Yujun Xu

9p21 is a shared susceptibility locus strongly for coronary artery disease and weakly for ischemic stroke in Chinese Han population.

Background—Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms. Methods and Results—We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P=0.002 to 0.0001, q=0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P=1.3×10−10, q=1.2×10−9) and ischemic stroke (P=1.7×10−6, q=7.7×10−6). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P=2.6×10−4, q=6.3×10−4). Conclusions—Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.

9p21 is a Shared Susceptibility Locus Strongly for CAD and Weakly for Ischemic Stroke in Chinese Han Population

Background—Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms. Methods and Results—We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P=0.002 to 0.0001, q=0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P=1.3×10−10, q=1.2×10−9) and ischemic stroke (P=1.7×10−6, q=7.7×10−6). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P=2.6×10−4, q=6.3×10−4). Conclusions—Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.

Telomere Length and Risk of Stroke in Chinese

Background and Purpose— Accumulating evidence suggests that telomere length is a maker for biological aging of the cardiovascular system. Whether stroke is associated with accelerated biological aging as measured by telomere length has not been conclusively demonstrated. Our aim was to determine whether mean leukocyte telomere length is a predictor for the development of stroke. Methods— The relative telomere length of leukocytes was determined by quantitative polymerase chain reaction in 1309 stroke patients and 1309 age- and sex-matched control subjects as well as 858 stroke patients followed prospectively for 5 years. For each measure, the study sample was divided into quartiles. The associations between the telomere length and risk of stroke as well as poststroke adverse outcomes were determined. Results— Mean telomere length was significantly shorter in stroke patients than in control subjects. Shorter telomere length levels were directly associated with a higher risk of stroke in the case/control sample. As compared with the fourth (longest) quartile, the odd ratios [OR] (and 95% confidence intervals [CI]) for ischemic stroke risk were as follows: third quartile, 1.37 (1.04–1.82); second quartile, 1.53 (1.17–2.02); and first quartile, 2.12 (1.62–2.77). Follow-up of the patients from the prospective cohort also showed that shorter telomere length levels were associated with mortality from all causes but not with recurrence of stroke. Conclusions— Shorter telomere length was associated with ischemic stroke and was a strong predictor of poststroke death.

C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population

AbstractAim:The inflammatory marker C-reactive protein (CRP) has been strongly correlated with the risk of cardiovascular disease. Some single-nucleotide polymorphisms (SNPs) have been reported to be associated with serum CRP levels. In this study, we assessed the genetic association between SNPs within the CRP gene and ischemic and hemorrhagic stroke in the Han Chinese population.Methods:This study comprises 564 ischemic stroke patients, 220 hemorrhagic stroke patients and 564 controls from the ethnic Han Chinese population in Wuhan. Four CRP SNPs, −757A>G (rs3093059), −717A>G (rs2794521), −286C>T>A (rs3091244) and +2147C>T (rs1205), were genotyped from patients using TaqMan assays.Results:The A allele frequency for the −717A>G polymorphism was significant higher in controls than in ischemic stroke patients (P=0.037), after adjustment for traditional risk factors (odds ratio 0.28; 95% CI 0.12–0.65; P=0.003), suggesting a protective effect for this allele against ischemic stroke. Haplotype analysis showed that the H3 (G-C-C) haplotype conferred a significantly increased risk of ischemic stroke (odds ratio 1.052, 95% CI 1.001–1.106: P=0.047). Neither CRP genotypes nor haplotypes showed an association with hemorrhagic stroke. However, the frequency for haplotype H5 (A-T-C) was significantly higher in ischemic stroke than hemorrhagic stroke patients (P=0.0003).Conclusion:These data suggest that the CRP gene −717A allele confers a protective effect against ischemic stroke. Furthermore, the H3 haplotype (G-C-C) is an independent risk marker for ischemic stroke, whereas the H5 haplotype (A-T-C) can be used as a prognostic marker of hemorrhagic stroke.

Association of Common Variants of CYP4A11 and CYP4F2 with Stroke in the Han Chinese Population

Objective 20-Hydroxyeicosatetraenoic acid has been shown to play an important role in cerebral vascular function. We hypothesized that polymorphisms in genes encoding 20-Hydroxyeicosatetraenoic acid synthesizing enzymes might confer susceptibility to stroke. Methods and results To test the hypothesis, haplotype tagging single nucleotide polymorphisms and potential functional polymorphisms of CYP4A11 and CYP4F2 genes were genotyped in 558 ischemic stroke patients, 221 hemorrhagic stroke patients and 557 controls. The association analyses were performed at both single nucleotide polymorphism and haplotype levels. We further verified our findings in an independent cohort of 551 ischemic stroke cases and 48 hemorrhagic stroke cases and 694 unaffected controls. We identified CYP4A11 C-296T and CYP4F2 V433M were associated with significantly increased risk of ischemic stroke (CT+TT vs. CC, adjusted odds ratio: 1.50, 95% confidence interval: 1.17–1.93, Pcombined=0.001, Pcorr=0.008; V/M+M/M vs. V/V, odds ratio: 1.38, 95% confidence interval: 1.15–1.65, Pcombined=5.6×10−4, Pcorr=0.005, respectively). Interestingly, the effects of CYP4F2 V433M on ischemic stroke in our study was only evident in male individuals. Conclusion Our results suggest that genetic variation in CYP4A11 and CYP4F2 alters susceptibility to stroke in the Han Chinese population.

Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population

Background Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population. Methodology/Principal Findings We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10−8), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10−4 and 0.001, respectively). Conclusions/Significance We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.

Polymorphism of HMGA1 is associated with increased risk of type 2 diabetes among Chinese individuals

Aims/hypothesisVariants of the high-mobility group A1 (HMGA1) gene have been shown to be associated with insulin resistance and type 2 diabetes in individuals of European origin. We aimed to determine whether this locus confers significant susceptibility to type 2 diabetes in the Han Chinese population, and thus cross-race susceptibility to type 2 diabetes.MethodsPolymorphisms in HMGA1 were identified by direct sequencing of genomic DNA derived from 192 Chinese participants (96 patients with type 2 diabetes and 96 controls). We then genotyped the common variant IVS5-13insC (c.136-14_136-13insC) in two other independent cohorts, including a total of 2,533 cases and 2,643 ethnically matched controls.ResultsWe confirmed the association of the HMGA1 variant IVS5-13insC (c.136-14_136-13insC) with type 2 diabetes with an OR of 1.34 (95% CI 1.15, 1.56, p = 0.0002 under a dominant model, and 95% CI 1.16, 1.55, p = 0.0002 under an additive model) in the Han Chinese population, corresponding to a population attributable risk fraction of 5.0%.Conclusions/interpretationHMGA1 is an important susceptibility locus that confers a high cross-race risk of the development of type 2 diabetes.

No evidence for association of 12p13 SNPs rs11833579 and rs12425791 within NINJ2 gene with ischemic stroke in Chinese Han population

Recent genome-wide association (GWA) studies have identified two intergenic single nucleotide polymorphisms (SNPs) (rs11833579 and rs12425791) on chromosome 12p13 and within 11 kb of the NINJ2 gene that were significantly associated with stroke in Caucasians. However, the validity of the association has remained controversial. We performed genetic association analyses in three independent cohorts, including total of 3042 cases and 2973 controls. No significant association between these two SNPs and ischemic stroke was detected by meta-analysis after adjustment for cardiovascular risk factors under the additive model. Our data does not support that the common variants on 12p13 are major contributors of ischemic stroke in the Chinese Han population.

Prevalence of common mutations in the CYP17A1 gene in Chinese Han population.

BACKGROUND Congenital adrenal hyperplasia owing to 17α-hydroxylase/17, 20-lyase deficiency is caused by genetic mutations in the CYP17A1 gene. To date, more than 80 different genetic lesions have been described in patients suffering from this disorder. We aimed to estimate the prevalence of CYP17A1 common mutations in Chinese Han population. METHODS We first reported two female patients with 17α-hydroxylase deficiency based on their clinical features and molecular genetics, and then summarized all the mutations of CYP17A1 gene reported around the world. The most common mutations of CYP17A1 among Chinese Han were genotyped in additional 3245 healthy Chinese using Taqman-assays. RESULTS The mutation spectrum in Asian is different from European decent. All healthy controls could detect two CYP17A1 mutations, D487-S488-F489 deletion and TAC329AA, with a prevalence of 1 in 1000 or 2 in 1000, respectively. CONCLUSION Our data demonstrates that these two mutations are major causes of 17α-hydroxylase deficiency in Chinese Han population.

Association between polymorphisms of CYP2J2 and EPHX2 genes and risk of coronary artery disease.

Objective Common polymorphisms within cytochrome P450 2J2 (CYP2J2) and epoxide hydrolase 2 (EPHX2), which are involved in the generation or hydrolysis of epoxyeicosatrienoic acids, may determine susceptibility to the development of cardiovascular disease. To derive a more precise estimation of their relationship, we undertook a case–control study as well as a meta-analysis to assess possible associations of coronary artery disease (CAD) risk with CYP2J2 and EPHX2 genetic variations. Methods Associations among four single nucleotide polymorphisms in CYP2J2 and five in EPHX2 with CAD were examined in a total of 1344 cases and 1267 ethnically and geographically matched controls. To further confirm the effect of two functional variants (G-50T and R287Q) in the development of CAD, we conducted a meta-analysis including seven studies on G-50T polymorphism and six studies on R287Q polymorphism before June 2010. Results No significant association between common polymorphisms within these two genes and CAD was observed in our sample, either using methods of single-locus analysis or haplotype-based analysis. In addition, no association was detected in our meta-analysis between these two functional variants and the risk of developing CAD. Conclusion This case–control study as well as meta-analysis suggested no association between CYP2J2 G-50T and EPHX2 R287Q and the risk of developing CAD.