Alexa Barad Zayat

All Publications

• Differences in nonheme iron absorption between healthy adults of East Asian or Northern European ancestry from the Iron Genes in East Asian and Northern European Adults Study (FeGenes): A cross-sectional stable iron isotope study. The American journal of clinical nutrition Barad, A., Xu, Y., Bender, E., Pressman, E. K., Gu, Z., O'Brien, K. O. 2025; 121 (2): 417-426

  Abstract

  Because humans lack mechanisms for excreting excess iron (Fe), dietary Fe absorption must be tightly regulated to ensure optimal Fe levels. We previously showed that East Asian (EA) individuals have higher Fe stores compared with Northern European (NE) individuals, but the physiological basis for this difference is unknown.Our aim is to compare nonheme Fe absorption and its regulation in healthy participants of genetically confirmed EA or NE ancestry.Participants of this cross-sectional study were males and premenopausal, nonpregnant females of EA (n = 253) or NE (n = 251) ancestry, aged 18-50 y, and without obesity. Participants ingested a stable 57Fe isotope as a FeSO4 solution mixed with syrup. Percent Fe absorption was calculated based on erythrocyte 57Fe enrichment 2 wk postdosing measured using magnetic sector thermal ionization mass spectrometry and normalized to a fixed serum ferritin (SF) level. Fe status traits (SF, soluble transferrin receptor, total body Fe), hormones (hepcidin, erythropoietin, erythroferrone), and inflammatory markers were evaluated.SF-corrected % Fe absorption was higher in EA females [27.4 (95% confidence interval (CI): 23.4, 32.0)] and males [19.8 (95% CI: 14.9, 26.4)] compared with NE females [14.8 (95% CI: 11.8, 18.2)] and males [14.9 (95% CI: 11.8, 18.9)], respectively (both P < 0.001). Percent Fe absorption was consistently associated with hepcidin in EA males [β = -0.64; standard error (SE) = 0.24; P = 0.008] and females (β = -0.61; SE = 0.12; P < 0.001), and in NE males (β = -0.63; SE = 0.22; P = 0.005) and females (β = -0.71; SE = 0.14; P < 0.001). Percent Fe absorption was linearly associated with SF in EA females (β = -0.57; SE = 0.09; P < 0.001) and NE males (β = -0.73; SE = 0.21; P < 0.001) and females (β = -0.68; SE = 0.12; P < 0.001), but in EA males, a U-shaped relationship was observed (P = 0.003).EA individuals have a greater SF-corrected Fe absorption compared with NE individuals. Increased Fe absorption and resulting excess Fe accumulation suggests that EA individuals may be at greater risk of Fe overload-related diseases. Further studies are needed to evaluate the long-term implications of these findings. This trial was registered at clinicaltrials.gov as NCT04198545.

  View details for DOI 10.1016/j.ajcnut.2024.11.015

  View details for PubMedID 39909711

• Iron regulatory hormones and their associations with iron status biomarkers among healthy adults of East Asian or Northern European ancestry: A cross-sectional comparison from the Iron Genes in East Asian and Northern European Adults Study (FeGenes). The American journal of clinical nutrition Barad, A., Xu, Y., Bender, E., Pressman, E. K., Gu, Z., O'Brien, K. O. 2025; 121 (2): 406-416

  Abstract

  Individuals of East Asian (EA) ancestry have greater risk of elevated iron (Fe) stores compared with individuals of Northern European (NE) ancestry, but no studies have assessed differences in Fe regulatory hormones between these populations.This study aimed to evaluate hepcidin, erythropoietin, and erythroferrone as a function of ancestry and examine their associations with Fe status markers in United States adults of genetically confirmed EA or NE ancestry.Participants in this cross-sectional study were healthy EA (n = 251) or NE (n = 253) males and premenopausal, nonpregnant females, aged 18-50 y, and without obesity. Serum hepcidin, erythropoietin, and erythroferrone concentrations were measured using ELISAs. Fe status [serum ferritin (SF), soluble transferrin receptor, total body iron, and transferrin], hematologic (complete blood count), and inflammatory (C-reactive protein and IL-6) markers were measured. Results are shown as the geometric mean (95% CI).Hepcidin (ng/mL) was significantly higher in EA (43.9; 95% CI: 39.6, 48.7) compared with NE (31.3; 95% CI: 28.4, 34.5) males (P < 0.001) but did not differ between EA (21.8; 95% CI: 19.4, 24.6) and NE (21.3; 95% CI: 19.0, 23.8) females (P = 0.66). Interestingly, the hepcidin:SF ratio was lower in EA males (0.26; 95% CI: 0.23, 0.28) and females (0.51; 95% CI: 0.46, 0.57) compared with NE males (0.37; 95% CI: 0.33, 0.40; P < 0.001) and females (0.65; 95% CI: 0.57, 0.73; P = 0.01), respectively. These differences remained significant after adjustment for C-reactive protein (males: P-adjusted < 0.001; females: P-adjusted = 0.008) or IL-6 (males: P-adjusted < 0.001; females: P-adjusted = 0.006). Erythropoietin did not differ between ancestry groups in males (P = 0.11) or females (P = 0.96). Lastly, erythroferrone (ng/mL) was higher in EA (1.3; 95% CI: 0.8, 1.9) compared with NE (0.6; 95% CI: 0.4, 0.9; P = 0.009) males but did not differ between females (EA: 0.7; 95% CI: 0.5, 1.1; NE: 0.5; 95% CI: 0.3, 0.7; P = 0.11).A lower hepcidin:SF ratio in EA compared with NE participants suggests that among EAs, hepcidin concentrations are lower relative to the load of Fe present. Further studies are needed to elucidate the mechanisms underlying the observed differences. This study was registered at clinicaltrials.gov as NCT04198545.

  View details for DOI 10.1016/j.ajcnut.2024.10.018

  View details for PubMedID 39909710

• Characterization of iron status biomarkers and hematological indices among young adults of East Asian or Northern European ancestry: A cross-sectional analysis from the Iron Genes in East Asian and Northern European Adults Study (FeGenes). The American journal of clinical nutrition Barad, A., Xu, Y., Bender, E., Kang, W., Xu, R., Gu, Z., Pressman, E. K., O'Brien, K. O. 2025; 121 (2): 394-405

  Abstract

  Excess body iron (Fe) accrual is linked to chronic diseases. East Asian (EA) adults (median age 50 y) were reported to have higher Fe stores compared to other populations despite lacking the mutation that causes Fe overload in Northern European (NE) adults. It is unknown if these differences are evident in a healthy population under 50 y of age.This cross-sectional study aims to compare Fe-related markers in young adults of EA and NE ancestry and identify determinants of Fe status.Participants were healthy United States males and premenopausal/nonpregnant females of genetically confirmed EA (n = 251) or NE (n = 253) ancestry, aged 18-50 y and without obesity. A complete blood count was obtained. Serum ferritin (SF; μg/L), c-reactive protein, and interleukin-6 were measured by immunoassay, and serum soluble transferrin receptor (mg/L) and transferrin by quantitative immunoturbidimetry. Total body Fe (mg/kg) was calculated. Elevated Fe stores were defined as SF >200 (females) or >300 (males) and c-reactive protein <5 mg/L. Results are shown as the geometric mean 95% confidence interval (CI) or mean ± standard deviation.The mean age of the population was (26.3 y; 25.6, 26.9 y), with 69.2% of participants aged under 30 y. SF was higher in EA (172; 152, 194) compared with NE (85.3; 76.8, 94.8) males (P < 0.001), and in EA (42.6; 36.7, 49.5) compared with NE (31.9; 27.8, 36.5) females (P = 0.004). The prevalence of elevated Fe stores was 16.7% in EA compared with 0.8% in NE males (P < 0.001) and 1.6% in EA compared with 0% in NE females (P = 0.47). Total body Fe was higher in EA (11.7 ± 2.7) compared with NE (9.1 ± 2.6) males (P < 0.001) and in EA (6.7 ± 3.6) compared with NE (5.6 ± 3.4) females (P = 0.01). All differences persisted after adjustment for confounders (all P < 0.05).Individuals of EA ancestry had a significantly greater body Fe burden compared to NE individuals. Of concern, these differences were evident in a cohort primarily consisting of young individuals aged 18-29 y. This trial was registered at clinicaltrials.gov as NCT04198545.

  View details for DOI 10.1016/j.ajcnut.2024.10.014

  View details for PubMedID 39909709

• Associations Between Genetically Predicted Iron Status and Cardiovascular Disease Risk: A Mendelian Randomization Study. Journal of the American Heart Association Barad, A., Clark, A. G., Pressman, E. K., O'Brien, K. O. 2024; 13 (11): e034991

  Abstract

  Mendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors.Iron biomarker instrumental variables (total iron-binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome-wide association study meta-analysis. We performed 2-sample univariate MR of each iron trait on CVD outcomes (all-cause ischemic stroke, cardioembolic ischemic stroke, large-artery ischemic stroke, small-vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron-CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03-1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02-1.44]; total iron-binding capacity: odds ratio, 0.81 [95% CI, 0.69-0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large-artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (all P>0.05).Higher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.

  View details for DOI 10.1161/JAHA.124.034991

  View details for PubMedID 38818967

  View details for PubMedCentralID PMC11255641

• Placental ferroportin protein abundance is associated with neonatal erythropoietic activity and iron status in newborns at high risk for iron deficiency and anemia. The American journal of clinical nutrition Barad, A., Guillet, R., Pressman, E. K., Katzman, P. J., Ganz, T., Nemeth, E., O'Brien, K. O. 2024; 119 (1): 76-86

  Abstract

  Murine data suggest that the placenta downregulates ferroportin (FPN) when iron is limited to prioritize iron for its own needs. Human data on the impact of maternal and neonatal iron status on placental FPN expression are conflicting.This study aimed to identify determinants of placental FPN protein abundance and to assess the utility of the placental iron deficiency index (PIDI) as a measure of maternal/fetal iron status in newborns at high risk for anemia.Placental FPN protein abundance was measured by western blots in placentae collected from 133 neonates born to adolescents (17.4 ± 1.1 y) carrying singletons (delivery gestational age [GA]: 39.9 ± 1.3 wk) and from 130 neonates born to 65 females (30.4 ± 5.2 y) carrying multiples (delivery GA: 35.0 ± 2.8 wk). Placental FPN and the PIDI (FPN:transferrin receptor 1) were evaluated in relation to neonatal and maternal iron-related markers (hemoglobin [Hb], serum ferritin [SF], soluble transferrin receptor [sTfR], total body iron [TBI], hepcidin, erythropoietin [EPO], erythroferrone).FPN protein was detected in all placentae delivered between 25 and 42 wk GA. Placental FPN protein abundance was associated with neonatal iron and erythropoietic markers (EPO: β: 0.10; 95% confidence interval [CI]: 0.06, 0.35; sTfR: β: 0.20; 95% CI: 0.03, 0.18; hepcidin: β: -0.06; 95% CI: -0.13, -0.0003; all P < 0.05). Maternal sTfR was only indirectly associated with placental FPN, with neonatal sTfR as the mediator (β-indirect: 0.06; 95% CI; 0.03, 0.11; P = 0.003). The PIDI was associated with neonatal Hb (β: -0.02; 95% CI: -0.03, -0.003), EPO (β: 0.07; 95% CI: 0.01, 0.14), and sTfR (β: 0.13; 95% CI: 0.004, 0.3) and with maternal SF (β: 0.08, 95% CI: 0.02, 0.14), TBI (β: 0.02; 95% CI: 0.009, 0.04), EPO (β: -0.10; 95% CI: -0.19, -0.01), sTfR (β: -0.16: 95% CI: -0.27, -0.06), and hepcidin (β: 0.05; 95% CI: 0.002, 0.11) at delivery (all P < 0.05).Placental FPN abundance was positively associated with neonatal indicators of increased erythropoietic activity and poor iron status. The PIDI was associated with maternal and neonatal iron-related markers but in opposite directions. More data are needed from a lower-risk normative group of females to assess the generalizability of findings. These trials were registered at clinicaltrials.gov as NCT01019902 and NCT01582802.

  View details for DOI 10.1016/j.ajcnut.2023.10.022

  View details for PubMedID 37890671

  View details for PubMedCentralID PMC10808842

• Placental Erythroferrone and Erythropoietin mRNA Expression is not Associated with Maternal or Neonatal Iron Status in Adolescents Carrying Singletons and Adult Women Carrying Multiples. The Journal of nutrition Delaney, K. M., Barad, A., Castillo, L. F., Hasund, C. M., Guillet, R., Pressman, E. K., Katzman, P. J., Ganz, T., Nemeth, E., O'Brien, K. O. 2023; 153 (7): 1950-1958

  Abstract

  The iron regulatory hormones erythroferrone (ERFE), erythropoietin (EPO), and hepcidin, and the cargo receptor nuclear receptor coactivator 4 (NCOA4) are expressed in the placenta. However, determinants of placental expression of these proteins and their associations with maternal or neonatal iron status are unknown.To characterize expression of placental ERFE, EPO, and NCOA4 mRNA in placentae from newborns at increased risk of iron deficiency and to evaluate these in relation to maternal and neonatal iron status and regulatory hormones.Placentae were collected from 114 neonates born to adolescents carrying singletons (14-18 y) and 110 neonates born to 54 adults (20-46 y) carrying multiples. Placental EPO, ERFE, and NCOA4 mRNA expression were measured by RT-qPCR and compared with maternal and neonatal iron status indicators (SF, sTfR, total body iron, serum iron) and hormones.Placental ERFE, EPO, and NCOA4 mRNA were detected in all placentae delivered between 25 and 42 wk of gestation. Relationships between placental ERFE and EPO differed by cohort. In the multiples cohort, placental EPO and ERFE were positively correlated (P = 0.004), but only a positive trend (P = 0.08) was evident in the adolescents. Placental EPO and ERFE were not associated with maternal or neonatal iron status markers or hormones in either cohort. Placental NCOA4 was not associated with placental EPO or ERFE in either cohort but was negatively associated with maternal SF (P = 0.03) in the multiples cohort and positively associated with neonatal sTfR (P = 0.009) in the adolescents.The human placenta expresses ERFE, EPO, and NCOA4 mRNA as early as 25 wk of gestation. Placental expression of ERFE and EPO transcripts was not associated with maternal or neonatal iron status. Greater placental NCOA4 transcript expression was evident in women and newborns with poor iron status (lower SF and higher sTfR, respectively). Further research is needed to characterize the roles of these proteins in the human placenta.These clinical trials were registered at clinicaltrials.gov as NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902) and NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802).

  View details for DOI 10.1016/j.tjnut.2023.05.023

  View details for PubMedID 37253412

  View details for PubMedCentralID PMC10375499

• Osteoporosis Nutritional Factors Encyclopedia of Human Nutrition Barad, A., O'Brien, K. O. Academic Press. 2023; 4th
• Placental Iron Content Is Lower than Previously Estimated and Is Associated with Maternal Iron Status in Women at Greater Risk of Gestational Iron Deficiency and Anemia. The Journal of nutrition Barad, A., Guillet, R., Pressman, E. K., Katzman, P. J., Miller, R. K., Darrah, T. H., O'Brien, K. O. 2022; 152 (3): 737-746

  Abstract

  Based on limited data, it is estimated that the placenta retains 90 mg of iron. Little is known about determinants of placental iron content. Animal data indicate that the placenta prioritizes iron for its own needs, but this hypothesis has not been evaluated in humans.To characterize placental iron content and placental iron concentration (p[Fe]) in pregnant women at risk of iron insufficiency and identify determinants of p[Fe].Placentas were collected from 132 neonates born to teens carrying singletons (≤18 y) and 101 neonates born to 48 women carrying multiples (20-46 y). Maternal and neonatal iron status indicators [hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), serum iron, total body iron (TBI)] and hormones (erythropoietin, hepcidin) were measured. p[Fe] was measured using inductively coupled plasma-mass spectrometry. Correlation analyses and mixed-effects models were constructed to identify determinants of p[Fe].Mean placental iron content was 23 mg per placenta (95% CI: 15, 33 mg) in the multiples and 40 mg (95% CI: 31, 51 mg) in the teens (P = 0.03). Mean p[Fe] did not differ between the cohorts. p[Fe] was higher in anemic (175 μg/g; 95% CI: 120, 254 μg/g) compared with nonanemic (46 μg/g; 95% CI: 26, 82 μg/g) women carrying multiples (P = 0.009), but did not differ between anemic (62 μg/g; 95% CI: 40, 102 μg/g) and nonanemic (73 μg/g; 95% CI: 56, 97 μg/g) teens. In women carrying multiples, low maternal iron status [lower SF (P = 0.002) and lower TBI (P = 0.01)] was associated with higher p[Fe], whereas in teens, improved iron status [lower sTfR (P = 0.03) and higher TBI (P = 0.03)] was associated with higher p[Fe].Placental iron content was ∼50% lower than previously estimated. p[Fe] is significantly associated with maternal iron status. In women carrying multiples, poor maternal iron status was associated with higher p[Fe], whereas in teens, improved iron status was associated with higher p[Fe]. More data are needed to understand determinants of p[Fe] and the variable iron partitioning in teens compared with mature women.

  View details for DOI 10.1093/jn/nxab416

  View details for PubMedID 34875094

• Ethnic Differences in Iron Status. Advances in nutrition (Bethesda, Md.) Kang, W., Barad, A., Clark, A. G., Wang, Y., Lin, X., Gu, Z., O'Brien, K. O. 2021; 12 (5): 1838-1853

  Abstract

  Iron is unique among all minerals in that humans have no regulatable excretory pathway to eliminate excess iron after it is absorbed. Iron deficiency anemia occurs when absorbed iron is not sufficient to meet body iron demands, whereas iron overload and subsequent deposition of iron in key organs occur when absorbed iron exceeds body iron demands. Over time, iron accumulation in the body can increase risk of chronic diseases, including cirrhosis, diabetes, and heart failure. To date, only ∼30% of the interindividual variability in iron absorption can be captured by iron status biomarkers or iron regulatory hormones. Much of the regulation of iron absorption may be under genetic control, but these pathways have yet to be fully elucidated. Genome-wide and candidate gene association studies have identified several genetic variants that are associated with variations in iron status, but the majority of these data were generated in European populations. The purpose of this review is to summarize genetic variants that have been associated with alterations in iron status and to highlight the influence of ethnicity on the risk of iron deficiency or overload. Using extant data in the literature, linear mixed-effects models were constructed to explore ethnic differences in iron status biomarkers. This approach found that East Asians had significantly higher concentrations of iron status indicators (serum ferritin, transferrin saturation, and hemoglobin) than Europeans, African Americans, or South Asians. African Americans exhibited significantly lower hemoglobin concentrations compared with other ethnic groups. Further studies of the genetic basis for ethnic differences in iron metabolism and on how it affects disease susceptibility among different ethnic groups are needed to inform population-specific recommendations and personalized nutrition interventions for iron-related disorders.

  View details for DOI 10.1093/advances/nmab035

  View details for PubMedID 34009254

  View details for PubMedCentralID PMC8483971

• Associations Between Intuitive Eating Behaviors and Fruit and Vegetable Intake Among College Students. Journal of nutrition education and behavior Barad, A., Cartledge, A., Gemmill, K., Misner, N. M., Santiago, C. E., Yavelow, M., Langkamp-Henken, B. 2019; 51 (6): 758-762

  Abstract

  To assess associations between intuitive eating behaviors and fruit and vegetable intake among college students.Intuitive eating behaviors were measured with the Intuitive Eating Scale-2 (IES-2), which reports a total and 4 subscale scores. Fruit and vegetable intake was measured with the National Institutes of Health Eating at America's Table Fruit and Vegetable screener. Questionnaires were completed online.Median age of participants was 20 years (n = 293; n = 72 male). Total IES-2 score was not correlated with fruit and vegetable intake. Body-Food Choice Congruence and Eating for Physical Rather Than Emotional Reasons subscales were positively associated with fruit and vegetable intake (r = .462, P < .001 and r = .177, P = .002, respectively). The Unconditional Permission to Eat subscale was negatively associated with fruit and vegetable intake (r = -.308, P < .001).Correlations between fruit and vegetable intake and intuitive eating behaviors differed by IES-2 subscale scores. If IES-2 is used in nutrition research, education, or counseling with the aim of increasing fruit and vegetable intake, addressing subscale behaviors individually might be considered.

  View details for DOI 10.1016/j.jneb.2019.03.010

  View details for PubMedID 31003936