A technique called whole-exome sequencing (WES) has been used for the first time at Vanderbilt University to identify new genetic variations associated with a common disease — a heart rhythm abnormality called atrial fibrillation (AF).
Reporting last month in the European Heart Journal, the researchers demonstrated that WES can be used to identify new genes, advance understanding and possibly to improve treatment of AF, which will affect one in four people sometime in their lifetime and increases significantly the risk of stroke.
Current drugs are “at best about 50 percent effective at preventing episodes of atrial fibrillation,” said Dawood Darbar, M.D., the study’s senior author and associate professor of Medicine. “And the drugs can have serious side effects … so the pharmacologic treatment of atrial fibrillation is very unsatisfactory right now.”
Whole-exome sequencing, essentially a “read-out” of that part of the DNA that encodes proteins, was conducted in 18 individuals from six families with an inherited form of AF, and identified many rare and potentially disease-causing genetic variants.
By testing family members, the researchers narrowed down the list to two variants in calcium channel genes in one family that previously had not been linked to AF and which could help identify an important pathway modulating susceptibility to the condition, the researchers concluded.
“The biggest implication … of this finding is that we will discover new genes … (and) identify novel mechanisms for atrial fibrillation,” said Darbar, who directs the Vanderbilt Heart Center for Atrial Fibrillation. “This will hopefully then allow us to develop new treatments that target the underlying mechanisms of atrial fibrillation.”
Because AF is a disease of many mechanisms and causes, current drugs don’t work in all patients, or they cause serious side effects preventing their use.
“Right now we can’t identify which patients are likely to respond to treatment,” he said. “So I think a better understanding of mechanisms … provides us with a way to … better target or ‘personalize’ treatment for the individual patient.”
Contributing to the study were first author Peter Weeke, M.D., research fellow in Clinical Pharmacology, research nurses led by Tanya Stubblefield, R.N., who recruited families with a familial atrial fibrillation, and the National Heart, Lung and Blood Institute’s Grand Opportunity Exome Sequencing Project.
Funding was also provided by National Institutes of Health grants HL065962 and HL092217 and by an American Heart Association Established Investigator Award.
