Balakrishnan Poojitha, Vaidya Dhananjay, Voruganti V Saroja, Haack Karin, Kent Jack W, North Kari E, Laston Sandra, Howard Barbara V, Umans Jason G, Lee Elisa T, Best Lyle G, MacCluer Jean W, Cole Shelley A, Navas-Acien Ana, Franceschini Nora
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, United States.
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States.
Front Genet. 2018 Oct 12;9:466. doi: 10.3389/fgene.2018.00466. eCollection 2018.
Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing ( < 4.13 × 10). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near (rs2961831, = 6.39 × 10). In the replication study, we found a signal at rs4607517 near ( = 0.01). Variants near candidate diabetes genes (especially and ) were also nominally associated with HOMA-IR and cHOMA-B. We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at , , and with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.
基因研究可能有助于揭示美国印第安人2型糖尿病负担差异的潜在机制。我们的目标是在强心脏家族研究（SHFS）中，通过稳态模型评估β细胞功能（HOMA-B）、胰岛素抵抗（HOMA-IR）以及2型糖尿病与心脏代谢候选基因中的遗传变异之间的关联。我们使用校正了HOMA-IR的HOMA-B残差（cHOMA-B）、对数转换后的HOMA-IR以及新发糖尿病的混合模型，研究了先前与心脏代谢性状相关的变异（来自Illumina心脏代谢芯片的约200,000个变异）的关联，并对年龄、性别、人群分层和家族相关性进行了调整。使用固定效应荟萃分析合并中心特异性估计值。我们使用Bonferroni校正来考虑多重检验（<4.13×10）。我们还评估了候选糖尿病基因中的变异与这些代谢性状之间的关联。我们在来自亚利桑那州西南部的独立重复样本中探索了顶级单核苷酸多态性（SNP）。我们在26个位点的常见变异中发现了与cHOMA-B的显著关联，其中8个是新发现的（）。在5号染色体上靠近（rs2961831，=6.39×10）的一个基因间变异中观察到与cHOMA-B最显著的变异关联。在重复研究中，我们在靠近（=0.01）的rs4607517处发现了一个信号。候选糖尿病基因附近的变异（尤其是和）也与HOMA-IR和cHOMA-B存在名义上的关联。我们在新位点鉴定出了变异，并证实了已知候选糖尿病位点与cHOMA-B的关联。这项研究还提供了证据，证明在美国印第安人中，、和处的变异与cHOMA-B存在关联。需要进一步的研究来解释SHFS队列中美国印第安参与者糖尿病的高遗传度。
