Linkage and Association Analysis Identifies TRAF1 Influencing Common Carotid Intima-Media Thickness

Abstract

Background and Purpose - Carotid intima-media thickness is a marker for subclinical atherosclerosis that predicts subsequent clinical cardiovascular events. The aim of this study was to identify chromosomal loci with linkage or association to common carotid intima-media thickness. Methods - Nuclear families were recruited using the single parental proband sib-pair design. Genotype data were available for 546 individuals from 132 nuclear families of the Bonn IMT Family Study using the Affymetrix GeneChip Human Mapping 250K Sty chip. Multipoint logarithm of the odds (LOD) scores were determined with the quantitative trait locus statistic implemented in multipoint engine for rapid likelihood. Linkage analysis and family-based association tests were conducted. Data from 2471 German participants from the HNR (Heinz Nixdorf Recall) Study were used for subsequent replication. Results - Two new genomic regions with suggestive linkage (LOD>2) were identified on chromosome 4 (LOD=2.26) and on chromosome 17 (LOD=2.01). Previously reported linkage findings were replicated on chromosomes 13 and 14. Fifteen single nucleotide polymorhisms, located on chromosomes 4, 6, and 9, revealed P<10 -4 in the family-based association analyses. One of these signals was replicated in HNR (rs2416804, 1-sided P=1.60×10 -3, located in the gene TRAF1). Conclusions - This study presents the first genome-wide linkage and association study of common carotid intima-media thickness in the German population. Alleles of rs2416804 in TRAF1 were identified as being linked and associated with carotid intima-media thickness. Further studies are needed to evaluate the contribution of this locus to the development of atherosclerosis.