Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Abstract

Background C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We aimed to identify genetic variants that are associated with CRP levels. Methods and Results We performed a genome wide association (GWA) analysis of CRP in 66,185 participants from 15 population-based studies. We sought replication for the genome wide significant and suggestive loci in a replication panel comprising 16,540 individuals from ten independent studies. We found 18 genome-wide significant loci and we provided evidence of replication for eight of them. Our results confirm seven previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2), immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1), or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found significant interaction of body mass index (BMI) with LEPR (p<2.9×10−6). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximately 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusion We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

Immunochip Identifies Novel, and Replicates Known, Genetic Risk Loci for Rheumatoid Arthritis in Black South Africans

“…Although none of these SNPs have been associated with RA in other studies, rs2522056 has been associated with Crohn's disease (42), an increase in acute phase response (43) and fibrinogen levels and, therefore, can be considered a risk factor for cardiovascular disease (44). The TRAF3IP2 gene has been associated with the risk of developing psoriasis (45) and psoriatic arthritis (46); ICOS, with alopecia areata; KIAA1542, with the presence of anti-dsDNA antibody postivity in systemic lupus erythematosus (47), with the function of the intergenic region between KIAA1919 and REV3L being unknown.…”

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

“…This was not unexpected as there is no evidence that CRP expression is regulated directly by HNF4A. Interestingly, a recent GWAS reported that common alleles near HNF4A were associated with CRP levels in healthy individuals; the small effect seen might be mediated indirectly via the regulation of HNF1A by HNF4A [19]. It is a challenging task to discriminate between patients with HNF1A-MODY and those with HNF4A-MODY by clinical presentation alone [20].…”

Genetic Architecture of the Pro-Inflammatory State in an Extended Twin-Family Design

“…Large-scale collaborative attempts to find actual genes that underlie this genetic variation are underway. In 2011, a meta-analysis of genome-wide association (GWA) studies of CRP in over 80,000 subjects identified several genes implicated in the functioning and inflammation of immune system (CRP,IL6R,NLRP3,IL1F10,IRF1,PPP1R3B,SALL1,PABPC4,ASCL1,RORA,and BCL7B) and the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) to be associated with circulating CRP levels (Dehghan et al, 2011). In a meta-analysis of six GWA studies on fibrinogen in over 22,000 subjects, significant genome-wide hits were found in the FGB, IRF1, PCCB, and NLRP3 genes (Dehghan et al, 2009).…”