Sakamoto Yukiko, Inoue Hiroshi, Keshavarz Parvaneh, Miyawaki Katsuyuki, Yamaguchi Yuka, Moritani Maki, Kunika Kiyoshi, Nakamura Naoto, Yoshikawa Toshikazu, Yasui Natsuo, Shiota Hiroshi, Tanahashi Toshihito, Itakura Mitsuo
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, #3-18-15, Kuramoto-cho, Tokushima-city, Tokushima, 770-8503, Japan.
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
J Hum Genet. 2007;52(10):781-793. doi: 10.1007/s10038-007-0190-x. Epub 2007 Sep 6.
Many genetic association studies support a contribution of genetic variants in the KCNJ11-ABCC8 gene locus to type 2 diabetes (T2D) susceptibility in Caucasians. In non-Caucasian populations, however, there have been only a few association studies, and discordant results were obtained. Herein, we selected a total of 31 SNPs covering a 211.3-kb region of the KCNJ11-ABCC8 locus, characterized the patterns of linkage disequilibrium (LD) and haplotype structure, and performed a case-control association study in a Japanese population consisting of 909 T2D patients and 893 control subjects. We found significant associations between eight SNPs, including the KCNJ11 E23K and ABCC8 S1369A variants, and T2D. These disease-associated SNPs were genetically indistinguishable because of the presence of strong LD, as found previously in Caucasians. For the KCNJ11 E23K variant, the most significant association was obtained under a dominant genetic model (OR 1.32, 95% CI 1.09-1.60, P = 0.004). A meta-analysis of East Asian studies, comprising a total of 3,357 T2D patients (77.4% Japanese) and 2,836 control subjects (77.8% Japanese), confirmed the significant role of the KCNJ11 E23K variant in T2D susceptibility. Furthermore, we found evidence suggesting that the KCNJ11 E23K genotype is independently associated with higher blood-pressure levels.
许多基因关联研究表明，KCNJ11 - ABCC8基因座中的基因变异对高加索人2型糖尿病（T2D）易感性有影响。然而，在非高加索人群中，仅有少数关联研究，且结果不一致。在此，我们共选择了覆盖KCNJ11 - ABCC8基因座211.3 kb区域的31个单核苷酸多态性（SNP），对连锁不平衡（LD）模式和单倍型结构进行了表征，并在一个由909例T2D患者和893例对照受试者组成的日本人群中开展了病例对照关联研究。我们发现包括KCNJ11 E23K和ABCC8 S1369A变异在内的8个SNP与T2D之间存在显著关联。正如之前在高加索人群中发现的那样，由于存在强LD，这些与疾病相关的SNP在基因上无法区分。对于KCNJ11 E23K变异，在显性遗传模型下获得了最显著的关联（比值比1.32，95%置信区间1.09 - 1.60，P = 0.004）。一项对东亚研究的荟萃分析，共纳入3357例T2D患者（77.4%为日本人）和2836例对照受试者（77.8%为日本人），证实了KCNJ11 E23K变异在T2D易感性中的重要作用。此外，我们发现有证据表明KCNJ11 E23K基因型与较高的血压水平独立相关。
