Atrial fibrillation (AF) is the most common arrhythmia in the clinical setting and an independent risk factor for stroke. Approximately 10 million Chinese people are affected by AF, but the genetic basis is largely unknown. A recent genome-wide association study in Iceland identified association between SNP rs2200733 on 4q25 and AF; however, many independent replication studies are essential to unequivocally validate this association. To assess the association between rs2200733 and AF as well as that between rs2200733 and ischemic stroke in a mainland Chinese Han population, we carried out case-control association studies with 383 AF patients versus 851 non-AF controls and 811 ischemic stroke patients versus 688 non-stroke controls. Highly significant association was detected between rs2200733 and AF in a Chinese Han population (allelic P = 3.7 × 10(-11) with OR = 1.81; genotypic P = 4.1 × 10(-12) with a dominant model). When the AF cases were divided into lone AF (32.6%) and other types of AF (67.4%), significantly stronger association was found with lone AF (OR = 2.40, P = 1.3 × 10(-9) compared to OR = 1.59, P = 6.2 × 10(-7) for other types of AF; P = 0.02 for two ORs). No significant association was found between rs2200733 and ischemic stroke. Our results suggest that SNP rs2200733 confers a highly significant risk of AF, but not ischemic stroke, in a more representative Chinese Han population in the mainland China.

Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.

Background The CAV1 gene encodes caveolin-1 expressed in cell types relevant to atherosclerosis. Cav-1-null mice showed a protective effect on atherosclerosis under the ApoE−/− background. However, it is unknown whether CAV1 is linked to CAD and MI in humans. In this study we analyzed a tagSNP for CAV1 in intron 2, rs3807989, for potential association with CAD. Methods and Results We performed case-control association studies in three independent Chinese Han populations from GeneID, including 1,249 CAD cases and 841 controls in Population I, 1,260 cases and 833 controls in Population II and 790 cases and 1,212 controls in Population III (a total of 3,299 cases and 2,886 controls). We identified significant association between rs3807989 and CAD in three independent populations and in the combined population (Padj=2.18×10−5, OR=1.19 for minor allele A). We also detected significant association between rs3807989 and MI (Padj=5.43×10−5, OR=1.23 for allele A). Allele A of SNP rs3807989 was also associated with a decreased level of LDL cholesterol. Although rs3807989 is a tagSNP for both CAV1 and nearby CAV2, allele A of SNP rs3807989 was associated with an increased expression level of CAV1 (both mRNA and protein), but not CAV2. Conclusions The data in this study demonstrated that rs3807989 at the CAV1/CAV2 locus was associated with significant risk of CAD and MI by increasing expression CAV1 (but not CAV2). Thus, CAV1 becomes a strong candidate susceptibility gene for CAD/MI in humans.

OBJECTIVERecent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease.RESEARCH DESIGN AND METHODSThree SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies.RESULTSThe association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002).CONCLUSIONSFor the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.

Background and Purpose— Genome-wide association studies found that the common allele T of single nucleotide polymorphism rs11206510 on chromosome 1p32 was associated with increased low-density lipoprotein-cholesterol levels (LDL-C) and with risk of coronary artery disease (CAD) in white populations. The goals of this study are to determine whether rs11206510 is associated with LDL-C and CAD in a different ethnic population, namely a Chinese cohort, and to investigate whether rs11206510 is associated with ischemic stroke. Methods— The association of rs11206510 with LDL-C was analyzed in 1415 Chinese Han subjects. The CAD study utilized a GeneID cohort with 1543 CAD patients and 1240 controls. For stroke studies, 2 independent cohorts were used and included the GeneID North cohort, with 1205 cases and 1205 controls, and the GeneID Central cohort, with 692 cases and 882 controls. Results— Different from white populations, the minor allele C of rs11206510 was associated with increased LDL-C levels in the Chinese Han population (adjusted P =0.002) and conferred risk of early-onset CAD (380 cases vs 1240 controls; adjusted P =0.002, odds ratio, 1.89), but not with overall CAD (adjusted P =0.82). The allelic association with ischemic stroke was highly significant in 2 independent cohorts, with adjusted P =1.13×10 −5 (odds ratio,1.71) in the GeneID North cohort and adjusted P =9.32×10 −5 (odds ratio, 1.70) in the GeneID Central cohort. Genotypic association was also significant for both early-onset CAD and ischemic stroke. Conclusions— Our results indicate that single nucleotide polymorphism rs11206510 is associated with LDL-C levels and early-onset CAD in the Chinese Han population. For the first time to our knowledge, this study also demonstrates that rs11206510 confers a significant risk of ischemic stroke.

Background Genomic variants identified by genome-wide association studies (GWAS) explain <20% of heritability of coronary artery disease (CAD), thus many risk variants remain missing for CAD. Identification of new variants may unravel new biological pathways and genetic mechanisms for CAD. To identify new variants associated with CAD, we developed a candidate pathway-based GWAS by integrating expression quantitative loci (eQTL) analysis and mining of GWAS data with variants in a candidate pathway. Methods and Results Mining of GWAS data was performed to analyze variants in 32 complement system genes for positive association with CAD. Functional variants in genes showing positive association were then identified by searching existing expression quantitative loci databases and validated by RT-PCR. A follow-up case control design was then used to determine whether the functional variants are associated with CAD in two independent GeneID Chinese populations. Candidate pathway-based GWAS identified positive association between variants in C3AR1 and C6 and CAD. Two functional variants, rs7842 in C3AR1 and rs4400166 in C6, were found to be associated with expression levels of C3AR1 and C6, respectively. Significant association was identified between rs7842 and CAD (P=3.99×10−6, OR=1.47) and between rs4400166 and CAD (P=9.30×10−3, OR=1.24) in the validation cohort. The significant findings were confirmed in the replication cohort (P=1.53×10−5, OR=1.37 for rs7842; P=8.41×10−3, OR=1.21 for rs4400166. Conclusions Integration of GWAS with biological pathways and eQTL is effective in identifying new risk variants for CAD. Functional variants increasing C3AR1 and C6 expression were shown to confer significant risk of CAD for the first time.

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