Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association

ObjectiveThe goal of this project was to identify genetic variants associated with abdominal aortic aneurysms (AAAs).MethodsA genome wide association study was carried out using pooled DNA samples from 123 AAA cases and 112 controls matched for age, gender, and smoking history using Affymetrix 500K single nucleotide polymorphism (SNP) arrays (Affymetrix, Inc, Santa Clara, Calif). The difference in mean allele frequency between cases and controls was calculated for each SNP and used to identify candidate genomic regions. Association of candidate SNPs with AAA was confirmed by individual TaqMan genotype assays in a total of 2096 cases and controls that included an independent replication sample set.ResultsA genome wide association study of AAA cases and controls identified a candidate AAA-associated haplotype on chromosome 3p12.3. By individual genotype analysis, four SNPs in this region were significantly associated with AAA in cases and controls from the original study population. One SNP in this region (rs7635818) was genotyped in a total of 502 cases and 736 controls from the original study population (P = .017) and 448 cases and 410 controls from an independent replication sample (P = .013; combined P value = .0028; combined odds ratio [OR] = 1.33). An even stronger association with AAA was observed in a subset of smokers (391 cases, 241 controls, P = .00041, OR = 1.80), which represent the highest risk group for AAA. The AAA-associated haplotype is located ∼200 kbp upstream of the CNTN3 gene transcription start site.ConclusionThis study identifies a region on chromosome 3 that is significantly associated with AAA in 2 distinct study populations.

Clinical RelevanceGenotype data can be used to identify individuals at increased genetic risk for AAA. Ultimately this genetic information may lead to improved diagnosis and better understanding of the pathophysiology of AAAs.