Large-scale association studies of variants in genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes
Large-scale association studies of variants in genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes
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DOI：
10.2337/diabetes.52.2.568
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发表时间：
2003-02-01
期刊：
影响因子：
7.7
通讯作者：
Frayling, TM
中科院分区：
文献类型：
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作者：
Gloyn, AL;Weedon, MN;Frayling, TM
ABCC8和KCNJ11基因编码β细胞ATP敏感性钾（K - ATP）通道的磺酰脲受体1（SUR1）亚基和内向整流钾通道（Kir6.2），控制胰岛素分泌。这些基因常见的多态性（ABCC8外显子16 - 3t/c、外显子18 T/C、KCNJ11 E23K）与2型糖尿病有不同程度的关联，但尚未进行大型（约2000名受试者）的病例对照研究。我们通过对2486名英国受试者进行研究来评估这三种变异的作用：其中854人患有2型糖尿病，1182人为普通对照人群，150个为2型糖尿病亲子三联体。在病例对照研究中，E23K等位基因与糖尿病相关（优势比[OR]为1.18[95%置信区间1.04 - 1.34]，P = 0.01），但未显示出与糖尿病的家族相关性。ABCC8基因的外显子16和外显子18变异均与糖尿病无关（分别为1.04[0.91 - 1.18]，P = 0.57；0.93[0.71 - 1.23]，P = 0.63）。对所有病例对照数据的荟萃分析表明，E23K等位基因与2型糖尿病相关（K等位基因OR为1.23[1.12 - 1.36]，P = 0.000015；KK基因型为1.65[1.34 - 2.02]，P = 0.000002）；但ABCC8变异与之无关。我们的研究结果证实E23K会增加2型糖尿病的风险，并表明大规模的关联研究对于确定糖尿病易感等位基因非常重要。
The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K-ATP) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large (similar to2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% Cl 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.