A genome-wide association study of high-sensitivity C-reactive protein in a large Korean population highlights its role in cholesterol metabolism

High-sensitivity C-reactive protein (hsCRP) is a representative biomarker of systemic inflammation and is associated with numerous complex diseases. To explore the biological pathways and functions underlying chronic inflammation, we conducted a genome-wide association study (GWAS) and several post-GWAS analyses of the hsCRP levels. This study was performed on data from 71,019 Koreans and is one of the largest East Asian studies. Overall, 69 independent single nucleotide polymorphisms (SNPs) were identified, including 12 novel variants located within SHE, RP11-740C1.2, FCRL6, STEAP1B, AC002480.5, TOMM7, SPPL3, RP11-216P16.6, RP11-209K10.2, CTC-490E21.12, CYP2F2P, CBLC, and PVRL2. The implicated genes and pathways are primarily involved in cholesterol metabolism and the immune response. A phenome-wide association study was performed based on a polygenic risk score constructed using 69 hsCRP-associated SNPs. Notably, the alleles associated with higher hsCRP levels appeared to be associated with lower low-density lipoprotein cholesterol levels (P=1.69 x 10-33, {beta}=-1.47). Our findings provide evidence of a link between hsCRP and cholesterol as well as the clinical importance of hsCRP. Specifically, we suggest that genetically determined hsCRP levels may be useful for predicting the potential risk of cardiovascular or other diseases related to lipid metabolism. Authors summaryChronic inflammation is associated with numerous complex diseases, including cancer, cardiovascular disease, and diabetes. Previous studies have shown that East Asians have lower levels of C-reactive protein (CRP), a biomarker of inflammation, than other ancestry groups. To identify East Asian-specific single nucleotide polymorphisms (SNPs) associated with chronic inflammation, we conducted a genome-wide association study and secondary genetic analyses on hsCRP in 71,019 Korean individuals. In total, 69 SNPs were identified, of which 12 were novel. A majority of the identified SNPs are located within genes (LEPR, IL6R, and APOE) that are involved in cholesterol metabolism and immune response. Notably, we found genetically determined hsCRP level may contribute to decrease cholesterol level, in contrast to previous epidemiological studies. Therefore, we suggest genetically determined hsCRP as a clinical tool for predicting the potential risk of abnormal cholesterol metabolism and its related diseases.