Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population

Genome-wide single nucleotide polymorphism (SNP) association studies recently identified four SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) on chromosome 9p21 that were associated with coronary artery disease (CAD) and myocardial infarction (MI) in Caucasian populations from northern Europe and North America. Our aim was to determine whether these SNPs were associated with MI in a southern Europe/Mediterranean population. We employed a case–control association design involving 416 MI patients and 308 non-MI controls from Italy. Significant allelic association was identified between all four SNPs and MI. The association remained significant after adjusting for covariates for MI (P = 0.007–0.029). One risk haplotype (GGGG; P = 0.028) and one protective haplotype (AAAA; P = 0.047) were identified. Genotypic association analysis demonstrated that the SNPs conferred susceptibility to MI most likely in a dominant model (P = 0.0007–0.013). When the case cohort was divided into a group of MI patients with a family history (n = 248) and one group without it (n = 168), the positive, significant association was identified only in the group with the family history. These results indicate that chromosome 9p21 confers risk for development of MI in an Italian population. G.-Q. Shen, S. Rao, N. Martinelli, L. Li contributed equally to this work.     

Genome-wide association study of coronary artery disease in the Japanese

A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10⁻³⁴), HLA-DQB1 on 6p21 (P=4.7 × 10⁻⁷), and CDKN2A/B on 9p21 (P=6.1 × 10⁻¹⁶). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10⁻⁴⁰). On 6p21, an HLA allele, DQB1^*0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects – population specific and common – on susceptibility to CAD.     

Variant on 9p21 strongly associates with coronary heart disease, but lacks association with common stroke

Recently, genome-wide analyses revealed that variants on chromosome 9p21 are associated with myocardial infarction. We investigated whether this association was also present in a Belgian population of coronary artery disease (CAD) patients. As CAD and ischemic cerebrovascular disease (CVD) are thought to share some pathogenic pathways, we further examined the association of 9p21 with this disease. SNP rs10757278 on chromosome 9 was genotyped in 926 patients with CAD from the CAREGENE study, in 648 patients with CVD from the Leuven Stroke Genetics Study (LSGS) and the Belgian Stroke Study (BSS) and in 828 unrelated controls. A systematic review and meta-analysis were carried out in both vascular diseases. The frequency of the risk allele, rs10757278^*G, was 55% in CAD cases versus 48% in controls, odds ratio (OR)=1.35 (1.18–1.54), P=1.3 × 10⁻⁵. No association was found with CVD, OR=1.03 (0.89–1.19), P=0.73. Meta-analysis revealed a consistent relationship between the risk variant and CAD. However, using a meta-analytic approach in CVD, only a marginal association was observed, which was no longer present after excluding patients with a history of CAD. The risk variant on chromosome 9, tagged by rs10757278, is associated with coronary heart disease in the Belgian population, but not with isolated CVD. These findings suggest different pathogenic mechanisms in CAD versus CVD.     

染色体12q24.31单核苷酸多态性与冠状动脉粥样硬化性心脏病遗传易感性的关联研究

目的 探讨中国西南地区汉族人群染色体12q24.31 rs2259816基因多态性与冠状动脉粥样硬化性心脏病(简称冠心病)的相关性.方法 收集592例经冠状动脉造影确诊的冠心病患者及同期冠状动脉造影阴性、排除冠心病诊断的463名正常对照,采用聚合酶链反应-限制性片段长度多态性(PCR-restriction fragment length polymorphism,PCR-RFLP)技术分析染色体12q24.31 rs2259816单核苷酸多态性,比较两组间rs2259816位点等位基因和基因型频率分布差异.结果 冠心病组与对照组中均检出AA、AC、CC基因型.rs2259816等位基因A在冠心病组的频率为49.5%,高于对照组的频率43.8%,两组差异有统计学意义(OR=1.129,95%CI:1.029～1.239,P=0.010).结论 中国西南地区汉族人群染色体12q24.31 rs2259816基因多态性与冠心病发生风险密切相关.     

Replication analysis of SNPs on 9p21.2 and 19p13.3 with amyotrophic lateral sclerosis in East Asians

We performed a replication study of the 2 genetic variants, rs2814707 on 9p21.2 and rs12608932 on 19p13.3 that are recently reported to be most significantly associated with sporadic amyotrophic lateral sclerosis (ALS) in Caucasians. Both rs12608932 and rs2814707 showed no evidence of association in Japanese and Chinese (rs12608932, combined p = 0.58, odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.93-1.13; rs2814707, combined p = 0.88, OR = 1.10, 95% CI 0.93-1.30). The association of these loci with susceptibility to sporadic ALS is considered negative in East Asians.     

Genetic polymorphisms of interleukin-6 gene and susceptibility to coronary artery disease in Chinese population: Evidence based on 4582 subjects

The aim of this study was to explore whether interleukin-6 (IL-6) gene (−174 G/C and −572 C/G) polymorphisms are associated with susceptibility to coronary artery disease (CAD) risk in Chinese population. All the statistical tests were performed using Stata version 11.0. Twelve articles involving 16 studies were included in this meta-analysis, covering a total of 2309 CAD cases and 2273 controls. For IL-6 gene −572 C/G polymorphism, the results showed evidence for significant association between IL-6 gene −572 C/G polymorphism and CAD risk (for G allele vs. C allele: OR = 1.48, 95% CI = 1.26–1.74, p < 0.001; for G/G vs. C/C: OR = 2.60, 95% CI = 1.54–4.39, p < 0.001; for G/G vs. G/C + C/C: OR = 2.15, 95% CI = 1.35–3.42, p = 0.001; for G/G + G/C vs. C/C: OR = 1.55, 95% CI = 1.29–1.85, p < 0.001). However, for IL-6 gene −174 G/C polymorphism, no significant association was found between this variation and CAD risk. In summary, our meta-analysis showed evidence that IL-6 gene −572 C/G polymorphism may be a risk factor for CAD susceptibility. For IL-6 gene −174 G/C polymorphism, no significant association was found between this variation and CAD risk.     

Comparative study of the haplotype structure and linkage disequilibrium of chromosome 1p36.2 region in the Korean and Japanese populations

The patterns of linkage disequilibrium (LD) in the human genome provide important information for disease gene mapping. LDs may vary depending on chromosomal regions and populations. We have compared LD and haplotypes defined by SNPs in the chromosome 1p36.2 region of the Korean and Japanese populations. Fifty-eight SNPs in about 418 kb ranging from tumor necrosis factor receptor 2 (TNFR2:TNFRSF1B) to procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) gene were examined in 96 healthy Koreans and Japanese each by direct sequencing and fluorescence correlation spectroscopy combined with the PCR-sequence specific primer method (PCR-SSP-FCS), respectively. Upon pair-wise LD analysis, a total of 25 and 16 out of 58 SNPs greater than MAF 10% were included in LD blocks, encompassing almost 81 kb and 55 kb in total, in Koreans and Japanese, respectively. Both similarities and differences were observed in LD strength and haplotype frequencies between the populations. Considerable similarities were observed in the telomeric region where a long-range block of approximately 80 kb including three genes was found to have strong LDs in both Koreans and Japanese. Significant difference in LD strength was present near the TNFR2 region between the Japanese and Korean populations.     

Associations between CD36 gene polymorphisms and susceptibility to coronary artery heart disease

Associations between polymorphisms of the CD36 gene and susceptibility to coronary artery heart disease (CHD) are not clear. We assessed allele frequencies and genotype distributions of CD36 gene polymorphisms in 112 CHD patients and 129 control patients using semi-quantitative polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Additionally, we detected CD36 mRNA expression by real-time quantitative PCR, and we quantified plasma levels of oxidized low-density lipoprotein (ox-LDL) using an enzyme-linked immunosorbent assay (ELISA). There were no significant differences between the two groups (P>0.05) in allele frequencies of rs1761667 or in genotype distribution and allele frequencies of rs3173798. The genotype distribution of rs1761667 significantly differed between CHD patients and controls (P=0.034), with a significantly higher frequency of the AG genotype in the CHD group compared to the control group (P=0.011). The plasma levels of ox-LDL in patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.010). In a randomized sample taken from patients in the two groups, the CD36 mRNA expression of the CHD patients was higher than that of the controls. In CHD patients, the CD36 mRNA expression in AG genotype patients was remarkably higher than in those with an AA genotype (P=0.005). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CHD (OR=2.337, 95% CI=1.336-4.087, P=0.003). In conclusion, the rs1761667 polymorphism may be closely associated with developing CHD in the Chongqing Han population of China, and an AG genotype may be a genetic susceptibility factor for CHD.     

Lack of replication of a previously reported association between polymorphism in the 3′UTR of the alpha-synuclein gene and Parkinson's disease in Chinese subjects

Recent studies have implicated polymorphisms in the 3′ untranslated region (3′UTR) of the alpha-synuclein (SNCA) gene in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs356165 is one of polymorphisms located in the 3′UTR and its association with PD has been reported but remains controversial. Herein, we conducted a case-control study to further evaluate the possible association between SNP rs356165 and PD in Chinese. All subjects (330 PD patients and 300 normal controls) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P = 0.863), suggesting no association of SNP rs356165 with PD in our population. Thus, it may be premature to conclude an association between the 3′UTR of the SNCA gene and PD, and this association should be further examined in different ethnic populations.     

载脂蛋白A5基因-1131T>C多态性与冠心病易感性的关联研究

目的探讨载脂蛋白A5(apoA5)-1131T>C单核苷酸多态性与冠心病(CAD)发病风险之间的关系。方法经冠状动脉造影确诊的江苏地区冠心病患者235例,同一地区正常对照262名,采用PCRRFLP分析对apoA5基因的-1131T>C多态进行检测,比较不同基因型与个体血脂水平和冠心病患病风险的关系。结果-1131T>C单核苷酸多态位点等位基因T、C频率在CAD组和正常对照组中分别为59.57%、40.43%和65.65%、34.35%。CAD组中C等位基因的频率高于对照组(P<0.05)。与-1131TT基因型者比较,CC基因型者的冠心病患病风险显著增加(OR=1.872,95%CI=1.039-3.376,P=0.037),用Logistic回归模型对个体的年龄、性别、体重指数和抽烟、高血压等因素后,其患病风险仍明显增加(OR=2.285,95%CI=1.222-4.274)。对照组中不同基因型个体血浆甘油三酯水平差异有统计学意义(P=0.007),携带C等位基因的个体TG水平显著高于TT基因型个体。结论apoA5基因-1131T>C多态性C等位基因是中国人群中冠心病发病的危险因素之一,且与血浆TG水平的变化密切相关。     

Chromosome 9p21.3 is associated with early-onset coronary heart disease in the Irish population

Coronary heart disease (CHD) remains a leading cause of death across the world. A region on chromosome 9p21.3 has been recently reported to be associated with CHD. We evaluated 3 SNPs and 3 common haplotypes in the 9p21.3 region in 1494 individuals from 580 Irish families, where at least 1 member had early-onset (males 相似文献   

Association between lipoprotein-associated phospholipase A2 gene polymorphism and coronary artery disease in the Chinese Han population

The role of the lipoprotein-associated phospholipase A(2) gene (PLA2G7) in atherosclerosis remains controversial. We investigated the frequency of single-nucleotide polymorphisms (SNPs) of PLA2G7 (rs16874954 and rs1051931) and their association with coronary artery disease (CAD) in a cohort of CAD patients (n= 806) and age-matched healthy controls (n= 482) in the Chinese Han population. The VF and FF genotype of rs16874954 was significantly more frequent in the CAD patients (13.5%) than in the controls (9.3%, P= 0.024). The association remained after adjustment for age, gender, body mass index, smoking status, history of diabetes, positive family history of CAD, high-density lipoprotein cholesterol, and triglyceride (OR = 1.922; 95% CI [1.146-3.224]; P= 0.013). There was no significant difference in the frequency of any genotype of rs1051931 between the two groups. However, the frequency of the allele V379 was significantly greater in CAD patients with a history of myocardial infarction (MI) than in those without a history of MI (18.7% and 14.8%, P= 0.038). We conclude that there is significant association between the rs16874954 mutation and CAD in the Chinese Han population. The expression of rs1051931 variant in CAD patients may entail increased risk of MI.     

Characterization of 458 single nucleotide polymorphisms of disease candidate genes in the Korean population

Single nucleotide polymorphisms (SNPs) are considered as very promising genetic markers for complex disease gene hunting. However, it has been demonstrated that there are significant ethnic differences in genetic variations. In order to investigate the genetic variations in the Korean population and their ethnic differences, a large number of SNPs of 161 disease candidate genes were collected from a publicly available SNP database and then tested for the distribution of allele frequency in the Korean population. Of all 458 SNPs tested, approximately 43.9% were polymorphic in the Korean population, whereas 44.5% were monomorphic. The remaining 11.6% were failed in the test. Significant differences have been observed when SNP allele frequency pattern of Koreans was compared with those of Caucasians and Africans, whereas this pattern was highly similar between Korean and Japanese populations. Our data indicate that although many of the SNPs available in publicly available database, especially coding-region SNPs (cSNPs), can be used as informative genetic markers for disease association studies, an extensive verification of public SNPs in a particular population studied should be undertaken prior to their association studies. Electronic Publication     

Four SNPS on Chromosome 9p21 Confer Risk to Premature, Familial CAD and MI in an American Caucasian Population (GeneQuest)

Genome-wide association studies have separately identified four single nucleotide polymorphisms (SNPs) on chromosome 9p21 that confer susceptibility to coronary artery disease (CAD) and myocardial infarction (MI). This study presents the first analysis of these SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) in a premature, familial CAD/MI population (GeneQuest). We performed a case-control analysis of the GeneQuest Caucasian population with 310 cases with premature CAD and MI (average age at onset of 40.3 ± 5.1) and 560 non-CAD controls to determine if these SNPs are associated with risk of CAD using both the population-based and family-based association study designs. The four SNPs are significantly associated with premature and familial MI and CAD in the GeneQuest Caucasian population (allelic P = 6.61 × 10⁻⁷ to 1.87 × 10⁻⁸). Sib-TDT analysis showed that three of the four SNPs could confer significant susceptibility to premature CAD and MI. These results indicate that the four SNPs on chromosome 9p21 are also associated with premature, familial CAD.     

Association of neuropeptide Y gene rs16147 polymorphism with metabolic syndrome in patients with documented coronary artery disease

Background and aims: There have been few epidemiological studies that have investigated genetic susceptibility to cardiovascular risk associated with the prevalence of metabolic syndrome (MetS). Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). Therefore, the aim of this study was to investigate the association between the NPY gene rs16147 polymorphism and the presence of MetS in a well defined group of Iranian subjects with angiographically-defined CAD.

Methods: A cross-sectional study design was used in which a total of 364 patients were recruited; 143 patients with MetS and 221 without MetS were genotyped using the ARMS-PCR technique. Logistic regression analyses were performed to determine the odds ratios (ORs) for the association of specific genotypes with the presence of MetS and related phenotypes.

Results: The frequency of the variant G allele of the NPY gene was significantly higher in CAD patients without MetS (p?=?0.032). Compared to the AA genotype of the NPY gene, individuals carrying the GG genotype had a reduced risk of MetS (OR?=?0.51, 95% CI?=?0.27–0.95, p?=?0.034).

Conclusion: The rs16147 polymorphism may be associated with presence of MetS among subjects with documented CAD. Carriage of NPY A allele in patients with CAD is associated with a higher prevalence of MetS.     

Effect of serum interleukin 21 on the development of coronary artery disease

There has been more and more evidence to confirm the essential role of inflammatory processes in the development of coronary artery disease (CAD). Interleukin‐21 (IL‐21), the most recently discovered CD132‐dependent cytokine, plays a key role in regulating inflammation. The aim of the study was to understand the effect of peripheral IL‐21 on the pathogenesis and progression of CAD. Serum level of IL‐21 in 92 CAD patients and 73 controls was measured by the enzyme‐linked immunosorbent assay. Data showed that IL‐21 expression was significantly increased in CAD than in controls (p < 0.001). Interestingly, when comparing IL‐21 level with different genders, male subjects revealed higher IL‐21 than female subjects (p = 0.024). Also, we observed that patients with hypertension had upregulated level of serum IL‐21 (p = 0.002). Moreover, serum level of IL‐21 was positively correlated with total cholesterol level (p = 0.015) or low‐density lipoprotein cholesterol (p = 0.0009) of CAD cases. In addition, we analyzed IL‐21 level with the severity of CAD, and identified that cases with 3‐vessel affected had significantly elevated level of IL‐21 than those with 1‐vessel or 2‐vessel affected. These data suggested that serum level of IL‐21 may be closely associated with the development and progression of CAD.     

广东汉族人PCSK9基因E670G位点多态性与冠心病相关性研究

目的通过对中国广东地区冠心病（CAD）患者和健康个体前蛋白转化酶枯草杆菌蛋白酶/西布曲明9a型（PCSK9）基因E670G位点单核苷酸多态性（SNP）的研究,分析其在CAD患者和健康人中的分布,以及与冠心病和血脂代谢的相关性。结论采集经冠脉造影确诊的CAD患者血液标本165例,健康人血液标本180例,分别提取基因组DNA模板,采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法分析PCSK9基因E670G位点SNP,并用基因测序法验证结果。血清总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）浓度水平采用酶法测定。结果中国广东地区CAD患者和健康人群在该位点的等位基因频率、基因型频率分布差异无统计学意义（P〉0.05）。CAD患者组和对照组之间TC、LDL-C、HDL-C水平差异具有统计学意义（P〈0.05）,TG水平差异无统计学意义（P〉0.05）。CAD患者组中AA和AG基因型之间LDL-C、HDL-C的差异具有统计学意义（P〈0.05）,TC、TG的差异没有统计学意义（P〉0.05）;与非670G携带者比较,670G携带者血LDL-C水平增高,血HDL-C水平降低。AG基因型的冠脉病变支数明显高于AA基因型,其差异具有统计学意义（P〈0.05）。结论 PCSK9基因E670G多态性与血LDL-C、HDL-C水平,以及冠心病病变严重程度相关联。     

P53 codon 72 polymorphism in coronary artery disease: no evidence for association with increased risk or micronucleus frequency

A common polymorphism at codon 72 (Arg72Pro) of the p53 gene, a gene which codes for a tumor-suppressor protein with both antiproliferative and pro-apoptotic actions, has recently been reported to be a risk factor for coronary luminal narrowing after angioplasty. However, the association of the polymorphism with coronary artery disease (CAD) risk has not been studied. We evaluated the distribution of the Arg72Pro genotype in 250 patients, 180 with angiographically documented CAD and 70 with normal coronary angiography, by using polymerase chain reaction amplification of patient DNA followed by restriction enzyme digestion. We also examined the association between the Arg72Pro genotype and chromosome damage in 82 male patients (60 CAD and 22 no-CAD) by the micronucleus (MN) test in human lymphocytes, a sensitive assay for chromosome breakage and aneuploidy. The frequencies of Pro/Pro, Pro/Arg, and Arg/Arg genotypes in CAD patients were not significantly different from those who were CAD-free (chi(2) = 0.20, P = 0.90) and not significantly associated with the extent and severity of CAD. A significant increase in MN frequency was observed in relation to smoking status (8.4 +/- 0.6, 11.9 +/- 1 and 12.0 +/- 1.6, for non smokers, ex-smokers and smokers, respectively; P = 0.02). Moreover, diabetic patients showed higher levels of MN than normal patients (13.5 +/- 1.4 vs. 9.6 +/- 0.5, P = 0.0025). Also, MN frequency was significantly higher in CAD patients than in no-CAD patients (11.2 +/- 0.7 vs. 8.0 +/- 0.9, P = 0.02) and increased with the number of affected vessels (9.3 +/- 0.1, 12.2 +/- 1.5 and 12.5 +/- 1.3 for one-, two-, and three-vessel disease, respectively; P = 0.02). However, there were no associations between MN frequency and the Arg72Pro polymorphism. Although there appears to be an association between CAD and MN frequency, our results indicate that the Arg72Pro polymorphism does not have a significant impact on CAD or MN frequencies.     

Impact of a 1-year lifestyle modification program on plasma lipoprotein and PCSK9 concentrations in patients with coronary artery disease

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