Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs
Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs
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DOI：
10.1038/jhg.2009.7
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Ralhan, Sarju
中科院分区：
文献类型：
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作者：
Sanghera, Dharambir K.;Been, Latonya;Ralhan, Sarju
最近对三种全基因组关联（GWA）扫描的荟萃分析确定了与高加索人II型糖尿病（T2 D）高度相关的六个位点（NOTCH 2，THADA，ADAMTS 9，JAZF 1，CDC 123/CAMKID和TSPAN 8/LGRS）。这项调查旨在确认这种关联与糖尿病和相关的代谢性状在印度北部的Khatri锡克教徒糖尿病患者。我们对680例T2 D病例和637例血糖正常（NG）对照的病例对照队列中每个位点的高度显著变异进行了基因分型。在初始测试期间，仅CDC 123/CAMKID（rs 12779790）复制了显性模型下与T2 D相关的早期证据（比值比（OR）：1.27; 95%置信区间（CI）：1.02-1.57; P = 0.031）。然而，我们无法使用多个测试校正来证实这种关联。在多元线性回归分析中，CDC 123/CAMKID中的相同变体显示，在NG对照（P = 0.030）和T2 D病例（P = 0.009）中，以及在校正协变量后的合并样本（P = 0.003）中，“G”（风险）等位基因携带者的空腹胰岛素水平显著降低。在T2 D病例（P 0.008）和联合队列（P = 0.026）的“G”（风险）等位基因携带者中也观察到β细胞功能受损的证据。我们的数据无法证实其余变体的作用，这些变体具有T2 D风险或测量胰岛素分泌或胰岛素抵抗的定量表型。这些研究结果表明，CDC 123/CAMKID可能是锡克教徒通过影响B细胞功能发展T2 D的主要风险因素。据我们所知，这是第一个研究报告的作用，最近出现的基因座在这一高风险人群从南亚次大陆。Journal of Human Genetics（2009）54，162-168; doi：10.1038/jhg.2009.7; 2009年2月27日在线发表
A recent meta-analysis on three genome-wide association (GWA) scans identified six loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) highly associated with type II diabetes (T2D) in Caucasians. This investigation seeks to confirm this association with diabetes and related metabolic traits in Khatri Sikh diabetics of North India. We genotyped highly significant variants from each locus in a case-control cohort consisting of 680 T2D cases and 637 normoglycemic (NG) controls. Only CDC123/CAMKID (rs12779790) replicated earlier evidence of association with T2D under a dominant model (odds ratio (OR): 1.27; 95% confidence interval (CI): 1.02-1.57; P = 0.031) during initial testing. However, we could not confirm this association using multiple testing corrections. In a multiple linear-regression analysis, the same variant in the CDC123/CAMKID revealed a marked decrease in fasting insulin levels among 'G' (risk) allele carriers independently in NG controls (P = 0.030) and in T2D cases (P = 0.009), as well as in the combined sample (P = 0.003) after adjusting for covariates. Evidence of impaired beta-cell function was also observed among 'G' (risk) allele carriers in T2D cases (P 0.008) and in a combined cohort (P = 0.026). Our data could not confirm the role of the remaining variants with risk either for T2D or quantitative phenotypes measuring insulin secretion or insulin resistance. These findings suggest that CDC123/CAMKID could be a major risk factor for the development of T2D in Sikhs by affecting b-cell function. To our knowledge, this is the first study reporting the role of recently emerging loci in this high-risk population from the South Asian subcontinent. Journal of Human Genetics (2009) 54, 162-168; doi: 10.1038/jhg.2009.7; published online 27 February 2009