|(C;C)||3||higher frequency of atrial fibrillation|
rs3903239 (1q23) is a SNP discovered 46kb upstream of the PRRX1 gene (1). Recent work has shown PRRX1 is a transcriptional co-activator that enhances the DNA affinity of serum response factor (2). This protein, in turn, regulates numerous growth and differentiation factors, including muscle creatine kinase (MCK) (2). MCK controls growth and development genes, specifically in developing mesodermal muscle such as the heart (2).
PrrX1-/- mice are embryonic lethal and have a significantly altered neonatal phenotype including microcephaly, cleft palate, and hypoplastic processes of the mandible (3). Other studies have shown this gene is involved in lung vascular development and skeletogenesis (4).
A meta-analysis GWA study correlated rs3903239 with atrial fibrillation (p = 9.1x10^-11, discovery phase) in a European cohort (1). Although many studies have identified loci associated with atrial fibrillation, much of the heritability remains unclear. In individuals with “lone” atrial fibrillation (atrial fibrillation with no obvious cause), only 10% of the heritability can be explained (5). Atrial fibrillation is particularly critical for clinical applications as the presence of a heart murmur can increase an individual’s risk of stroke up to five times that of normal (6).
In [PMID 22544366] Ellinor et al investigated a cohort of individuals (European ancestry) composed of 6,707 people with confirmed atrial fibrillation and 52,426 without (1). Six novel SNPs, including rs3903239, were discovered, and several previously known SNPs confirmed.
These results were validated in a cohort composed of 5,381 European individuals with atrial fibrillation and 10,030 individuals without (1). rs3903239 had a p-value of 2x10^-4 and a risk frequency of 1.13 in this second cohort. Overall, the meta-analysis and validation yielded a p-value of 8.4x10^-14 and a risk frequency of 1.14.
Drawbacks to this meta-study are the wide range of ages included and the high prevalence of potentially correlated atrial fibrillation-based traits, such as hypertension, relative body mass index, and diabetes. Thus, SNPs discovered could correlate to these secondary traits rather than the primary issue of atrial fibrillation. The authors attempt to address this by noting none of the variants associated with atrial fibrillation were “strongly associated” with systolic dysfunction in a second cohort of 12,000 European individuals (p<1x10^-5) (1).
This SNP did not meet standard GWAS thresholds for a Japanese cohort composed of 843 individuals with atrial fibrillation and 3,350 without (1). However, there was atrial fibrillation-association of an alternative SNP near PRRX1. This SNP, rs593479 (minor allele T, major C), had an associated p-value of 2.4x10^-3 and an odds ratio of 1.21 (1). This may be the result of linkage disequilibrium between rs3903239 and PRRX1, although deep sequencing would be required for confirmation.
Currently, knowledge of the rare allele variant of either of these SNPs is not being using for treatment of atrial fibrillation symptoms or as a diagnosis for atrial fibrillation.
1. Ellinor, P.T., et al., Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nature Genetics, 2012. Advance Online Publication.[PMID 22544366]
2. GeneCards.org. "Paired Related Homeobox 1". [cited 2012 May 17]; Available from: http://www.genecards.org/cgi-bin/carddisp.pl?gene=PRRX1.
3. Martin, J.F., Bradley, A., Olson, E.N. (1995) Thepaired-like homeo box gene MHox is required for early event of skeletogenesis in multiple lineages. Genes & Development. 9:1237–1249. [PMID 7758948]
4. Ihida-Stansbury, K., et al., Paired-related homeobox gene Prx1 is required for pulmonary vascular development. Circulation research, 2004. 94(11): p. 1507-1514. [PMID 15117820]
5. Parvez,B., and Darbar, D., The “missing” link in atrial fibrillation heritability. Journal of Electrocardiology, 2011. 44(6): p. 641-644. [PMID 21924735]
6. Controllable Risk Factors – Atrial Fibrillation. 2012 [cited 2012 June 5]. Available from: http://www.stroke.org/site/PageServer?pagename=afib.
[PMID 25196315] The rs3807989 G/A Polymorphism in CAV1 is Associated with the Risk of Atrial Fibrillation in Chinese Han Populations
[PMID 29624624] Genetic modulation of atrial fibrillation risk in a Hispanic/Latino cohort.