Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?
Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?
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DOI：
10.1371/journal.pgen.1000694
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发表时间：
2009-10-01
期刊：
影响因子：
4.5
通讯作者：
Wichmann, H-Erich
中科院分区：
文献类型：
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作者：
Heid, Iris M.;Huth, Cornelia;Wichmann, H-Erich
在第一个全基因组关联研究中，INSIG2 rs7566605 多态性被鉴定为肥胖（BMI >= 30 kg/m(2)），但重复结果不一致。我们收集了 34 项研究 (n = 74,345) 的统计数据，包括一般人群 (GP) 研究、基于人群的研究（选择与更好的健康状况相关的条件的受试者（“健康人群”，HP）和肥胖研究 (OB)）。我们测试了五种假设来探索异质性的潜在来源。对 27 项针对白人成年人 (n = 66,213) 的研究进行的荟萃分析结合了不同的研究设计，并不支持 CC 基因型与肥胖的整体关联，得出的比值比 (OR) 为 1.05（p 值 = 0.27）。 41% 的 I-2 测量值（p 值 = 0.015）表明研究间存在异质性。限制全科医生研究导致 I-2 测量值下降 11%（p 值 = 0.33），OR 为 1.10（p 值 = 0.015）。关于这五个假设，我们的数据显示 (a) GP 和 HP 研究之间存在一些差异（p 值 = 0.012），以及 (b) 极端比较（BMI >= 32.5、35.0、37.5、40.0 kg/m(2) 与 BMI、25 kg/m(2)）之间的关联，产生的 OR 为 1.16、1.18、1.22 或1.27（p 值 0.001 至 0.003），BMI 类别中 CC 基因型频率显着增加（10.4% 至 12.5%，趋势 p 值 = 0.0002）也强调了这一点。我们没有发现差异 OR 的证据 (c) 肥胖患病率高于平均水平的研究与低于平均水平的研究之间，(d) 2000 年之后 BMI 评估的研究与 2000 年前相比，或 (e) 老年人与年轻人的研究之间。对非白人成人 (n = 4889) 或儿童 (n = 3243) 的分析得出的 OR 分别为 1.01（p 值 = 0.94）或 1.15（p 值 = 0.22）。没有证据表明 rs7566605 多态性与肥胖总体相关。我们的数据表明与极端程度的肥胖有关，因此不同研究设计的异质效应可能会掩盖潜在的关联（当未考虑到时）。迄今为止，研究设计的重要性在基因发现和关联复制方面可能尚未得到充分认识。
The INSIG2 rs7566605 polymorphism was identified for obesity (BMI >= 30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I-2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I-2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI >= 32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI, 25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.