Gene locus tied to sharply raised sudden-death risk

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Gene locus tied to sharply raised sudden-death risk

Post by freckles1880 » July 11th, 2011, 4:35 pm ... _Heartwire

Gene locus tied to sharply raised sudden-death risk
July 8, 2011 | Steve Stiles
San Francisco, CA - A region of the human genome not previously associated with heart disease has been identified as the home of gene variants that may double the risk of sudden cardiac death (SCD), according to a report published June 30, 2011 in PLoS Genetics [1].
Combined analysis of five genomewide association studies (GWAS) involving people of European ancestry in the community, encompassing 1283 cases of SCD and >20 000 controls, identified the BAZ2B locus as associated with a near doubling of SCD risk: 1.92 (95% CI 1.57-2.34).
"That's a substantially increased risk, twofold per copy of the allele," lead author Dr Dan E Arking (Johns Hopkins University School of Medicine, Baltimore, MD) told heartwire. The risk doubles again, to nearly fourfold, in people with two copies of the allele.
But the allele is fairly rare, he observed, with a prevalence of only about 1.4%, attenuating its population effect.
The five studies were the Atherosclerosis Risk in Communities (ARIC), Framingham Heart Study, Finnish Genetic Study of Arrhythmic Events, Oregon Sudden Unexplained Death Study (Oregon-SUDS), and Rotterdam Study.
Having identified increased SCD risk for the BAZ2B locus in those populations, Arking et al went on to explore its influence in 11 other studies involving people of European ancestry. That analysis included 3119 SCD cases and 11 146 controls, and the results confirmed the GWAS meta-analysis.
It's hard to say whether, down the road, the discovery could contribute to a broad screening test for SCD, according to Arking. "The amount of risk that it explains is pretty small," probably not enough to make a difference to management decisions.
It might be more useful in populations with known risk factors for substantially increased SCD risk, according to Arking. "In people with long-QT syndrome or people who have had first heart attacks, the variants could play a much bigger role," identifying those who might especially benefit from implantable defibrillators or other treatments, Arking said.
The "unbiased" analysis identified only a gene region associated with SCD, not specific gene variants. But in a second part of their report, Arking et al looked into the same GWAS databases at 49 single-nucleotide polymorphisms (SNPs) seen in previous studies to have effects on ECG features linked to SCD risk, such as the QRS (reflecting ventricular depolarization), QT (depolarization/repolarization), and RR (heart rate) intervals. They then sought to determine whether those SNPs might also be markers of increased SCD risk.
The SNPs associated with prolongation of QRS and QT intervals together were associated with a significant increased risk of SCD (p=0.006), as hypothesized, "suggesting that larger GWAS of these and other intermediate risk factors may yield additional SCD loci," the group writes.
According to Arking, "Once we start finding genes that are involved in the underlying biology of SCD, it will be very useful for understanding what's really going wrong in these people and [determining whether] there are other things besides sticking in defibrillators that would help these folks at risk that are not quite as invasive."
Arking had no disclosures; disclosures for the coauthors are listed in the paper.

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