rs2200733

This genome-wide admixture analysis of three population-based cohorts (CHS, ARIC, Health ABC; n=17,325) investigated whether 9 known atrial fibrillation (AF) SNPs explain the paradoxically higher AF risk in Whites compared to Blacks. Using Cox proportional hazards models, rs10824026 (in SYNPO2L/MYOZ1) significantly mediated 11.4% (95% CI 2.9-29.9%) and 31.7% (95% CI 16.0-53.0%) of the excess AF risk in Whites in CHS and ARIC respectively. Admixture mapping across 4,938 Black participants identified no loci reaching genome-wide significance (p<7×10⁻⁶), suggesting the racial differential in AF risk is driven by multiple genetic and/or environmental factors rather than single variants.

This case-control association study of 5,792 Chinese Han subjects (2,283 ischemic stroke cases, 3,509 controls) found that rs1122608 in the BRG1/SMARCA4 gene on chromosome 19p13.2 confers protection against ischemic stroke (combined OR 0.73, P adj = 7.86 × 10-5). The protective allele T is associated with increased expression of SFRS3, a splicing factor that may regulate IL-1β expression and reduce atherosclerosis risk.

Case-control association study of 650 Chinese Han AF patients and 1,447 controls identified significant association between rs2106261 in ZFHX3 and atrial fibrillation (OR=1.32, P=0.001 for allelic frequencies; OR=1.77, P=0.00018 for recessive model). Two other SNPs tested (rs7193343 in ZFHX3 and rs13376333 in KCNN3) showed no association, suggesting population-specific genetic architecture at the 16q22 locus.

This case-control association study assessed rs2200733 on chromosome 4q25 in a mainland Chinese Han population, replicating previous findings. The T allele showed highly significant association with atrial fibrillation (AF) with OR=1.81 (P=3.7×10⁻¹¹), particularly in lone AF cases (OR=2.40, P=1.3×10⁻⁹). The study found no significant association between rs2200733 and ischemic stroke in the general population (P=0.43), though early-onset stroke showed marginal significance with the opposite risk allele, suggesting a false positive.

This review examines 15 years of ischemic stroke susceptibility gene research, organized into three periods: early candidate gene studies (1985-1995) testing variants in hemostasis and homocysteine metabolism genes; expansion period with functional variants discovered from other diseases tested on larger stroke cohorts; and current GWAS-driven large-scale genotyping studies. Key findings include identification of susceptibility loci in CELSR1 (rs6007897, rs4044210 in Japanese populations), PITX2 (rs2200733, rs10033464), and other genes involved in lipid metabolism (APOA5, APOCIII, MLXIPL) and signal transduction (PDE4D, ALOX5AP), with evidence that alleles are often shared across diseases and that careful clinical stratification is critical.

This comprehensive review article traces the evolution of pharmacogenetics from single-gene analysis to whole-genome approaches. It discusses validated pharmacogenetic biomarkers with clinical impact including CYP2D6, CYP2C9, CYP2C19, TPMT, DPD, VKORC1, UGT1A1, and ADRB1/ADRB2, providing examples of how genetic variants affect drug metabolism and response. The paper emphasizes the importance of integrating pharmacogenetic information into clinical practice and drug development.