New variants including ARG1 polymorphisms associated with C-reactive protein levels identified by genome-wide association and pathway analysis.
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.
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.
Nadimuthu
N
Vinayagamoorthy
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.
Hae-Jin
HJ
Hu
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.
Seon-Hee
SH
Yim
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.
Seung-Hyun
SH
Jung
Institute of Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
Jaeseong
J
Jo
Institute of Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
Sun Ha
SH
Jee
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.
Yeun-Jun
YJ
Chung
D001119:Arginase / Q000235:genetics*; D002097:C-Reactive Protein / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015810:Linkage Disequilibrium; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea
D002097:C-Reactive Protein; D001119:Arginase