HMGA1 IVS5-13insC 变异与种族多样化的高血压病例对照队列 2 型糖尿病无关。

Lack of association of the HMGA1 IVS5-13insC variant with type 2 diabetes in an ethnically diverse hypertensive case control cohort.

机构信息

Division of Clinical Pharmacology, Vanderbilt University, Nashiville, TN 37232-0575, USA.

出版信息

J Transl Med. 2013 Jan 9;11:12. doi: 10.1186/1479-5876-11-12.

DOI:10.1186/1479-5876-11-12

PMID:23302499

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3558451/

Abstract

BACKGROUND

Recently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).

METHODS

INVEST was a randomized, multicenter trial comparing two antihypertensive treatment strategies in an ethnically diverse cohort of hypertensive, coronary artery disease patients. Controls, who were diabetes-free throughout the study, and type 2 diabetes cases, either prevalent or incident, were genotyped for IVS5-13insC using Taqman®, confirmed with Pyrosequencing and Sanger sequencing. For LD analysis, genotyping for eight additional HMGA1 single nucleotide polymorphisms (SNPs) was performed using the Illumina® HumanCVD BeadChip. We used logistic regression to test association of the HMGA1 IVS5-13insC and diabetes, adjusted for age, gender, body mass index, and percentage European, African, and Native American ancestry.

RESULTS

We observed IVS5-13insC minor allele frequencies consistent with previous literature in Caucasians and African Americans (0.03 in cases and 0.04 in controls for both race/ethnic groups), and higher frequencies in Hispanics (0.07 in cases and 0.07 in controls). The IVS5-13insC was not associated with type 2 diabetes overall (odds ratio 0.98 [0.76-1.26], p=0.88) or in any race/ethnic group. Pairwise LD (r2) of IVS5-13insC and rs9394200, a SNP previously used as a tag SNP for IVS5-13insC, was low (r2=0.47 in Caucasians, r2=0.25 in Hispanics, and r2=0.06 in African Americans). Furthermore, in silico analysis suggested a lack of functional consequences for the IVS5-13insC variant.

CONCLUSIONS

Our results suggest that IVS5-13insC is not a functional variant and not associated with type 2 diabetes in an ethnically diverse, hypertensive, coronary artery disease population. Larger, more adequately powered studies need to be performed to confirm our findings.

摘要

背景

最近，高迁移率族蛋白 A1 基因（HMGA1）变体 IVS5-13insC 与 2 型糖尿病相关，但报道的相关性不一致，且缺乏西班牙裔和非裔美国人的数据。我们旨在研究 HMGA1 与糖尿病的关联，并在来自 INternational VErapamil SR-Trandolapril STudy（INVEST）的 3070 名白种人、西班牙裔和非裔美国人患者中描述 IVS5-13insC 等位基因频率和连锁不平衡（LD）。

方法

INVEST 是一项随机、多中心试验，比较了两种降压治疗策略在一个种族多样化的高血压、冠心病患者队列中的效果。对照组在整个研究期间均无糖尿病，2 型糖尿病病例为现患或新发，使用 Taqman®对 IVS5-13insC 进行基因分型，并用 Pyrosequencing 和 Sanger 测序进行验证。为了进行 LD 分析，使用 Illumina® HumanCVD BeadChip 对 8 个额外的 HMGA1 单核苷酸多态性（SNP）进行基因分型。我们使用逻辑回归检验 HMGA1 IVS5-13insC 与糖尿病的关联，调整年龄、性别、体重指数和欧洲、非洲和美洲原住民血统的百分比。

结果

我们观察到 IVS5-13insC 等位基因频率与之前的文献一致，在白种人和非裔美国人中（两组的病例分别为 0.03，对照组为 0.04），在西班牙裔中更高（病例为 0.07，对照组为 0.07）。IVS5-13insC 总体上与 2 型糖尿病无关（比值比 0.98 [0.76-1.26]，p=0.88），也与任何种族/族裔群体无关。IVS5-13insC 与之前用作 IVS5-13insC 标记 SNP 的 rs9394200 的成对 LD（r2）较低（白种人 r2=0.47，西班牙裔 r2=0.25，非裔美国人 r2=0.06）。此外，计算机分析表明 IVS5-13insC 变体没有功能后果。