TY - JOUR
T1 - Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese
AU - Enya, Mayumi
AU - Horikawa, Yukio
AU - Iizuka, Katsumi
AU - Takeda, Jun
N1 - Funding Information:
We thank Dr Y. Hirota and S. Seino (Kobe University, Kobe, Japan) for providing some of the DNA samples, and H. Tsuchida, K. Yokoyama, and J. Kawada for their technical assistance. This work was supported by a Health and Labor Science Research Grant for Research on Rare and Intractable Diseases from the Japanese Ministry of Health, Labor and Welfare (ID. 12944234 ), a Grant-in-Aid for Scientific Research from the Japanese Ministry of Science, Education, Sports, Culture and Technology (ID. 13374321 , 14499754 ), and a Strategic International Research Cooperative Program Grant from Japan Science and Technology Agency (ID. 10104011 ).
PY - 2014
Y1 - 2014
N2 - Background: 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. Method: 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. Result: 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). Conclusion: 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.
AB - Background: 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. Method: 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. Result: 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). Conclusion: 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.
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U2 - 10.1016/j.ymgmr.2014.07.009
DO - 10.1016/j.ymgmr.2014.07.009
M3 - Article
AN - SCOPUS:84916601729
SN - 2214-4269
VL - 1
SP - 350
EP - 361
JO - Molecular Genetics and Metabolism Reports
JF - Molecular Genetics and Metabolism Reports
IS - 1
ER -