Abstract
BackgroundIncreased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations.MethodsThe Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses.ResultsCRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10−20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10−7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10−4.ConclusionIn agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.
Highlights
Immune and inflammatory factors have longstanding roles in microbial infection [1,2] and auto-immune disorders [3]; it is becoming increasingly clear that they influence the pathogenesis and complications of metabolic conditions [4], cancer [5] and other chronic diseases [6]
No individual single nucleotide polymorphisms (SNP) were found associated with C-reactive protein (CRP) levels after Bonferroni adjustment for multiple testing, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci
In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups
Summary
Immune and inflammatory factors have longstanding roles in microbial infection [1,2] and auto-immune disorders [3]; it is becoming increasingly clear that they influence the pathogenesis and complications of metabolic conditions [4], cancer [5] and other chronic diseases [6]. Within 5 Mb of the CRP gene, variants of IL6R were shown to be independently associated to CRP levels [19] Another chromosome (chr) 1 locus encompassing the LEPR/JAK1 genes (which play a key role in immune response pathways [23]) has several SNPs associated with serum CRP [21,24]. Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations
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