Multiancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture Using Genomics and Epidemiology Study

Abstract

Background C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP. Methods and Results We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40,473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected p<3.1×10−3 for replication, p<2.0×10−4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (p=2.0×10−6) and rs646776 (p=3.1×10−5). Conclusions We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and LDL cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups, and of looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

Coronary artery disease-associated genetic variants and biomarkers of inflammation

“…However, our findings are consistent with results from several previous large population-based cohort studies. In these studies, the same inverse relationship between the CAD risk allele and lower levels of hs-CRP has also been observed in European Americans [21], Australian twin families [22], Asians [23], and Hispanics [21] but not Afro-Americans [21]. Our work extends these findings by demonstrating an association in patients with established CAD.…”

Vascular inflammation and low‐density lipoproteins: is cholesterol the link? A lesson from the clinical trials

“…More recently, cholesterol has been directly linked to inflammation via the activation of the NLRP3 inflammasome (Grebe and Latz, ), which might favour the instauration and amplification of a local and systemic immuno‐inflammatory response (Tabas and Bornfeldt, ), characterized by the production of several pro‐inflammatory cytokines; among them, C‐reactive protein (CRP), IL‐6 and IL‐1 are well‐established markers of inflammation and their possible causal role in atherosclerosis has been widely investigated (Ridker, ). In addition, among genetic traits associated with LDL‐C levels, single nucleotide polymorphisms (SNPs) in the CELSR2/PSRC1/SORT1 locus and in the APOE/APOC1/TOMM40 locus have been associated also with inflammatory‐related phenotypes (Kocarnik et al , ), which further supports the strong relationship between cholesterol and inflammation.…”

Combined Effects of Single Nucleotide Polymorphisms (SNPs) within C-reactive Protein (CRP) and Environmental Parameters on Risk and Prognosis for Diabetic Foot Osteomyelitis Patients

“…Based on genome-wide association studies (GWASs) relevant to CRP [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38], the SNPs that could affect serum level of CRP were selected and included in this investigation. We also included SNPs with a confirmed association with inflammatory disorders [39][40][41][42][43]. Finally, rs11265260, rs1205, rs12093699, rs1800947, rs2794520, rs1341665, rs3093059, rs3093068, rs3122012, rs7553007, and rs1130864 were assessed in this study.…”