Contact

  • Academic
    rbchoi@stanford.edu
    University - Student Department: School of Medicine Position: Graduate, Medicine

All Publications

  • Dissecting the Genetic Architecture of Intracranial Aneurysms. Circulation. Genomic and precision medicine Adkar, S. S., Lynch, J., Choi, R. B., Roychowdhury, T., Judy, R. L., Paruchuri, K., Go, D. C., Bamezai, S., Cabot, J., Sorondo, S., Levin, M. G., Milewicz, D. M., Willer, C. J., Natarajan, P., Pyarajan, S., Chang, K. M., Damrauer, S., Tsao, P., Skirboll, S., Leeper, N. J., Klarin, D. 2025: e004626

    Abstract

    The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; P=8.8×10-17), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; P=1.2×10-3), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; P=1.0×10-4) ancestries.Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.

    View details for DOI 10.1161/CIRCGEN.123.004626

    View details for PubMedID 40255156

  • Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis. Nature communications Bamezai, S., Zhang, Y., Kumari, M., Lotfi, M., Alsaigh, T., Luo, L., Kumar, G. S., Wang, F., Ye, J., Puri, M., Manchanda, R., Paluri, S., Adkar, S. S., Kojima, Y., Ingelsson, A., Bell, C. F., Lopez, N. G., Fu, C., Choi, R. B., Miller, Z., Barrios, L., Walsh, S., Ahmad, F., Maegdefessel, L., Smith, B. R., Leeper, N. J. 2024; 15 (1): 8034

    Abstract

    Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.

    View details for DOI 10.1038/s41467-024-52005-1

    View details for PubMedID 39271657

    View details for PubMedCentralID 4826466

  • X-linked genetic associations in sporadic thoracic aortic dissection. American journal of medical genetics. Part A Musfee, F. I., Jun, G., Mitchell, L. E., Chen, H., Guo, D., Prakash, S. K., Adkar, S. S., Grove, M. L., Choi, R. B., Klarin, D., Boerwinkle, E., Milewicz, D. M. 2024: e63644

    Abstract

    The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF <0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios. Furthermore, we conducted a meta-analysis of overlapping common variants between the Discovery and Replication cohorts. For analysis of rare variants, we used a sex-stratified optimized sequence kernel association test model. Common variants results showed no statistically significant findings in the Discovery cohort. An intergenic common variant near SPANXN1 was statistically significant in the Replication cohort (p = 1.81 × 10-8). The highest signal from the meta-analysis of the Discovery and Replication cohorts was a ZNF182 intronic common variant (p = 3.5 × 10-6). In rare variants results, RTL9 reached statistical significance (p = 5.15 × 10-5). Although most of our results were statistically insignificant, our analysis is the most comprehensive X-chromosome association analysis of sporadic TAD to date.

    View details for DOI 10.1002/ajmg.a.63644

    View details for PubMedID 38688863