New variants including ARG1 polymorphisms associated with C-reactive protein levels identified by genome-wide association and pathway analysis

Nadimuthu Vinayagamoorthy; Hae-Jin Hu; Seon-Hee Yim; Seung-Hyun Jung; Jaeseong Jo; Sun Ha Jee; Yeun-Jun Chung

doi:10.1371/journal.pone.0095866

New variants including ARG1 polymorphisms associated with C-reactive protein levels identified by genome-wide association and pathway analysis

PLoS One. 2014 Apr 24;9(4):e95866. doi: 10.1371/journal.pone.0095866. eCollection 2014.

Authors

Nadimuthu Vinayagamoorthy¹, Hae-Jin Hu¹, Seon-Hee Yim², Seung-Hyun Jung¹, Jaeseong Jo³, Sun Ha Jee³, Yeun-Jun Chung¹

Affiliations

¹ Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, College of Medicine, Seoul, Korea; Department of Microbiology, The Catholic University of Korea, College of Medicine, Seoul, Korea.
² Integrated Research Center for Genome Polymorphism, The Catholic University of Korea, College of Medicine, Seoul, Korea; Department of Medical Education, The Catholic University of Korea, College of Medicine, Seoul, Korea.
³ Institute of Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.

Abstract

C-reactive protein (CRP) is a general marker of systemic inflammation and cardiovascular disease (CVD). The genetic contribution to differences in CRP levels remains to be explained, especially in non-European populations. Thus, the aim of this study was to identify genetic loci associated with CRP levels in Korean population. We performed genome-wide association studies (GWAS) using SNPs from 8,529 Korean individuals (7,626 for stage 1 and 903 for stage 2). We also performed pathway analysis. We identified a new genetic locus associated with CRP levels upstream of ARG1 gene (top significant SNP: rs9375813, Pmeta = 2.85×10(-8)), which encodes a key enzyme of the urea cycle counteract the effects of nitric oxide, in addition to known CRP (rs7553007, Pmeta = 1.72×10(-16)) and HNF1A loci (rs2259816, Pmeta = 2.90×10(-10)). When we evaluated the associations between the CRP-related SNPs with cardiovascular disease phenotypes, rs9375813 (ARG1) showed a marginal association with hypertension (P = 0.0440). To identify more variants and pathways, we performed pathway analysis and identified six candidate pathways comprised of genes related to inflammatory processes and CVDs (CRP, HNF1A, PCSK6, CD36, and ABCA1). In addition to the previously reported loci (CRP, HNF1A, and IL6) in diverse ethnic groups, we identified novel variants in the ARG1 locus associated with CRP levels in Korean population and a number of interesting genes related to inflammatory processes and CVD through pathway analysis.

Publication types

Meta-Analysis

MeSH terms

Arginase / genetics*
C-Reactive Protein / metabolism*
Cardiovascular Diseases / blood
Cardiovascular Diseases / genetics*
Gene Regulatory Networks
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inflammation / genetics
Linkage Disequilibrium
Phenotype
Polymorphism, Single Nucleotide*
Republic of Korea

Substances

C-Reactive Protein
Arginase

Grants and funding

This study was supported by a grant from the Korea Healthcare Technology R&D Project (A092258), MRC (2012047939), and NRF grant funded by the Korean government (MEST) (2011-0029348), Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.