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Abstract
Genome-wide association studies (GWAS) have identified genetic variants in nine chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these associations are unknown.
To investigate these mechanisms, we mapped associations between single nucleotide polymorphisms (SNPs) and allelic expression of candidate genes in the region of interest.
Methods Whole blood was collected for DNA and RNA extraction from 447 patients at the time of cardiac catheterisation or cardiac surgery. 45 participants had a history of AF. We confirmed expression in whole blood of candidate genes at four loci; KCNN3 in 1q22, CAV1 and CAV2 in 7q31, C9orf3 and FANCC 9q22 and SYNE2 and ESR2 in 14q23 (Table).
In order to tag genetic variation at each locus, a total of 136 SNPs were genotyped using the Sequenom platform. The same platform was used to quantify the relative expression of each allele of the candidate genes using one or more transcribed SNPs. Associations between SNP genotype and allelic expression ratios were tested by phasing the genotypes and performing likelihood ratio tests.
Results 7 SNPs in a 67kb region of chromosome 7q31 were associated with CAV1 expression. The risk [G] allele of the AF-associated SNP rs3807989 was associated with a 0.91-fold decrease in expression of CAV1 (p = 4.15e-05). 5 SNPs in the same region were associated with CAV2 expression. The pattern of association between genotype and expression was different for CAV1 and CAV2 and the AF-associated SNPs were not associated with CAV2 expression. The risk [A] allele of a glaucoma-associated SNP, rs4236601, was associated with a 1.12-fold increase in expression of CAV2 (p = 3.14e-03).
24 SNPs in a 359kb region of chromosome 14q23 were associated with SYNE2 expression. The risk [T] allele of the AF-associated SNP rs1152591 was associated with a 1.12-fold increase in expression of SYNE2 (p = 4.35e-27). No SNPs in this region were associated with ESR2 expression.
The strength of association between SNP genotype and CAV1 expression at chromosome 7 and SYNE2 expression at chromosome 14 are shown in the figure. The positions of GWAS hit SNPs and candidate genes are marked.
3 SNPs in a 244kb region of chromosome 9q22 were associated with C9orf3 expression. The AF-associated SNP, rs10821415, lay within the region of association, but was not itself significantly associated with expression. No SNPs were associated with FANCC expression.
No associations were found between SNP genotype and expression of KCNN3 in chromosome 1q22.
Conclusions We have mapped cis-regulation of gene expression in peripheral blood cells at 4 loci associated with AF. We have identified associations between the risk alleles of AF-associated SNPs and decreased expression of CAV1 and increased expression of SYNE2 in blood, providing further evidence for the role of these genes in the pathophysiology of AF and highlights them as potential targets of future drug treatments.
- Atrial fibrillation
- Genetics
- Gene expression