Genetic analysis of over half a million people characterises C-reactive protein loci

Abstract

Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10−6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study

“…Alongside that, we performed leave one out analyses, removing individual SNPs from the analyses and re-running IVW MR. For ease, we show this for the first four outcomes only in Supplementary Figure 6 , which show the removal of any individual SNP does not alter the main results. Finally, we restricted analyses to the seven SNPs within 10kb of IL6R , ( Supplementary Table 11 ) and the rs2228145 SNP, which has a known functional effect on IL6R and downstream effects 36 ( Supplementary Figure 7, Supplementary Table 12 ). Again, these effects were all concordant with our primary results, although with reduced power as expected by removing multiple SNPs from the meta-analysis.…”

“…These variants were weighted using the same UK Biobank-CHARGE meta-analysis of high sensitivity CRP. 36…”

“…These variants were weighted using the same UK Biobank-CHARGE meta-analysis of high sensitivity CRP. 36 After weighting, we performed Two Sample Mendelian randomisation analyses using this instrument on each outcome in turn, comparing results to that generated using the cisIL6R instrument.…”

The combined impact of persistent infections and human genetic variation on C-reactive protein levels

“…Circulating amounts of CRP are positively associated with age, body mass index (BMI), and smoking and inversely with male sex and physical activity [6][7][8]. In addition, large-scale genomic analyses have found multiple associations with hs-CRP levels, mainly in the loci enriched in hepatic, immune, and metabolic pathways, such as CRP, LEPR, IL6R, GCKR, APOE, and HNF1A-AS1 [9][10][11][12][13][14]. Altogether, genetic variation explains up to 16% of the variance in plasma CRP levels [14].…”

“…In addition, large-scale genomic analyses have found multiple associations with hs-CRP levels, mainly in the loci enriched in hepatic, immune, and metabolic pathways, such as CRP, LEPR, IL6R, GCKR, APOE, and HNF1A-AS1 [9][10][11][12][13][14]. Altogether, genetic variation explains up to 16% of the variance in plasma CRP levels [14].…”