Abstract 1966: Additional Independent Susceptibility Markers for Atrial Fibrillation on Chromosome 4q25
Background: We sought to define the genetic architecture at chromosome 4q25 as it relates to atrial fibrillation (AF) and test the feasibility of a multimarker risk-score for AF based on SNPs from the region.
Methods and results: 34 haplotype tagging SNPs spanning 200 kilobases at the 4q25 locus were genotyped in 790 cases and 1,177 controls from Massachusetts General Hospital (MGH) and tested for association with AF. Associated SNPs were genotyped in 2,145 cases and 4,073 controls from the German Competence Network for Atrial Fibrillation (AFNET). Results were meta-analyzed. SNPs representing independent signals were tested in silico for association with incident AF in 7,927 individuals from the Atherosclerosis Risk in Communities (ARIC) study, 743 of who developed AF. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele OR 1.80, 95%CI 1.50 –2.15, P = 1.2 ×10 –20) in the discovery sample. Adjusting for rs2200733 genotype in the MGH and AFNET samples revealed two additional and independent susceptibility signals marked by rs17570669 (minor allele OR 0.65, 95%CI 0.56 – 0.75, P = 1.3×10 – 8) and rs3853445 (minor allele OR 0.80, 95%CI 0.73– 0.87 P = 7.8×10 –7). Independent validation of these SNPs as a multimarker risk-score in ARIC identified individuals at increased risk for developing AF relative to those with common genotypes, with the greatest risk occurring in 0.7% of individuals in ARIC (HR 4.26, 95%CI 2.53–7.17, P = 4.9×10 – 8, Figure⇓).
Conclusions: In addition to the signal tagged by rs2200733, we identified two novel AF susceptibility signals on chromosome 4q25. The biological basis for these associations requires further investigation.