Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese

• Published in: Molecular genetics and metabolism reports Vol. 1; no. C; pp. 350 - 361
• Main Authors: Enya, Mayumi, Horikawa, Yukio, Iizuka, Katsumi, Takeda, Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.01.2014
• Subjects: Incretin; Obesity; PCSK1; Polymorphism; Research Paper; Type 2 diabetes; GLP-1, glucagon-like peptide 1; IRI, immunoreactive insulin; Type 2 diabetes; Incretin; Obesity; PCSK1; LD, linkage disequilibrium; HOMA-R, homeostasis model assessment as an index of insulin resistance; GIPR, GIP receptor; CPR, c-peptide immunoreactivity; OR, odds ratio; HOMA-B, homeostasis model assessment as an index of insulin secretion; GWAS, genome-wide association study; GCG, proglucagon gene; BMI, body mass index; PCSK1, prohormone convertase (PC) enzymes. PC1/3; DPP4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic peptide; SNP, single nucleotide polymorphism; HbA1c, hemoglobin A1c; PCR, polymerase chain reaction; GLP1R, GLP-1 receptor; Polymorphism
• ISSN: 2214-4269; 2214-4269
• DOI: 10.1016/j.ymgmr.2014.07.009

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 ( , , , , , and ) 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 , 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 was nominally associated with higher fasting insulin and HOMA-R (  = 0.034 and  = 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 (  = 0.0043). Rare variants of may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of 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.