Abstract 2299: TNFα-M-Ras-LFA-1 Pathway Analysis of Genome-wide SNP Data in Patients of the German Mi Family Studies
TNFα-M-Ras-LFA-1 pathway analysis of genome-wide SNP data in myocardial infarction patients BACKGROUND: Recently, we identified the MRAS gene as a new risk gene for CAD/MI (rs9818870 P=7.44 × 10−13 (OR=1.15; 95% CI=1.11–1.19) through genome-wide association study (GWAS). However, GWAS typically focus on single-locus analysis only, which may not have the power to detect the majority of genuinely associated loci.
AIM: To perform a MRAS gene based pathway analysis (TNFα-M-Ras-LFA-1 pathway) using Affymetrix genotype data from the German MI Family Studies (GerMIFS I, GerMIFS II, and GERMIFS III (KORA)) comprising a total of 3,500 MI cases and 4,500 population-based controls.
METHODS: Identification of relevant genes was undertaken by means of medical literature [pubmed] and internet databases [Ensembl, SNPper]. Available SNPs were investigated in silico in three independent genome-wide SNP data sets genotyped on different Affymetrix platforms; missing genotypes were subsequently imputed (GerMIFS I [875 MI cases, 1644 controls], GerMIFS II [1221 MI cases, 1298 controls] and GerMIFS III (KORA) [1359 MI cases, 1883 controls]).
RESULTS: Thirteen genes were identified in TNFα-M-Ras-LFA-1 pathway. Among them, 6 genes encoding for ICAM-1, ITGB2, Rap1A, RAPL, RIAM, and TNFRSF1B carried several SNPs significantly associated with CAD/MI in all three GWAS and multiple SNPs significantly associated with MI in at least two of the three GWAS. Four additional genes encoding for ITGAL, TNFα, TNFRSF1A and, as anticipated MRAS, carried several SNPs significantly associated with CAD/MI in at least two of the three GWAS. In ICAM-1 17/70 SNPs, in ITGAL 7/47 SNPs, in ITGB2 25/147 SNPs, in MRAS 43/91 SNPs, in Rap1A 29/276 SNPs, in RAPL 30/194 SNPs, in RIAM 16/228 SNPs, TNFα 13/140 SNPs, in TNFRSF1A 7/56 SNPs and in TNFRSF1B 12/91 SNPs were significant in at least two GWAS for CAD/MI. P-Values ranged from 2.1 × 10−8 to 0.049.
CONCLUSIONS: Several SNPs in genes of the TNFα-M-Ras-LFA-1 pathway revealed highly significant results for CAD/MI in at least two of the three GWAS. However, further replication steps are needed to further establish the role of these SNPs in the etiology of CAD/MI.