Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies.
Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies.
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DOI：
10.1086/381400
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发表时间：
2004-02
影响因子：
9.8
通讯作者：
Yiqing Song;T. Niu;J. Manson;D. Kwiatkowski;Simin Liu
中科院分区：
文献类型：
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作者：
Yiqing Song;T. Niu;J. Manson;D. Kwiatkowski;Simin Liu
染色体 2q37.3 上的 calpain-10 基因 (CAPN10) 是通过全基因组筛选和定位克隆鉴定出的第一个 2 型糖尿病 (T2D) 候选基因。一种多态性（UCSNP-43：G-->A）和由三种多态性（UCSNP-43、-19和-63）定义的特定单倍型组合与多个人群中T2D风险增加相关。为了定量评估 CAPN10 对 T2D 风险影响的集体证据，我们对基于人群和基于家庭的关联研究进行了荟萃分析。我们从 MEDLINE、PubMed 和 Online Mendelian Inheritance in Man 数据库以及截至 2003 年 7 月发表的其他相关报告和摘要中检索了数据。从总共 26 项原始数据研究（21 项基于人群的研究：5,013 例病例和 5,876 例对照；5 项基于家庭的研究：487 个亲子三人组）中，我们开发了一个汇总数据库，其中包含研究设计、研究变量人口/种族、CAPN10 中的特定多态性和单倍型组合以及糖尿病相关的代谢表型。对于基于人群的研究，我们使用固定效应和随机效应模型来计算 CAPN10 基因型与 T2D 风险关联的汇总比值比 (OR) 和 95% 置信区间 (CI)。我们还计算了 CAPN10 与糖尿病相关数量性状之间关联的加权平均差异。在加性效应或显性效应模型下，我们发现 UCSNP-43 基因座中的 CAPN10 基因型与 T2D 风险之间没有统计学上的显着关系。然而，在隐性模型下，常见 G 等位基因纯合子个体患 T2D 的风险比 A 等位基因携带者高 19%，具有统计学意义（OR 1.19；95% CI 1.07-1.33）。几项初步小型研究的阳性结果似乎高估了 112/121 单倍型组合与 T2D 风险之间的关联（OR 1.38；95% CI 1.04-1.84）。在我们删除这些初始研究后，这种关联变得不显着（OR 1.11；95% CI 0.91-1.35）。此外，我们没有发现 UCSNP-43 G/G 基因型与 112/121 单倍型组合和代谢表型之间存在关联的证据。我们对基于家庭的研究的荟萃分析显示，UCSNP-44 中的罕见等位基因 C 仅从杂合父母过度传播至其患有 T2D 的后代。我们的分析表明，统计功效不足、等位基因频率、单倍型和单倍型组合的种族/民族差异、潜在的基因-基因或基因-环境相互作用、发表偏倚和多重假设检验可能导致CAPN10和T2D先前研究中的显着异质性。我们的研究结果还表明，大规模、精心设计的关联研究和功能研究都有必要可靠地证实或最终反驳关于 CAPN10 在 T2D 风险中的作用的最初假设。
The calpain-10 gene (CAPN10) on chromosome 2q37.3 was the first candidate gene for type 2 diabetes (T2D) identified through a genomewide screen and positional cloning. One polymorphism (UCSNP-43: G-->A) and a specific haplotype combination defined by three polymorphisms (UCSNP-43, -19, and -63) were linked to an increased risk of T2D in several populations. To quantitatively assess the collective evidence for the effects of CAPN10 on risk of T2D, we conducted a meta-analysis of both population-based and family-based association studies. We retrieved data from the MEDLINE, PubMed, and Online Mendelian Inheritance in Man databases, as well as from other relevant reports and abstracts published up to July 2003. From a total of 26 studies with primary data (21 population-based studies: 5,013 cases and 5,876 controls; 5 family-based studies: 487 parent-offspring trios), we developed a summary database that contains variables of study design, study population/ethnicity, specific polymorphisms and haplotype combinations in CAPN10, and diabetes-related metabolic phenotypes. For population-based studies, we used both fixed-effects and random-effects models to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) for the associations of CAPN10 genotypes with the risk of T2D. We also calculated weighted mean differences for the associations between CAPN10 and diabetes-related quantitative traits. Under either an additive or a dominant effect model, we found no statistically significant relation between CAPN10 genotypes in the UCSNP-43 locus and T2D risk. However, under a recessive model, individuals homozygous for the common G allele had a statistically significant 19% higher risk of T2D than carriers of the A allele (OR 1.19; 95% CI 1.07-1.33). The association between the 112/121 haplotype combination and T2D risk appeared to be overestimated by several initial small studies with positive findings (OR 1.38; 95% CI 1.04-1.84). After we removed these initial studies, this association became nonsignificant (OR 1.11; 95% CI 0.91-1.35). Moreover, we found no evidence for the associations between the UCSNP-43 G/G genotype and the 112/121 haplotype combination and metabolic phenotypes. Our meta-analysis of family-based studies showed only an overtransmission of the rare allele C in UCSNP-44 from heterozygous parents to their affected offspring with T2D. Our analysis indicates that inadequate statistical power, racial/ethnic differences in frequencies of alleles, haplotypes and haplotype combinations, potential gene-gene or gene-environment interactions, publication bias, and multiple hypothesis testing may contribute to the significant heterogeneity in previous studies of CAPN10 and T2D. Our findings also suggest that both large-scale, well-designed association studies and functional studies are warranted to either reliably confirm or conclusively refute the initial hypothesis regarding the role of CAPN10 in T2D risk.