Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p
Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p
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DOI：
10.1093/hmg/ddm352
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发表时间：
2008-03-15
影响因子：
3.5
通讯作者：
Watkins, Hugh
中科院分区：
文献类型：
--
作者：
Broadbent, Helen M.;Peden, John F.;Watkins, Hugh
全基因组关联研究已确定 9p 染色体上的一个区域与冠状动脉疾病 (CAD) 相关。该区域还与 2 型糖尿病 (T2D) 相关，而 2 型糖尿病是 CAD 的危险因素，尽管在单独的研究中报道不同的 SNP 与每种疾病相关。我们使用先前报道的（“文献”）和标记 SNP，对四个欧洲人群的 4251 例 CAD 病例和 4443 例对照进行了病例对照研究。我们复制了文献中的 SNP（P = 8x10(-13)；OR = 1.29；95% CI：1.20-1.38），并表明这些 SNP 检测到的强一致关联是跨越 53 kb 的“阴阳”单倍型模式的结果。没有证据表明主要风险单倍型存在额外的 CAD 易感性等位基因。没有心肌梗塞 (MI) 的 CAD 患者表现出比 MI 患者更强的关联趋势。该位点所赋予的 CAD 易感性不因性别、年龄、吸烟、肥胖、高血压或糖尿病而异。使用 CAD 和 T2D 相关 SNP 对 CAD 和糖尿病易感性进行的同时测试表明，这些关联是相互独立的。此外，该区域与低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、纤维蛋白原、白蛋白、尿酸、胆红素或同型半胱氨酸的血浆水平差异无关，尽管CAD高危等位基因与较低的甘油三酯水平矛盾地相关。大反义非编码 RNA 基因 (ANRIL) 与高风险单倍型搭配，在受动脉粥样硬化影响的组织和细胞类型中表达，是染色体 9p CAD 基因座的主要候选基因。
Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studies. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8x10(-13); OR = 1.29; 95% CI: 1.20-1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'yin-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglyceride levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus.