非复制研究：一项针对非裔美国人高血压和血压的全基因组关联研究。
Non-replication study of a genome-wide association study for hypertension and blood pressure in African Americans.
机构信息
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
出版信息
BMC Med Genet. 2012 Apr 11;13:27. doi: 10.1186/1471-2350-13-27.
BACKGROUND
A recent genome wide association study in 1017 African Americans identified several single nucleotide polymorphisms that reached genome-wide significance for systolic blood pressure. We attempted to replicate these findings in an independent sample of 2474 unrelated African Americans in the Milwaukee metropolitan area; 53% were women and 47% were hypertensives.
METHODS
We evaluated sixteen top associated SNPs from the above genome wide association study for hypertension as a binary trait or blood pressure as a continuous trait. In addition, we evaluated eight single nucleotide polymorphisms located in two genes (STK-39 and CDH-13) found to be associated with systolic and diastolic blood pressures by other genome wide association studies in European and Amish populations. TaqMan MGB-based chemistry with fluorescent probes was used for genotyping. We had an adequate sample size (80% power) to detect an effect size of 1.2-2.0 for all the single nucleotide polymorphisms for hypertension as a binary trait, and 1% variance in blood pressure as a continuous trait. Quantitative trait analyses were performed both by excluding and also by including subjects on anti-hypertensive therapy (after adjustments were made for anti-hypertensive medications).
RESULTS
For all 24 SNPs, no statistically significant differences were noted in the minor allele frequencies between cases and controls. One SNP (rs2146204) showed borderline association (p = 0.006) with hypertension status using recessive model and systolic blood pressure (p = 0.02), but was not significant after adjusting for multiple comparisons. In quantitative trait analyses, among normotensives only, rs12748299 was associated with SBP (p = 0.002). In addition, several nominally significant associations were noted with SBP and DBP among normotensives but none were statistically significant.
CONCLUSIONS
This study highlights the importance of replication to confirm the validity of genome wide association study results.
背景
最近，一项针对 1017 名非裔美国人的全基因组关联研究发现了几个与收缩压达到全基因组显著相关的单核苷酸多态性。我们试图在密尔沃基大都市区的 2474 名无关非裔美国人的独立样本中复制这些发现；其中 53%是女性，47%是高血压患者。
方法
我们评估了上述全基因组关联研究中与高血压作为二分类性状或血压作为连续性状相关的 16 个顶级相关单核苷酸多态性。此外，我们还评估了两个基因（STK-39 和 CDH-13）中发现的 8 个单核苷酸多态性，这些单核苷酸多态性在欧洲和阿米什人群的全基因组关联研究中与收缩压和舒张压相关。使用 TaqMan MGB 荧光探针化学法进行基因分型。我们有足够的样本量（80%的功效）来检测所有单核苷酸多态性作为二分类性状的高血压的效应大小为 1.2-2.0，以及血压作为连续性状的 1%方差。在排除和包括接受抗高血压治疗的患者（在调整抗高血压药物后）的情况下，对定量性状进行了分析。
结果
对于所有 24 个 SNP，病例组和对照组之间的次要等位基因频率没有统计学差异。一个 SNP(rs2146204) 显示出与高血压状态（隐性模型，p = 0.006）和收缩压（p = 0.02）的边缘关联，但在调整多重比较后并不显著。在定量性状分析中，仅在血压正常者中，rs12748299 与 SBP（p = 0.002）相关。此外，在血压正常者中还观察到 SBP 和 DBP 与几个名义上显著相关，但均无统计学意义。
结论
这项研究强调了复制的重要性，以确认全基因组关联研究结果的有效性。
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