title: Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese.
abstract: 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.
  
  
  METHODS
  We screened all exons of the incretin-related genes (GCG,GLP1R,DPP4,PCSK1,GIP, andGIPR) 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.
  
  
  RESULTS
  Two mutations ofGIPR, 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) ofPCSK1was nominally associated with higher fasting insulin and HOMA-R (P= 0.034 andP= 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).
  
  
  CONCLUSIONS
  Rare variants ofGIPRmay contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant ofPCSK1might 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.
authors.affiliation: Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Enya
authors.affiliation: Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Horikawa
authors.affiliation: Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Iizuka
authors.affiliation: Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
keywords: BMI, body mass index; CPR, c-peptide immunoreactivity; DPP4, dipeptidyl peptidase 4; GCG, proglucagon gene; GIP, glucose-dependent insulinotropic peptide; GIPR, GIP receptor; GLP-1, glucagon-like peptide 1; GLP1R, GLP-1 receptor; GWAS, genome-wide association study; HOMA-B, homeostasis model assessment as an index of insulin secretion; HOMA-R, homeostasis model assessment as an index of insulin resistance; HbA1c, hemoglobin A1c; IRI, immunoreactive insulin; Incretin; LD, linkage disequilibrium; OR, odds ratio; Obesity; PCR, polymerase chain reaction; PCSK1; PCSK1, prohormone convertase (PC) enzymes. PC1/3; Polymorphism; SNP, single nucleotide polymorphism; Type 2 diabetes