Independent susceptibility markers for atrial fibrillation on chromosome 4q25

Abstract

Background: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.

Methods and results: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.

Conclusions: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

Figure 1. Regional plot of SNPs associated with prevalent AF in the MGH discovery sample

Panel A displays the associations between SNPs included in the analysis and AF in the MGH sample, adjusted for age, sex and hypertension. Panel B displays the associations after additional adjustment for rs2200733 genotype, with the rs2200733 position corresponding to the unadjusted association significance level. SNPs are plotted according to their genomic position (NCBI Build 36) and –log₁₀ P value for the association. The intensity of shading for each SNP corresponds to the strength of linkage disequilibrium (r²) relative to rs2200733. Estimated recombination rates are shown by the blue line. PITX2 is indicated by the dark green arrow. LD and recombination rates are based on the CEU HapMap release 22. SNPs that were associated with AF after adjusting for rs2200733 genotype and meta-analyzing results from both the MGH and AFNET samples are labeled. Figures were prepared using SNAP.

Figure 2. SNPs associated with AF after adjusting for rs2200733 genotype

SNPs associated with AF after adjusting for rs2200733 genotype in the MGH discovery sample were tested for association in the replication samples. The meta-analyzed effects are plotted according to prevalent (odds ratio), incident (hazard ratio), or pooled (relative risk) analysis status. Associations are adjusted for age, sex, and hypertension (MGH, AFNET, ARIC, CHS, RS) or sex only (CCAF). Samples with prevalent AF included MGH, AFNET, CHS, CCAF, and RS. Samples with incident AF included ARIC, CHS, and RS.

Figure 3. Multimarker risk score for AF based on combined rs2200733, rs17570669, and rs3853445 genotypes

The meta-analyzed relative risk of AF for each multimarker combination of rs2200733, rs17570669, and rs3853445 genotypes relative to the most common multimarker combination are shown. Only multimarker combinations with an average sample frequency of ≥ 0.2% are displayed, though the effects are adjusted for all potential combinations, as well as age, sex, and hypertension, or sex only (CCAF). Individuals with incomplete genotypes were not included. Risk alleles for AF were the minor T allele for rs2200733, the major A allele for rs17570669, and the major T allele for rs3853445.