鉴定与 2 型糖尿病风险升高或降低相关的低频和罕见序列变异。
Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.
机构信息
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
出版信息
Nat Genet. 2014 Mar;46(3):294-8. doi: 10.1038/ng.2882. Epub 2014 Jan 26.
Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2, rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10(-21)) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10(-12) and 0.56 kg/m(2) per allele, P = 6.5 × 10(-7), respectively). In addition, two missense variants in PAM, encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10(-10) and OR = 1.47, P = 1.7 × 10(-5), respectively), and a rare (0.20%) frameshift variant in PDX1, encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10(-7)).
通过对 2630 名冰岛人的全基因组测序，并将其导入到 11114 例冰岛病例和 267140 例对照中，随后在丹麦和伊朗样本中进行检测，我们发现了 4 个以前未报道的影响 2 型糖尿病（T2D）风险的变异。CCND2 内含子 1 中的低频（1.47%）变异 rs76895963[G]使 T2D 的风险降低了一半（比值比（OR）= 0.53，P = 5.0×10(-21))，并且与 CCND2 表达增加相关。值得注意的是，该变体也与身高和体重指数（BMI）均升高相关，每个等位基因分别增加 1.17 厘米（P = 5.5×10(-12)）和 0.56 千克/平方米（P = 6.5×10(-7)）。此外，编码 p.Asp563Gly（频率为 4.98%）和 p.Ser539Trp（频率为 0.65%）的 PAM 中的两个错义变体赋予 T2D 中等偏高的风险（OR = 1.23，P = 3.9×10(-10)和 OR = 1.47，P = 1.7×10(-5)），而 PDX1 中的罕见（0.20%）移码变异，编码 p.Gly218Alafs*12，与 T2D 的高风险相关（OR = 2.27，P = 7.3×10(-7)）。
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