Genetic analysis of hsCRP in American Indians: The Strong Heart Family Study

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.

Genetic Variant rs1205 is Associated with COVID-19 Outcomes: The Strong Heart Study and Strong Heart Family Study

“…[26] Additionally, reduced expression of serum CRP is consistently reported associated with the rs1205 T allele, with the beta coefficient for each additional T allele ranging between -0.17 and -0.27; [25,28,29] and estimated at -0.23 in the SHS Dakota center. [50] As noted in Table S2 the mean serum CRP level is lower in the present study, among those with the rs1205 T-Dom genotype compared with those homozygous for the C allele, although the difference is not significant.…”

“…While our study has a modest number of cases, these results derive from a large cohort of American Indian individuals who are being followed longitudinally using standardized, physician review of medical records [4] The rs1205 variant has been recognized as functionally affecting serum levels of CRP, [25,28,29] in several populations and, in the present SHFS population as well. [50] CRP is an important component of the innate immune system, thus supporting a role of the gene and this variant's potential effects on the pathophysiology of COVID-19. A genome-wide association meta-analysis has reported an intron variant (rs67579710) associated with COVID-19 hospitalization among 24,741cases and 2,835,201controls.…”

“…Further details related to quality filters and data preparation have been published. [50] The SHS participants were genotyped using the Illumina Infinium Multi-Ethnic…”

Differences in epidemiology of patients with preeclampsia between China and the US (Review)

“…Best et al ( 31 ) reported on the association between severe PE in a population of American Indians of Asian descent and a 3'UTR functional variant of the C-reactive protein (CRP) gene. They also indicated that the CRP variants rs876538 and rs3093068 were associated with PE in American Indians, additionally confirming a potential activity of CRP in PE ( 32 ).…”

Interaction of polygenetic variants related to inflammation with carbohydrate and vitamin D intakes in middle-aged and older adults in a large hospital-based cohort

“…Genetic factors can affect serum CRP concentrations. In the Strong Heart Family Study, the genetic variants at the CRP, hepatocyte nuclear factor-1 alpha and other loci exhibited nominal associations with increased serum CRP concentrations (10) . The genetic variants related to immune response, including IL10 , CRP , glutathione S-transferase P-1 , IL1B and nitric oxide synthase-2 , are associated with prostate cancer recurrence independent of its prognostic factors.…”