Genetic Polymorphisms of PCSK2 Are Associated with Glucose Homeostasis and Progression to Type 2 Diabetes in a Chinese Population

Overview

Journal Sci Rep

Specialty Science

Date 2015 Nov 27

PMID 26607656

Citations 10

Authors

Tien-Jyun Chang

Yen-Feng Chiu

Wayne H-H Sheu

Kuang-Chung Shih

Chii-Min Hwu

Thomas Quertermous

Yuh-Shan Jou

Shan-Shan Kuo

Yi-Cheng Chang

Lee-Ming Chuang

Affiliations

Soon will be listed here.

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.

Citing Articles

Single-Cell Transcriptomics Identifies Pituitary Gland Changes in Diet-Induced Obesity in Male Mice.

Ruggiero-Ruff R, Le B, Villa P, Lainez N, Athul S, Das P Endocrinology. 2023; 165(3).

PMID: 38146776 PMC: 10791142. DOI: 10.1210/endocr/bqad196.

Dose-dependent progression of multiple low-dose streptozotocin-induced diabetes in mice.

Bauer B, Bhattacharya S, Bloom-Saldana E, Irimia-Dominguez J, Fueger P Physiol Genomics. 2023; 55(9):381-391.

PMID: 37458461 PMC: 10642924. DOI: 10.1152/physiolgenomics.00032.2023.

Association between Genotype and the Glycemic Response to an Oral Glucose Tolerance Test: A Systematic Review.

Bayer S, Reik A, von Hesler L, Hauner H, Holzapfel C Nutrients. 2023; 15(7).

PMID: 37049537 PMC: 10096950. DOI: 10.3390/nu15071695.

Bioinformatics Analysis of Next Generation Sequencing Data Identifies Molecular Biomarkers Associated With Type 2 Diabetes Mellitus.

Alur V, Raju V, Vastrad B, Vastrad C, Kavatagimath S, Kotturshetti S Clin Med Insights Endocrinol Diabetes. 2023; 16:11795514231155635.

PMID: 36844983 PMC: 9944228. DOI: 10.1177/11795514231155635.

Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Broadaway K, Yin X, Williamson A, Parsons V, Wilson E, Moxley A Am J Hum Genet. 2023; 110(2):284-299.

PMID: 36693378 PMC: 9943750. DOI: 10.1016/j.ajhg.2023.01.002.

References

Cai G, Cole S, Freeland-Graves J, MacCluer J, Blangero J, Comuzzie A . Genome-wide scans reveal quantitative trait Loci on 8p and 13q related to insulin action and glucose metabolism: the San Antonio Family Heart Study. Diabetes. 2004; 53(5):1369-74. DOI: 10.2337/diabetes.53.5.1369. View

Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2004; 21(2):263-5. DOI: 10.1093/bioinformatics/bth457. View

Ng M, So W, Lam V, Cockram C, Bell G, Cox N . Genome-wide scan for metabolic syndrome and related quantitative traits in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. Diabetes. 2004; 53(10):2676-83. DOI: 10.2337/diabetes.53.10.2676. View

Davidson H, Rhodes C, Hutton J . Intraorganellar calcium and pH control proinsulin cleavage in the pancreatic beta cell via two distinct site-specific endopeptidases. Nature. 1988; 333(6168):93-6. DOI: 10.1038/333093a0. View

Saad M, Knowler W, Pettitt D, Nelson R, Charles M, BENNETT P . A two-step model for development of non-insulin-dependent diabetes. Am J Med. 1991; 90(2):229-35. View

Kahn S, Leonetti D, Prigeon R, Boyko E, Bergstrom R, Fujimoto W . Proinsulin as a marker for the development of NIDDM in Japanese-American men. Diabetes. 1995; 44(2):173-9. DOI: 10.2337/diab.44.2.173. View

Yoshida H, Ohagi S, Sanke T, Furuta H, Furuta M, Nanjo K . Association of the prohormone convertase 2 gene (PCSK2) on chromosome 20 with NIDDM in Japanese subjects. Diabetes. 1995; 44(4):389-93. DOI: 10.2337/diab.44.4.389. View

Naggert J, Fricker L, Varlamov O, Nishina P, Rouille Y, Steiner D . Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet. 1995; 10(2):135-42. DOI: 10.1038/ng0695-135. View

Furuta M, Yano H, Zhou A, Rouille Y, Holst J, Carroll R . Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci U S A. 1997; 94(13):6646-51. PMC: 21212. DOI: 10.1073/pnas.94.13.6646. View

10.

Jackson R, Creemers J, Ohagi S, Raffin-Sanson M, Sanders L, Montague C . Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997; 16(3):303-6. DOI: 10.1038/ng0797-303. View

11.

Pratley R, Thompson D, Prochazka M, Baier L, Mott D, Ravussin E . An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest. 1998; 101(8):1757-64. PMC: 508758. DOI: 10.1172/JCI1850. View

12.

Gerich J . The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998; 19(4):491-503. DOI: 10.1210/edrv.19.4.0338. View

13.

Wareham N, Byrne C, Williams R, Day N, Hales C . Fasting proinsulin concentrations predict the development of type 2 diabetes. Diabetes Care. 1999; 22(2):262-70. DOI: 10.2337/diacare.22.2.262. View

14.

Thorisson G, Lancaster O, Free R, Hastings R, Sarmah P, Dash D . HGVbaseG2P: a central genetic association database. Nucleic Acids Res. 2008; 37(Database issue):D797-802. PMC: 2686551. DOI: 10.1093/nar/gkn748. View

15.

Li Y, Willer C, Sanna S, Abecasis G . Genotype imputation. Annu Rev Genomics Hum Genet. 2009; 10:387-406. PMC: 2925172. DOI: 10.1146/annurev.genom.9.081307.164242. View

16.

Chiu Y, Chuang L, Hsiao C, Hung Y, Lin M, Chen Y . An autosomal genome-wide scan for loci linked to pre-diabetic phenotypes in nondiabetic Chinese subjects from the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Family Study. Diabetes. 2005; 54(4):1200-6. DOI: 10.2337/diabetes.54.4.1200. View

17.

An P, Freedman B, Hanis C, Chen Y, Weder A, Schork N . Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. Diabetes. 2005; 54(3):909-14. DOI: 10.2337/diabetes.54.3.909. View

18.

Voight B, Scott L, Steinthorsdottir V, Morris A, Dina C, Welch R . Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010; 42(7):579-89. PMC: 3080658. DOI: 10.1038/ng.609. View

19.

Freedman B, Rich S, Sale M, Heiss G, Djousse L, Pankow J . Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families. Diabetologia. 2005; 48(4):661-8. DOI: 10.1007/s00125-005-1679-5. View

20.

Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V . Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet. 2005; 37(8):863-7. PMC: 2000804. DOI: 10.1038/ng1604. View