Department of Cardiology, Lund University, Lund, Sweden.
J Intern Med. 2012 Dec;272(6):573-82. doi: 10.1111/j.1365-2796.2012.02563.x. Epub 2012 Jul 27.
Genetic polymorphisms associated with common aetiologically complex diseases have recently been identified through genome-wide association studies. Direct-to-consumer genetic testing for such polymorphisms, with provision of absolute genetic risk estimates, is marketed by several commercial companies. Polymorphisms associated with atrial fibrillation (AF) have shown relatively large risk estimates, but the robustness of such estimates across populations and study designs has not been investigated.
A systematic literature review with meta-analysis and assessment of between-study heterogeneity was carried out for single-nucleotide polymorphisms (SNPs) in the six genetic regions associated with AF in genome-wide or candidate gene studies.
Data were identified from 18 samples of European ancestry (n=12,100 cases, 115,702 controls) for the single-nucleotide polymorphisms (SNP) on chromosome 4q25 (rs220733), from 16 samples (n=12,694 cases, 132,602 controls) for the SNP on 16q22 (rs2106261) and from four samples (n=5272 cases, 59,725 controls) for the SNP in KCNH2 (rs1805123). Only the publications in which the associations were initially reported were identified for SNPs on 1q21 and in GJA5 and IL6R, why meta-analyses were not performed for those SNPs. In overall random-effects meta-analyses, association with AF was observed for both SNPs on chromosomes 4q25 [odds ratio (OR), 1.67; 95% CI, 1.50-1.86, P=2×10(-21)] and 16q22 (OR, 1.21; 95% CI, 1.13-1.29, P=1×10(-8)) from genome-wide studies, but not the SNP in KCNH2 from candidate gene studies (P=0.15). There was substantial effect heterogeneity across case-control and cross-sectional studies for both polymorphisms (I(2)=0.50-0.78, P<0.05), but not across prospective cohort studies (I(2)=0.39, P=0.15). Both polymorphisms were robustly associated with AF for each study design individually (P<0.05).
In meta-analyses including up to 150,000 individuals, polymorphisms in two genetic regions were robustly associated with AF across all study designs but with substantial context-dependency of risk estimates.
通过全基因组关联研究，最近发现了与常见病因复杂疾病相关的遗传多态性。几家商业公司提供针对这些多态性的直接面向消费者的基因检测，并提供绝对遗传风险估计。与心房颤动（AF）相关的多态性显示出相对较大的风险估计值，但这些估计值在不同人群和研究设计中的稳健性尚未得到调查。
对全基因组或候选基因研究中与 AF 相关的六个遗传区域中的单核苷酸多态性（SNP）进行了系统文献综述和荟萃分析，并评估了研究间异质性。
在全基因组研究中，从 18 个欧洲血统样本（n=12100 例病例，115702 例对照）中确定了染色体 4q25（rs220733）上的单核苷酸多态性（SNP），从 16 个样本（n=12694 例病例，132602 例对照）中确定了 16q22 上的 SNP（rs2106261），从 4 个样本（n=5272 例病例，59725 例对照）中确定了 KCNH2 上的 SNP（rs1805123）。只有在最初报道关联的出版物中才确定了 1q21 上和 GJA5 和 IL6R 上的 SNP 进行了荟萃分析，因为那些 SNP 没有进行meta 分析。在总体随机效应荟萃分析中，全基因组研究中观察到与 AF 相关的染色体 4q25 上的两个 SNP [比值比（OR），1.67；95%置信区间，1.50-1.86，P=2×10(-21)]和 16q22 上的 SNP（OR，1.21；95%置信区间，1.13-1.29，P=1×10(-8)），但候选基因研究中 KCNH2 上的 SNP 没有（P=0.15）。在病例对照和横断面研究中，这两种多态性均存在显著的效应异质性（I(2)=0.50-0.78，P<0.05），但在前瞻性队列研究中则没有（I(2)=0.39，P=0.15）。在每种研究设计中，这两种多态性都与 AF 显著相关（P<0.05）。
在包括多达 150000 人的荟萃分析中，两个遗传区域中的多态性在所有研究设计中均与 AF 显著相关，但风险估计值存在实质性的背景依赖性。
