Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese.
Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese.
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DOI：
10.1016/j.ymgmr.2014.07.009
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发表时间：
2014
影响因子：
1.9
通讯作者：
Takeda, Jun
中科院分区：
文献类型：
--
作者：
Enya, Mayumi;Horikawa, Yukio;Iizuka, Katsumi;Takeda, Jun
全基因组关联研究（GWAS）未发现肠促胰岛素相关基因的高频变异与日本人2型糖尿病的发生相关。然而，影响葡萄糖代谢性状的低频率和罕见和/或高频率变体仍有待研究。我们筛选了肠促胰岛素相关基因的所有外显子（GCG、GLP1R、DPP4、PCSK 1、GIP、（GIPR）在96名2型糖尿病患者中，研究了这些基因的遗传变异与38名年轻健康志愿者在试验餐后的定量代谢特征的关联，以及与日本受试者（包括1303名2型糖尿病患者和1014名2型糖尿病患者）中2型糖尿病的发生的关联。对照GIPR的两个突变p.Thr3Alafsx21和Arg 183 Gln仅在2型糖尿病患者中发现，且均接受胰岛素治疗。在10个tagSNPs中，我们发现PCSK 1的SNP 393（rs6235）的风险等位基因C名义上与较高的空腹胰岛素和HOMA-R相关（P = 0.034和P = 0.030），但与胰岛素原水平、肠促胰岛素水平或BMI无关。在校正年龄、性别和BMI后，该变异与2型糖尿病的发生显著相关（P = 0.0043）。GIPR的罕见变异可能通过胰岛素分泌缺陷促进2型糖尿病的发展。此外，PCSK 1的遗传变异可能通过改变胰岛素抵抗影响葡萄糖稳态，而与BMI、肠促胰岛素水平或胰岛素原转化无关，并可能与日本人2型糖尿病的发生相关。
None of the high frequency variants of the incretin-related genes has been found by genome-wide association study (GWAS) for association with occurrence of type 2 diabetes in Japanese. However, low frequency and rare and/or high frequency variants affecting glucose metabolic traits remain to be investigated. We screened all exons of the incretin-related genes (GCG, GLP1R, DPP4, PCSK1, GIP, and GIPR) in 96 patients with type 2 diabetes and investigated for association of genetic variants of these genes with quantitative metabolic traits upon test meal with 38 young healthy volunteers and with the occurrence of type 2 diabetes in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls. Two mutations of GIPR, p.Thr3Alafsx21 and Arg183Gln, were found only in patients with type 2 diabetes, and both of them were treated with insulin. Of ten tagSNPs, we found that risk allele C of SNP393 (rs6235) of PCSK1 was nominally associated with higher fasting insulin and HOMA-R (P = 0.034 and P = 0.030), but not with proinsulin level, incretin level or BMI. The variant showed significant association with occurrence of type 2 diabetes after adjustment for age, sex, and BMI (P = 0.0043). Rare variants of GIPR may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of PCSK1 might influence glucose homeostasis by altered insulin resistance independently of BMI, incretin level or proinsulin conversion, and may be associated with the occurrence of type 2 diabetes in Japanese.