rs6817105

Atrial Fibrillation (rs6817105) The rs6817105 single nucleotide polymorphism (SNP) is 150 kb upstream of the PITX2 gene and has been strongly associated with hereditary risk of atrial fibrillation. Atrial fibrillation is an irregularity of heart rate resulting in, shortness of breath, heart rate palpations and poor blood flow, which results in strokes, heart failure and death (PMID 16908781). The irregularity is a result of the hearts upper chambers (atria) beating at an irregular pace compared to the lower two chambers (ventricles) of the heart (Mayo clinic). Atrial fibrillation is a major public health concern as risk increases with age, particularly after the age of 60. According to the CDC, Atrial fibrillation affects one in every 10 individuals over the age of 80. Atrial fibrillation is predicted to affect 6-12 million people in the USA by 2050 and 17.9 million in Europe by 2060 (PMID 25960110). However the causal mutation that increases risk of atrial fibrillation has not been fully elucidated. A potential candidate causal mutation associated with atrial fibrillation is PITX2, paired-like homeodomain transcription factor 2, a bicoid-related homeodomain transcription factor that is located in the 4q25 locus and plays important roles in embryonic development (OMIM). The PITX2 gene is important in developing the left–right symmetry of the heart. PITX2 loss of function mutations in mice resulted in severe defects in heart. (PMID 12732450) Additionally PITX2 was found to be associated with atrial fibrillation in a meta-analysis of multiple well phenotyped GWAS studies of atrial fibrillation in 2015 by Ellinor et al. The study involved six cohorts of patients from European ancestry to identify genetic variants that are associated with heritability and risk of atrial fibrillation. Genomic sequence analysis included 6,707 patients with Atrial fibrillation and 52,426 patients without atrial fibrillation. The study identified 10 loci that exceeded the studies threshold for genome-wide significance (P-value < 5 x 10-8). The study identified three previously known genes. The most significantly associated loci was at previously identified atrial fibrillation susceptibility loci on chromosomes 4q25 near PITX2 (rs6817105; P = 1.8 × 10−74 ; odds ratio = 1.64). The rs6817105 SNP has a minor allele of C and major allele of T with Minor allele frequency being 13.1%. Replicate studies of six newly identified Atrial fibrillation loci were done in additional patients European ancestry, 5,381 with and 10,030 patients without Atrial fibrillation. Four of the six loci identified in Europeans were replicated in silico in GWAS of patients of Japanese ancestry, 843 patients with and 3,350 patients without Atrial Fibrillation The six novel susceptibility loci in or near plausible genes associated with atrial fibrillation are implicated in the regulation of the heart development through transcription factors, ion channel and cell signaling molecules, which may help explain the heritability of atrial fibrillation. However, further biological studies are warranted to verify the newly identified loci associated with atrial fibrillation. (PMID 22544366)