Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population.

Tien-Jyun Chang,Yi-Cheng Chang,Chii-Min Hwu,Yen-Feng Chiu,Shan-Shan Kuo,Wayne H-H Sheu,Lee-Ming Chuang,Thomas Quertermous,Kuang-Chung Shih,Yuh-Shan Jou

doi:10.1038/srep14380

Abstract

Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.

Highlights

NA environmental factors influence susceptibility to T2DM2
We found the genetic polymorphism of proprotein convertase subtilisin/kexin type 2 (PCSK2) was responsible for the linkage peak of fasting insulin, HOMA-IR, and glucose levels at 1 hr after 75 gm oral glucose loading
The aim of the current study is to investigate the association between genetic variants of PCSK2 and fasting insulin and glucose concentration, the homeostasis model assessment of beta cell function (HOMA-beta) and HOMA-IR, various parameters during the 75 g oral glucose tolerance test (OGTT), and clinical progression from normal glucose tolerance to diabetes after a follow-up of 5 years

Summary

Introduction

NA environmental factors influence susceptibility to T2DM2. identification of the genes responsible for T2DM is complicated by the high degree of genetic heterogeneity, the involvement of multiple genes, and a small to moderate risk conferred by each of the genes. We previously identified a QTL located at 37 cM on chromosome 20 for the fasting insulin and insulin resistance index by homeostasis model assessment (HOMA-IR) in 1,365 non-diabetic Chinese subjects from 411 nuclear families[7]. We found the genetic polymorphism of proprotein convertase subtilisin/kexin type 2 (PCSK2) was responsible for the linkage peak of fasting insulin, HOMA-IR, and glucose levels at 1 hr after 75 gm oral glucose loading (data not shown). The aim of the current study is to investigate the association between genetic variants of PCSK2 and fasting insulin and glucose concentration, the homeostasis model assessment of beta cell function (HOMA-beta) and HOMA-IR, various parameters during the 75 g oral glucose tolerance test (OGTT), and clinical progression from normal glucose tolerance to diabetes after a follow-up of 5 years

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