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Identifying genes that contribute to type 2 diabetes susceptibility in Caucasian and African Americans.

机译：在高加索人和非裔美国人中识别导致2型糖尿病易感性的基因。

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摘要

The chromosome 20q12--13.1 region is one of the most consistently replicated areas of linkage to T2DM in Caucasian populations. In a dense SNP analysis of this region we observed suggestive evidence of association with T2DM for SNPs within the genes NCOA5, CDH22, and PREX1. We aimed to evaluate these three genes in two independent Caucasian case-control populations.;Seventy two SNPs were genotyped in 300 diabetic nephropathy patients and 310 controls. Evidence of association with T2DM was observed in all three candidate genes (additive P-value [Pa] =0.00090--0.045). Six of these associations, all near PREX1, were replicated in an independent population (Pa=0.017--0.042). The combined analysis resulted in the same six SNPs, among others, associated with T2DM (Pa=0.0013--0.041). After testing for association with T2DM while adjusting for body mass index, which resulted in only 2 SNPs remaining nominally associated, association with BMI was observed with 10 SNPs in the PREX1 region (Pa=0.0015--0.029). Stratifying by T2DM status, however, showed that association with BMI was observed solely in cases (Pa=0.0018--0.041) suggesting that BMI may mediate effects of these SNPs on T2DM. Mediation testing revealed the effects of six SNPs were significantly mediated by BMI (30--40% effect).;Also as part of this project we evaluated 12 T2DM susceptibility loci identified in genome-wide association analyses of European-derived populations in a large African American population consisting of 993 diabetic cases and 1054 controls. Sixty eight ancestry-informative markers (AIMs) were also genotyped to account for the impact of admixture on association results. Apart from TCF7L2 (rs7903146, Pa=1.59x10-6), we observed little evidence of association with T2DM in AAs. In fact, only rs9300039 in an intragenic region of chromosome 11p12 was associated with T2DM after admixture adjustment (Pd=0.029).;The primary objective of this project was to evaluate susceptibility genes in Caucasian and African American populations. In the T2DM-linked region of chromosome 20q13.1 we have identified up to 3 genes that contribute to the formation of T2DM. In addition, evidence suggests variants near PREX1 are mediated by measures of adiposity. In the African American population we observed little evidence of association with T2DM for some of the most highly replicated susceptibility genes in European-derived populations suggesting that some different genetic risk factors may exist between populations. However, risk allele fixation of some of these loci may contribute to the increased overall prevalence of T2DM in the African American population.
机译：染色体20q12--13.1区是白种人群体中与T2DM连锁的最一致复制的区域之一。在该区域的密集SNP分析中，我们观察到了与暗示的证据相关联的基因，即NCOA5，CDH22和PREX1中的SNP。我们旨在在两个独立的白种人病例对照人群中评估这三个基因。在300例糖尿病肾病患者和310例对照中对70个SNP进行了基因分型。在所有三个候选基因中均观察到与T2DM相关的证据（加性P值[Pa] = 0.00090--0.045）。这些关联中的六个都在PREX1附近，被复制到一个独立的群体中（Pa = 0.017--0.042）。组合分析得出与T2DM相关的相同六个SNP（Pa = 0.0013--0.041）。在调整了体重指数并测试了与T2DM的关联后，仅导致2个SNP名义上保持关联，然后在PREX1区域观察到与BMI关联的10个SNP（Pa = 0.0015--0.029）。然而，根据T2DM状况进行分层显示，仅在病例（Pa = 0.0018--0.041）中观察到与BMI的关联，表明BMI可能介导了这些SNP对T2DM的影响。中介试验显示，六种SNP的作用受到BMI的显着介导（30--40％的作用）。此外，作为该项目的一部分，我们评估了在欧洲人群中全基因组关联分析中鉴定出的12个T2DM易感基因座非裔美国人人口包括993例糖尿病病例和1054例对照。还对68个祖先信息标记（AIM）进行了基因分型，以说明混合物对关联结果的影响。除了TCF7L2（rs7903146，Pa = 1.59x10-6），我们几乎没有发现与AA中T2DM相关的证据。实际上，混合调节后，只有染色体11p12的基因内区域中的rs9300039与T2DM相关（Pd = 0.029）。该项目的主要目的是评估白种人和非裔美国人的易感基因。在染色体20q13.1的T2DM连锁区域中，我们鉴定出多达3个基因有助于T2DM的形成。此外，有证据表明PREX1附近的变异体是通过肥胖的手段介导的。在非裔美国人人群中，我们观察到很少证据表明欧洲人群中某些最高度复制的易感基因与T2DM相关联，表明人群之间可能存在一些不同的遗传危险因素。但是，其中一些基因座的风险等位基因固定可能会导致T2DM在非裔美国人人群中的总体患病率增加。

著录项

  • 作者

    Lewis, Joshua P.;

  • 作者单位

    Wake Forest University, The Bowman Gray School of Medicine.;

  • 授予单位 Wake Forest University, The Bowman Gray School of Medicine.;
  • 学科 Biology Molecular.;Biology Genetics.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;生物化学;遗传学;
  • 关键词

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