Abstract 291: Association of Single Nucleotide Polymorphisms in Inflammatory Candidate Genes with Circulating Inflammatory Biomarker Concentrations: The Framingham Heart Study
Background: Chronic subclinical inflammation is a prominent feature of atherosclerotic disease. The genetic background for this pro-inflammatory state is not well-established. Circulating biomarker concentrations have become attractive candidates to measure disease activity and prognosis.
Methods: We examined 2356 single-nucleotide polymorphisms (SNPs) in 235 inflammatory pathway genes in association with 11 circulating inflammatory biomarkers in about 1800 Framingham Offspring cohort participants [CD40 ligand, CRP, intercellular adhesion molecule-1, interleukin-6 (IL6), urinary isoprostanes, monocyte chemoattractant protein-1 (MCP1), myeloperoxidase, P-selectin, tumor necrosis factor alpha, tumor necrosis factor receptor-2, fibrinogen]. We created residuals of log transformed biomarker concentrations adjusting for 16 potential confounders. Only SNPs with call rate ≥0.98 and HWE p>0.01, which had at least 5 minor allele carriers entered analyses. False discovery rate (FDR) and q-value methods were applied.
Results: We observed similar results with FDR and q-value methods. A total of 45 associations were significant at a cutoff q value of 0.25. The top SNPs were observed in the SELP gene in association with P-selectin concentrations (rs6136 [nonsynonymous], p= 5.17*10−39, rs3753305 [intronic], p= 6.17*10−9) and the ICAM1 gene in relation to ICAM-1 concentrations (rs1799969 [coding-nonsynonymous], p= 1.32*10−8). Lowest p-values for trans-acting SNPs were observed for APCS (rs1374486 [function unknown], p= 1.01*10−7, and rs6695377 [function unknown], p= 1.85*10−7) with MCP-1 concentrations and for IL6R (rs8192284 [coding-nonsynonimous,intronic], p= 3.36*10−5) with IL6 concentrations. In addition, we could replicate reported findings for rs1799969, and rs5498 in the ICAM-1 gene in relation to ICAM-1 concentrations as well as associations of SNPs rs2857654, rs1024611, and rs2857657 in the CCL-2 gene with MCP-1 concentrations.
Conclusions: The results of this candidate gene approach support the relevance of genetic variation for circulating inflammatory biomarker traits. Some former findings were confirmed and novel potential candidates are reported. Our findings merit replication in other cohorts.