time PCR assay.MNS16A appears associated to longevity, showing significant associations in Comparison 2 (Age Class 3 vs. Age Class 2) under both additive (odds ratio [O.R.] 0.749; p=0.019) and dominant (O.R. 0.579; p=0.011) models. The MNS16A*L allele is significantly underrepresented in Age Class 3 (O.R. 0.759; p=0.020) compared to Age Class 2. A significant telomere attrition is reported along the three age classes (p=0.0001), that remains significant only in L*/L* genotype carriers (p=0.002) when the analysis was conducted according to MNS16A genotype.The TERT MNS16A*L allele appears negatively associated with longevity. The concomitant significant telomere cross sectional attrition rate observed for L*/L* genotype suggests that this polymorphism could influence human longevity by affecting TL.
View details for DOI 10.1016/j.exger.2013.03.009
View details for Web of Science ID 000318616800008
View details for PubMedID 23562826
CDA gene polymorphisms and enzyme activity: genotype-phenotype relationship in an Italian-Caucasian population
2013; 14 (7): 769-781
To assess the distribution of CDA activity from whole blood of 142 healthy subjects, determining its main predictors among genetic (six CDA SNPs) and physiological factors (age and gender). Moreover, we performed a kinetic study of the two CDA protein variants (Q27 and K27) determined by the rs2072671 SNP.CDA activity was assessed by HPLC. Selected CDA SNPs were genotyped by PCR-based methods. Recombinant CDA protein variants (Q27 and K27) were expressed in an Escherichia coli strain SØ5201 and kinetic assays were performed.The mean value of CDA activity was 0.051 ± 0.024 mU/mg and followed a normal distribution in the study population. Carriers of the CDA*2B (-451T/-92G/-31Del/79C/435C) haplotype displayed higher CDA activity compared with the others. CDA -451G>A, -92A>G and 79A>C (K27Q) SNPs displayed significant associations with CDA activity. The best predictive model of CDA activity included the variables gender and CDA 79A>C (K27Q). Cytidine is the preferential substrate for the variant Q27.We suggest the analysis of both CDA activity and CDA 79A>C (K27Q) SNP in future prospective trials with cytidine analogs, alone or in combination, in order to identify the best marker to secure the administration of these anticancer therapies.
View details for DOI 10.2217/PGS.13.56
View details for Web of Science ID 000318846100017
View details for PubMedID 23651026
TP53*P72 Allele Influences Negatively Female Life Expectancy in a Population of Central Italy: Cross-Sectional Study and Genetic-Demographic Approach Analysis
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
2013; 68 (5): 539-545
The association of TP53 P72R (rs1042522) with longevity remains uncertain and varies with ethnicity. Here, we tested its association with longevity in a cross-sectional population of Central Italy (18-106 years, N = 1,072), by integrating demographic information and frequency data to account for the different survival rates between sexes through the application of a genetic-demographic approach. rs1042522 affects females longevity, showing significant associations in Comparison 2 (Age Class 3 [>91 years] vs Age Class 2 [73-91 years]) under both additive (odds ratio [OR] 0.574; p = .006) and dominant (OR 0.513; p = .006) models. The TP53*P72 allele is significantly underrepresented in Age Class 3 only in women (OR 0.575; p = .008). The genetic-demographic approach demonstrated that the frequency of female TP53*P72 carriers underwent a significant reduction after 82 years (OR 0.586; p = .002). The same analyses gave nonsignificant results in men. The discrepancies among the results obtained on rs1042522 for longevity could result from the pleiotropic effects of p53 and the potential ethnic variation of its functional variants.
View details for DOI 10.1093/gerona/gls223
View details for Web of Science ID 000317538900005
View details for PubMedID 23125046
Urinary p-cresol in autism spectrum disorder
NEUROTOXICOLOGY AND TERATOLOGY
2013; 36: 82-90
Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children.
View details for DOI 10.1016/j.ntt.2012.09.002
View details for Web of Science ID 000317889000008
View details for PubMedID 22975621
Spermidine and Spermine Are Enriched in Whole Blood of Nona/Centenarians
2012; 15 (6): 590-595
Polyamines (putrescine, spermidine, and spermine) are a family of molecules that derive from ornithine through a decarboxylation process. They are essential for cell growth and proliferation, stabilization of negative charges of DNA, RNA transcription, translation, and apoptosis. Recently, it has been demonstrated that exogenously administered spermidine promotes longevity in yeasts, flies, worms, and human cultured immune cells. Here, using a cross-sectional observational study, we determined whole-blood polyamines levels from 78 sex-matched unrelated individuals divided into three age groups: Group 1 (31-56 years, n=26, mean age 44.6±6.07), group 2 (60-80 years, n=26, mean age 68.7±6.07), and group 3 (90-106 years, n=26, mean age 96.5±4.59). The total content of polyamines is significantly lower in groups 2 and 3 compared to group 1 (p=3.6×10(-12)). Interestingly, this reduction is mainly attributable to the lower putrescine content. Group 2 displays the lowest levels of spermidine and spermine. On the other hand, nona/centenarians (group 3) display a significantly higher median relative percentage content of spermine with respect to total polyamines, compared to the other groups (13.2% vs. 14.1% vs. 30.6%, p=6.0×10(-4)). For the first time, we report profiles of polyamines from the whole blood of healthy nona/centenarians, and our results confirm and extend previous findings on the role of polyamines in determining human longevity. However, although we found an important correlation between polyamines levels and age groups, further studies are warranted to fully understand the role of polyamines in determining life span. Also, longitudinal and nutritional studies might suggest potential therapeutic approaches to sustain healthy aging and to increase human life span.
View details for DOI 10.1089/rej.2012.1349
View details for Web of Science ID 000313675200007
View details for PubMedID 22950434
The Effect of ACP(1)-ADA(1) Genetic Interaction on Human Life Span
2012; 84 (6): 725-733
Acid phosphatase (ACP₁) is a polymorphic enzyme that catalyzes the conversion of flavin-mononucleotide (FMN) to riboflavin and regulates the cellular concentration of flavin-adenine-dinucleotide (FAD) and, consequently, energy metabolism. Its activity is modulated by adenosine deaminase locus 1 (ADA₁) genotype. The aim of our work is to verify whether individuals with a high proportion of ACP₁ f-isozyme and carrying the ADA₁*2 allele, displaying the highest phosphatase activity, may have a higher life expectancy. Genomic DNA was extracted from the peripheral blood of 569 females and 509 males (18 to 106 years of age) randomly recruited from Central Italy. These samples were subdivided into three sex-specific age groups (the ages of women are in square bracket): Class 1: age <66 [<73]; Class 2: ages 66 to 88 [73 to 91]; Class 3: age >88 [>91]. ACP₁and ADA₁ singlenucleotide polymorphisms (SNPs) were genotyped by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods and statistical analyses were performed with SPSS 14.0. The results showed a larger proportion of Class 3 individuals displaying high ACP₁ f-isozyme concentration and carrying the ADA₁*2 allele than those individuals of Class 2 and Class 2 plus Class 1. Thus, we postulate that in Class 3 individuals the high phosphatase activity, resulting from the combined presence of high ACP₁ f-isozyme concentration and the ADA₁*2 allele, lowers the rate of glycolysis that may reduce the amount of metabolic calories and, in turn, activate Sirtuin genes that protect cells against age-related diseases.
View details for Web of Science ID 000322906700004
View details for PubMedID 23959645
DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: Association and gene-gene interaction study in a population of Central Italy
2012; 522 (2): 103-107
Dopamine is a neurotransmitter whose functions are mediated by five receptors expressed in several organs and tissues. Dopaminergic system dysfunctions are involved in the etiology or treatment of several pathological conditions, including drug addiction. Alcohol dependence (AD) is a widespread psychiatric disorder, affecting 5.4% of the general population lifetime. Family and twins studies support the role of a genetic component in AD. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to AD. Here, we evaluated both the DRD2/ANKK1 TaqIA (rs1800497) and SLC6A3 40 bp-VNTR SNP and gene-gene interaction analysis in AD patients from a population of Central Italy. The study design was a case-control. In total, 280 alcoholic subjects (213 men and 67 woman) and 280 age- and sex-matched control subjects were recruited for this study. Case subjects met the DSM-IV criteria for AD and they are free from any psychiatric co-morbidities. Controls were subjects who had non-alcohol problem either never drank; those who have smoked at least one pack of cigarettes per day for at least 1 year were excluded. Genotyping was performed by allele-specific PCR and RFLP-PCR. SLC6A3 40 bp 3'UTR-VNTR displays no association with AD. DRD2/ANKK1 TaqIA genotype distribution is significantly associated to AD (O.R.=1.551, p=0.023), with A1* allele displaying an O.R.=1.403 (p=0.029). Gene-gene interaction analysis using three-way contingency table analysis by a log-linear model yielded no significant result. Our study in a population of Central Italy extends and confirms previous results and, for the first time, tested the gene-gene interaction between SLC6A3 and DRD2 in AD.
View details for DOI 10.1016/j.neulet.2012.06.008
View details for Web of Science ID 000307035800005
View details for PubMedID 22698582
Population variability in CD38 activity: Correlation with age and significant effect of TNF-alpha-308G > A and CD38 184C > G SNPs
MOLECULAR GENETICS AND METABOLISM
2012; 105 (3): 502-507
CD38 (EC 184.108.40.206, NAD(+)-glycohydrolase) is a multifunctional enzyme catalyzing the synthesis and hydrolysis of cyclic ADP-ribose from NAD(+) to ADP-ribose. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications. Notably, it has been linked to HIV infection, leukemias, myelomas, solid tumors, Type II Diabetes mellitus, bone metabolism, as well as Autism Spectrum Disorder. Taking into account the crucial role played by CD38 in many diseases and in clinical practice, here we assessed the distribution of CD38 NADase activity in a healthy population (104 sex-matched unrelated individuals, 12-98 years) and determined its main predictors among genetic and physiological factors (age and sex). The mean value of CD38 NADase activity was 0.051±0.023 mU/mg (0.010-0.099 mU/mg), following a normal distribution in the study population (Kolmogorov-Smirnov test P=0.200). The TNF-α -308G>A (rs1800629) resulted the main predictor (β=0.364, P=0.00008), followed by Age (β=0.280, P=0.002) and the CD38 184C>G (rs6449182) (β=0.193, P=0.033). Our study contributes to understanding CD38 enzyme physiological functions, by reporting, for the first time, its activity distribution in healthy individuals and demonstrating a significant positive correlation with age. Moreover, the possible use of TNF-α -308G>A (rs1800629) and the CD38 184C>G (rs6449182) SNPs as predictive genetic markers of CD38 activity, clearly point toward possible pharmacogenomic applications and to a more refined use of CD38 in clinical settings.
View details for DOI 10.1016/j.ymgme.2011.12.016
View details for Web of Science ID 000301906400179
View details for PubMedID 22236458
Single dose bioavailability and pharmacokinetic study of a innovative formulation of alpha-lipoic acid (ALA600) in healthy volunteers
2011; 102 (6): 475-482
α-Lipoic acid is an important micronutrient with several pharmacological as well as antioxidant properties. The present study was aimed to examine the human bioavailability, pharmacokinetics (PK) and tolerability of an innovative oral formulation (ALA600) containing racemic α-lipoic acid 600 mg.After a single 600-mg oral administration in healthy volunteers, blood samples were collected up to 8 hours post dosing, and plasma α-lipoic acid concentrations were determined by Liquid Chromatography-Mass Spectrometry (LC-MS) detection.The PK data revealed a short time to reach plasma peak oncentrations (50.8± 4.2 min) with a C(max) of 6.86±1.29 µg/mL. The C(max) implying that the new pharmaceutical form positively influences absorption and absorption time. The AUC value of 5.65±0.79 µg/mL*h is the more reliable measure of new formulation bioavailability. The half-life and MRT values further show that new formulation is absorbed consistently and rapidly and is eliminated efficiently. These PK data appear to promote further refinement of present formulation. Should the authors compare the obtained data with the recent published data, the new formulation of α-lipoic acid tends to show an improvement of C(max) value (2.5-5.4 times) and AUC (1.8 times).ALA600 formulation is characterized by rapid absorption, high bioavailability, brief half-life and low toxicity. These PK parameters could significantly increase clinical use of lipoic acid with improvement of the therapeutic effects at the cellular level and might also prove to be the most suitable formulation for chronic administration such as peripheral neuropathies.
View details for Web of Science ID 000299453700005
View details for PubMedID 22193379
Rapid Allele-Specific PCR method for CDA 79A > C (K27Q) genotyping: A useful pharmacogenetic tool and world-wide polymorphism distribution
CLINICA CHIMICA ACTA
2011; 412 (23-24): 2237-2240
The CDA 79A>C (K27Q, rs2072671) functional SNP has recently shown a crucial role in the pharmacogenetics of cytidine-based anticancer drugs widely administered to different subsets of patients. Current gold standard in screening for the CDA rs2072671 is the sequence-based genotyping method. Here we developed a novel, rapid Allele-Specific PCR method for CDA rs2072671 genotyping.DNA was extracted from 324 healthy individuals from two different populations (Italian and Han Chinese). CDA rs2072671 genotyping was performed by Allele-Specific PCR. Sequencing was performed to validate the test results. Results obtained from population screening were compared to that already available in HapMap and in the literature.Samples analyzed were successfully genotyped and the results were confirmed by sequencing. Genotype distribution does not differ significantly from that previously reported for each relative ethnic group. Also, the world-wide distribution of the CDA rs2072671 SNP is reported. A striking difference is present among the main ethnicities (p=1.715×10(-77)), with CDA*27Q allele showing the lowest frequency in African group (9.7%) and the highest in Caucasians (35.9%).This Allele-Specific PCR method is a useful tool in pharmacogenetics research and a valid and reliable alternative for CDA rs2072671 screening where sequencing or Real-Time PCR is not available.
View details for DOI 10.1016/j.cca.2011.08.015
View details for Web of Science ID 000296686100037
View details for PubMedID 21884687
Age- and gender-specific epistasis between ADA and TNF-alpha influences human life-expectancy
2011; 56 (2): 481-488
Aging is a complex phenotype with multiple determinants but a strong genetic component significantly impacts on survival to extreme ages. The dysregulation of immune responses occurring with increasing age is believed to contribute to human morbidity and mortality. Conversely, some genetic determinants of successful aging might reside in those polymorphisms for the immune system genes regulating immune responses. Here we examined the main effects of single loci and multi-locus interactions to test the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-α) genes may influence human life-expectancy. ADA (22G>A, rs73598374) and TNF-α (-308G>A, rs1800629; -238G>A, rs361525) functional SNPs have been determined for 1071 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals<66 years old (<73 years old), the second class of individuals 66-88 years old (73-91 years old), and the third class of individuals>88 years old (>91 years old). Single-locus analysis showed that only ADA 22G>A is significantly associated with human life-expectancy in males (comparison 1 (age class 2 vs. age class 1), O.R. 1.943, P=0.036; comparison 2 (age class 3 vs. age class 2), O.R. 0.320, P=0.0056). Age- and gender-specific patterns of epistasis between ADA and TNF-α were found using Generalized Multifactor Dimensionality Reduction (GMDR). In comparison 1, a significant two-loci interaction occurs in females between ADA 22G>A and TNF-α -238G>A (Sign Test P=0.011). In comparison 2, both two-loci and three-loci interaction are significant associated with increased life-expectancy over 88 years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-α genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity.
View details for DOI 10.1016/j.cyto.2011.07.023
View details for Web of Science ID 000296214200050
View details for PubMedID 21865054
APOE haplotypes are associated with human longevity in a Central Italy population: Evidence for epistasis with HP 1/2 polymorphism
CLINICA CHIMICA ACTA
2011; 412 (19-20): 1821-1824
Apolipoprotein E (APOE) functional haplotypes determined by rs429358 and rs7412 SNPs have been extensively studied and found to be one of the most consistent association in human longevity studies. However, the search for longevity-determining genes in human has largely neglected the operation of genetic interactions.APOE haplotypes have been determined for 1072 unrelated healthy individuals from Central Italy, 18-106 years old, divided into three gender-specific age classes defined according to demographic information and accounting for the different survival between sexes. The epistasis between APOE haplotypes and Haptoglobin (HP) 1/2 polymorphism was tested according to three-way contingency table analysis by a log-linear model.APOE genotype and haplotype distributions differ significantly along the age classes (Genotype: p=0.014; Haplotype: p=0.005) with APOE*ε4 genotype status and haplotype displaying negative association (Genotype: O.R.=0.377, p=0.002, Haplotype: O.R.=0.447, p=0.005). A significant interaction between APOE*ε4 genotype status, HP 1/2 genotype and age classes is reported (p=0.006).APOE haplotypes are significantly associated with longevity in our population. Of note, HP*1/*1 genotype seems to protects APOE*ε4 carriers from age-related negative selection. Collectively, these results also suggest and claim for further investigations on APOE/HP interaction in other age-related diseases such as Alzheimer's disease, atherosclerosis and Parkinson's disease.
View details for DOI 10.1016/j.cca.2011.06.012
View details for Web of Science ID 000294396500019
View details for PubMedID 21703254
PTPN22 1858C > T Polymorphism Distribution in Europe and Association with Rheumatoid Arthritis: Case-Control Study and Meta-Analysis
2011; 6 (9)
The PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data.A total of 396 RA cases and 477 controls, all of Italic ancestry, were genotyped for PTPN22 rs2476601 polymorphism. Patients were tested for autoantibodies positivity. The meta-analysis was performed on 23 selected studies.The PTPN22 T1858 allele was significantly more frequent in RA patients compared to controls (5.7% vs. 3.7%, p = 0.045). No clear relationship arose with the autoantibodies tested. The 1858T allele frequency in Italian RA patients was lower than the one described in northern European populations and similar to the frequency found in Spain, Turkey, Greece, Tunisia. A clear-cut North-South gradient arose from the analysis.The PTPN22 T1858 allele is associated with RA in the Italian population. A North-South gradient of the allele frequency seems to exist in Europe, with a lower prevalence of the mutation in the Mediterranean area.
View details for DOI 10.1371/journal.pone.0024292
View details for Web of Science ID 000295173800016
View details for PubMedID 21949702
PTPN22 1858C > T (R620W) functional polymorphism and human longevity
MOLECULAR BIOLOGY REPORTS
2011; 38 (6): 4231-4235
The PTPN22 gene, located on chromosome 1p13, encoding lymphoid protein tyrosine phosphatase (LYP), plays a crucial role in the negative control of T lymphocyte activation. Since the age-related change in T-cell signal transduction may be one of the most important causes of cell-mediated immune response decline with ageing, we performed a population-based association study to test whether the PTPN22 1858C>T (R620W) functional polymorphism affects the ability to survive to old age and to reach even exceptional life expectancy. 892 unrelated healthy individuals (age range 8-106 years, 403 males and 489 females) from central Italy were studied. For both gender, the frequency of PTPN22*T1858 carriers does not differ significantly in nona/centenarians and in octogenarians respect to young group. Allele and genotype frequencies of age groups were compared to those reported in previously published studied carried out on control individuals with Italic ancestry (N = 1393), further confirming results obtained from our sample population. Overall, our study suggests that PTPN22*T1858 allele is not negatively selected at oldest ages and we speculate that its increased ability to protect individuals against development of infectious diseases may counteract its deleterious effect on immune system leading to autoimmunity.
View details for DOI 10.1007/s11033-010-0546-8
View details for Web of Science ID 000291656800075
View details for PubMedID 21113673
Human DNA extraction methods: patents and applications.
Recent patents on DNA & gene sequences
2011; 5 (1): 1-7
Since the pioneer experiments conducted by Friedrich Miescher in 1861, extraordinary advances have been achieved in the field of DNA handling. Today nucleic acids can be extracted from any type of biological material such as tissues, cells and viruses. Moreover, increasing knowledge of human genome is paving the way to an effective employment of pharmacogenomics and genetic-based predictive tests in medicine. In this context, the recovery of DNA from different sources of biological samples (e.g. archived formalin-fixed autopsy tissues, dried blood spots, frozen serum or plasma, long-term stored whole blood) is also an emerging field in genetic epidemiology studies. Thus, given the crucial role played by DNA in bio-medical research and in its related applications, here we review the main relevant issued patents and recently published advances in the field of DNA extraction and purification from human specimens.
View details for PubMedID 21303346
Haptoglobin (HP) polymorphisms and human longevity: A cross-sectional association study in a Central Italy population
CLINICA CHIMICA ACTA
2011; 412 (7-8): 574-577
Haptoglobin (HP), which scavenges free, cell-toxic hemoglobin and has anti-inflammatory and immune-modulatory function in extravascular tissues, may represent an excellent candidate gene to investigate the life-span expectancy.HP 1/2 polymorphism has been determined for 1072 (569 females, 503 males) unrelated healthy individuals from Central Italy, 18-106 years old, divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes. HP*1F/S subtyping was also performed to check the possible existence for a preferential advantage of HP*1F or HP*1S allele.HP*1/*1 genotype results associated to increased probability of young subjects of attaining longevity (Comparison 1: O.R. 1.709, p=0.0114) with a concomitant advantage of HP*1 allele (Comparison 1: O.R. 1.273, p=0.0194). On the other side, carriers of HP*2 allele displayed an overall significant disadvantage in reaching Age Class 2 (O.R. 0.585, p=0.0092). No significant differences were noticed between age groups either considering total HP*1F and HP*1S allele frequencies or according to HP 1/2 genotypes.The crucial role played by HP in aging process is warranted by its many established functions and its related phenotypes so that it may be considered an important gene involved in the determination of human survival.
View details for DOI 10.1016/j.cca.2010.12.006
View details for Web of Science ID 000287840600016
View details for PubMedID 21147083
Genomic DNA extraction from whole blood stored from 15- to 30-years at -20 degrees C by rapid phenol-chloroform protocol: A useful tool for genetic epidemiology studies
MOLECULAR AND CELLULAR PROBES
2011; 25 (1): 44-48
Long-term stored (LTS) whole blood collection can be an important source of DNA without collection costs, but there is a lack of information on methods useful to extract genomic DNA from such type of biological material. Here we report a simple and fast revisited phenol/chloroform extraction method from LTS whole blood. Protocol reliability was assessed by comparison with proteinase K and silica-gel membrane spin column-based DNA extraction methods using LTS -20 °C whole blood from 1980, and by testing it on 82 whole blood samples, collected from 1980 to 1995, with high quality (A(260/280) = 1.79 ± 0.32 O.D., A(260/230) = 1.45 ± 0.52 O.D.) and quantity results. Genotyping efficiency was also checked by performing RFLP-PCR and ASP-PCR of p53 Pro72Arg (rs1042522) SNP and hTERT MNS16A VNTR, respectively, resulting in 100% of samples successfully typed. In addition to the goodness and the efficiency of method proposed here, this protocol achieves working time reduction combining extraction and purification steps, allowing to work at room temperature. Furthermore, phenol is able to inactivate any potential nuclease and potential infective sources from the first step on. Based on these results we also conclude that LTS -20 °C whole blood samples may be considered a reliable and potential resource for future genotyping studies and retrospective analysis in a genetic epidemiological setting.
View details for DOI 10.1016/j.mcp.2010.10.003
View details for Web of Science ID 000287276000007
View details for PubMedID 21029772
- Regarding "Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms" JOURNAL OF VASCULAR SURGERY 2011; 53 (1): 266-267
Insights into the Role of Fc Gamma Receptors (Fc gamma Rs) Genetic Variations in Monoclonal Antibody-Based Anti-Cancer Therapy
RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY
2010; 5 (3): 197-204
Recently, the field of oncology has witnessed the introduction of several effective chemotherapeutic agents. Still, not all cancers respond to the use of conventional chemotherapy and thus combination therapy is an emerging weapon in the battle against cancer. There is emerging evidence in support of the use of Monoclonal antibodies (MoAbs) in cancer therapy. The mechanisms behind their efficacy are multi-faceted; they can kill tumor cells through antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis as well as target ligands or growth factor receptors favoring tumor growth. The interaction of the Fc domains of antibodies with the Fcgamma (gamma) receptors is an essential checkpoint in ADCC. This interaction is strongly regulated and is largely dependent upon receptor conformation and number. It is accepted that germ-line single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) have the potential to predict the outcome of therapy. The possibility of predicting patients response to monoclonal antibody therapy is of particular importance, as response rates are moderate, with the risk of serious side effects all at a high financial cost. This patent review provides an insight into the role of Fcgamma receptors (FcgammaRs) genetic variation in Monoclonal Antibody-based anti-cancer therapy.
View details for Web of Science ID 000286927600003
View details for PubMedID 20594185
- ADA (22G>A) polymorphism: a possible genetic marker for predictive medicine of human reproduction? Metabolism: clinical and experimental 2010; 59 (10): e9-e10
Age- and gender-specific association between ADA (22G > A) and TNF-alpha (-308G > A) genetic polymorphisms
2010; 76 (4): 311-314
During the last years, several investigations have been performed to examine the influence of the tumor necrosis factor alpha (TNF-α) -308G>A single nucleotide polymorphism (SNP) in the susceptibility or severity of diseases and in many inflammatory conditions. However, the results of these studies have been conflicting, suggesting that, under normal/physiologic conditions, important disturbances in expression of major physiologic components can be compensated by mediators of the same system. In the present study, we evaluated the genetic relationship between the functional adenosine deaminase (ADA) (22G>A, rs73598374) and TNF-α (-308G>A, rs1800629) SNPs in a healthy population from central Italy. An association between ADA*2 and TNF-α*A was observed in males aged ≥ 50 [odds ratio (OR) = 5.16, P = 0.001]; a three-way contingency table analysis by a log-linear model shows a significant interaction between TNF-α genotype, ADA genotype, and age group (P = 0.012) for this gender. Overall, we may speculate that, in males, higher adenosine levels (conferred by ADA*2) may counteract the higher levels of TNF-α (conferred by TNF-α*A) in protective model of inheritance.
View details for DOI 10.1111/j.1399-0039.2010.01510.x
View details for Web of Science ID 000281553000007
View details for PubMedID 20522203
PCR-based methods for CDA K27Q and A70T genotyping: genotypes and alleles distribution in a central Italy population
MOLECULAR BIOLOGY REPORTS
2010; 37 (7): 3363-3368
Cytidine deaminase (CDA) is a pyrimidine salvage pathway enzyme that catalyzes the hydrolytic deamination of cytidine and deoxycytidine to their corresponding uracil nucleosides. CDA also catalyzes the inactivation of some chemotherapeutic nucleoside analogues such as cytosine arabinoside and gemcitabine. CDA 79A > C (K27Q, rs2072671) and 208G > A (A70T, rs60369023) were found to be associated either with clinical outcomes as well as with pharmacokinetics and toxicity of drugs administered to different subsets of patients. In this paper we reported two PCR-based methods for CDA 79A > C (K27Q) and 208G > A (A70T) genotyping and tested their feasibility using DNA extracted from whole blood as well as from buccal swabs. The aim of this study was also to assess the distribution of genotypic variants in a central Italy population. The allele frequencies were 56.3% (K*) and 43.7% (Q*) for K27Q and 100% (A*) and 0% (T*) for A70T. The genotype frequencies were 32.8% (K*/K*), 46.9% (K*/Q*) and 20.3% (Q*/Q*) for K27Q. The genotype frequencies did not deviate from Hardy-Weinberg equilibrium. The results were compared with those of other reported populations. They showed marked ethnic group differences.
View details for DOI 10.1007/s11033-009-9923-6
View details for Web of Science ID 000281985400041
View details for PubMedID 19941076
Gender-specific association of ADA genetic polymorphism with human longevity
2010; 11 (4): 457-462
Aim of this study was to investigate whether the polymorphic ADA (Adenosine Deaminase, EC 220.127.116.11) gene, which determines the cellular level of adenosine and plays a crucial role in the regulation of the immune system and in the control of metabolic rates, is involved in longevity. 884 unrelated healthy individuals (age range 10-106 years, 400 males and 484 females) from central Italy were studied. ADA genotyping was performed by RFLP-PCR. Frequency distributions were compared using the chi-square test and a three-way contingency table analysis by a log linear model was applied to test independence between the variables. We found that ADA influences human life-span in a sex and age specific way. An increased frequency of ADA*2 carriers was found in males aged 80-85, and a decreased frequency in males over 85 (chi(2) = 13.93; df = 3; P = 0.003); significant differences among the age groups was not found in females. A strong interaction among age groups, ADA genotype and sex (G = 15.086; df = 3; P = 0.0017) was found. Males aged 80-85 could be protected from ischemic stroke by higher levels of adenosine (determined by the ADA*2 allele). The decrease of ADA*2 carriers in males over 85 may depend essentially on immunological factors; reduced levels of adenosine protect from asthma and other pulmonary diseases and lead to a reduced activation of inflammatory cells and pro-inflammatory cytokines production. Moreover, the low level of adenosine may potentiate the activity of NK and other cellular effectors against tumor cells. The negligible effect of ADA genetic polymorphism in females suggest a marginal influence of genetic factors in determining longevity in this sex, confirming previous reports.
View details for DOI 10.1007/s10522-010-9266-7
View details for Web of Science ID 000279654800006
View details for PubMedID 20174870
Autism Spectrum Disorders in Tuberous Sclerosis: Pathogenetic Pathways and Implications for Treatment
JOURNAL OF CHILD NEUROLOGY
2010; 25 (7): 873-880
Autism spectrum disorders have been reported as being much more frequent in individuals with tuberous sclerosis than in the general population. Previous studies have implicated early seizure onset and the localization of cortical tubers in the temporal lobes as risk factors for autism. However, the underlying reasons for this association remain largely unclear. The dysregulation of intracellular signaling through the activation of mTOR pathway could play a direct role in determining susceptibility to autism. Early control of seizures and an early intensive behavioral intervention of autism during the period of brain plasticity can mitigate, but not reverse the final outcome. A greater understanding of the pathogenetic mechanisms underlying autism in tuberous sclerosis could help in devising targeted and potentially more effective treatment strategies.
View details for DOI 10.1177/0883073810361789
View details for Web of Science ID 000279409100011
View details for PubMedID 20207609
Recent advances in neurobiology of Tuberous Sclerosis Complex
BRAIN & DEVELOPMENT
2009; 31 (2): 104-113
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with variable phenotypic expression, due to a mutation in one of the two genes, TSC1 and TSC2, and a subsequent hyperactivation of the downstream mTOR pathway, resulting in increased cell growth and proliferation. The central nervous system is consistently involved in TSC, with 90% of individuals affected showing structural abnormalities, and almost all having some degree of CNS clinical manifestations, including seizures, cognitive impairment and behavioural problems. TSC is proving to be a particularly informative model for studying contemporary issues in developmental neurosciences. Recent advances in the neurobiology of TSC from molecular biology, molecular genetics, and animal model studies provide a better understanding of the pathogenesis of TSC-related neurological symptoms. Rapamycin normalizes the dysregulated mTOR pathway, and recent clinical trials have demonstrated its efficacy in various TSC manifestations, suggesting the possibility that rapamycin may have benefit in the treatment of TSC brain disease.
View details for DOI 10.1016/j.braindev.2008.09.013
View details for Web of Science ID 000263455500002
View details for PubMedID 19028034
Unfaithful association of FCGR2B genetic polymorphisms with susceptibility to SLE
2009; 42 (2): 139-142
Correcting errors and proofreading are crucial in a post-genomic era, when DNA sequences are already part of an effective medical screening and treatments. SNPs genotyping of complex human genes can lead to questionable associations if not properly handled. Here, we report about a spurious (reitered) association between FCGR2B genetic polymorphisms and systemic lupus erythematosus.
View details for DOI 10.1080/08916930802438782
View details for Web of Science ID 000262514700007
View details for PubMedID 19005878
Recent patents on epilepsy genetics.
Recent patents on DNA & gene sequences
2009; 3 (3): 183-192
The field of epilepsy genetics is contentious, particularly when it concerns the common epilepsies. More than a dozen loci have been suggested, the result of either linkage analysis and/or association analysis, but few of these findings have been replicated, let alone proven, and those that have are mostly for rare forms of epilepsy. Molecular genetics has revolutionised the understanding of epilepsy genetics and is beginning to have a significant clinical impact. Technological advances have resulted in new high-throughput approaches that promise to further our understanding of the molecular genetics of the epilepsies. The patents discussed in this review highlight the important discoveries that have contributed to our understanding of epilepsy genetics and provide valuable information as to where research in this area will be heading in the future. This knowledge not only informs clinicians about the biology of the epilepsies but also has important consequences for clinical practice and genetic counselling.
View details for PubMedID 19702560
Genetics and Molecular Biology of Tuberous Sclerosis Complex
2008; 9 (7): 475-487
Tuberous Sclerosis Complex is a multisystem disorder exhibiting a wide range of manifestations characterized by tumour-like lesions called hamartomas in the brain, skin, eyes, heart, lungs and kidneys. Tuberous Sclerosis Complex is genetically determined with an autosomal dominant inheritance and is caused by inactivating mutations in either the TSC1 or TSC2 genes. TSC1/2 genes play a fundamental role in the regulation of phosphoinositide 3-kinase (PI3K) signalling pathway, inhibiting the mammalian target of rapamycin (mTOR) through activation of the GTPase activity of Rheb. Mutations in TSC1/2 genes impair the inhibitory function of the hamartin/tuberin complex, leading to phosphorylation of the downstream effectors of mTOR, p70 S6 kinase (S6K), ribosomal protein S6 and the elongation factor binding protein 4E-BP1, resulting in uncontrolled cell growth and tumourigenesis.Despite recent promising genetic, diagnostic, and therapeutic advances in Tuberous Sclerosis Complex, continuing research in all aspects of this complex disease will be pivotal to decrease its associated morbidity and mortality. In this review we will discuss and analyse all the important findings in the molecular pathogenesis of Tuberous Sclerosis Complex, focusing on genetics and the molecular mechanisms that define this multisystemic disorder.
View details for Web of Science ID 000261496400005
View details for PubMedID 19506736
Genetic polymorphisms and idiopathic generalized epilepsies
2007; 37 (3): 157-164
In recent years, progress in understanding the genetic basis of idiopathic generalized epilepsies has proven challenging because of their complex inheritance patterns and genetic heterogeneity. Genetic polymorphisms offer a convenient avenue for a better understanding of the genetic basis of idiopathic generalized epilepsy by providing evidence for the involvement of a given gene in these disorders, and by clarifying its pathogenetic mechanisms. Many of these genes encode for some important central nervous system ion channels (KCNJ10, KCNJ3, KCNQ2/KCNQ3, CLCN2, GABRG2, GABRA1, SCN1B, and SCN1A), while many others encode for ubiquitary enzymes that play crucial roles in various metabolic pathways (HP, ACP1, ME2, LGI4, OPRM1, GRIK1, BRD2, EFHC1, and EFHC2). We review the main genetic polymorphisms reported in idiopathic generalized epilepsy, and discusses their possible functional significance in the pathogenesis of seizures.
View details for DOI 10.1016/j.pediatrneurol.2007.06.001
View details for Web of Science ID 000249545200001
View details for PubMedID 17765802