Abstract 3397: The Common E298D-Variant of the Endothelial Nitric Oxide Synthase is Associated with Atrial Fibrillation in a Large Linkage-Disequilibrium Based Approach
INTRODUCTION: Atrial fibrillation (AF), the most common arrhythmia in man with a 1% prevalence in the general population, is a cause of high morbidity and mortality. Evidence for genetic susceptibility is increasing. In a candidate gene approach we screened the gene coding for endothelial nitric oxide synthase (eNOS, NM 000603) for single nucleotide polymorphisms (SNPs) associated with AF. This gene has been shown to be potentially involved in the pathophysiology of AF via altering calcium channel function or angiotensin-converting-enzyme regulation. PATIENTS and
METHODS: In a first approach we genotyped 657 patients with and 672 individuals without AF for the common E298D-variant (rs1799983) using TaqMan assays. In a second step we performed a linkage disequilibrium-based (LD) systematic analysis of haplotype-tagging SNPs and of all non-synonymous coding SNPs within a 40kb genomic region around the eNOS-gene. A total of 11 SNPs was studied using Sequenom MALDI-TOF technique (rs2373962, rs2373961, rs1799983, rs3918227, rs7792133, rs3918232, rs3918201, rs743507, rs3918234, rs6947833, rs2373929). For the second step the control population was replaced with 702 population-based recruited individuals from the KORA-study.
RESULTS: First-step results revealed no significant association of the tested polymorphism taking into account the entire study population (odds ratio (OR) 1.15, p=0.094). However previously defined substrata of individuals of age 60 or below and female participants, respectively, showed significant association of the E298D-variant with the disease (OR 1.41, p=0.029 and OR 1.38, p=0.030, respectively). The LD-based analysis indicated that also in a multi-SNP-analysis the strongest effect is found with the E298D-variant. In addition, with a bias-free, population-based control group the effect reached significance also in the unstratified sample (OR 1.23, p=0.015).
CONCLUSION: Our results suggest the E298D-variant of the eNOS-gene to be associated with AF. A systematic analysis of the genomic region showed no other SNPs in this area to be associated with AF stronger than the E298D-variant. To our knowledge this is the first LD-based SNP-association study exploring AF in a large sample size. Replication study is ongoing.