Genetic risk of atrial fibrillation. July 12, 2007

July 12, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Reykjavik, Iceland A genome-wide search has identified DNA sequences within the long arm of chromosome 4 which correlate with risk of atrial fibrillation (AF). The research, to be published in the journal Nature, marks a major advance in our understanding of the genetic determinants of AF.

Investigators screened over 300,000 single nucleotide polymorphisms (SNPs) in 550 cases of AF or atrial flutter and 4476 controls from two major Icelandic hospitals. Amazingly, only two SNPs were identified which correlated with AF. The predictive value of these SNPs was then validated in three separate case-control studies using patients from the USA, Sweden and Iceland.

In people of European descent, possession of one copy of the first SNP confers a 1.72-fold risk of AF, the second SNP a 1.39-fold risk. These polymorphisms are present in 35% and 75% of people of European or Chinese decent, respectively. Younger patients with lone AF and patients with AF with hypertension are more likely to have these SNPs; however, the association remained with all categories of AF.

It is not yet clear why possession of these genetic polymorphisms increases ones risk of AF. It is possible that these SNPs track with a certain gene or a gene regulatory region which puts one at risk for AF. Interestingly, the DNA region containing these SNPs has no known gene and only three espressed sequence tags (ESTs), short sequences of possible gene transcripts. The researchers searched various human tissues and could not find expression of any gene transcript from these regions. The nearest known gene is called PITX2. This gene is of great interest because it is known to be important for specifying heart asymmetry.

deCODE Genetics has unveiled a reference laboratory test to detect these SNPs in patients. More research will be necessary to demonstrate that knowledge of a patient’s AF risk genotype is clinically useful. Nonetheless, these findings mark a major advance in our understanding of the genetics of cardiovascular disease, and they mark a step forward towards treatment of AF tailored to an individual patient’s genetics.