Researchers have found a genetic variant on chromosome 5 that strongly raises the risk of congenital heart disease.
Although congenital heart disease represents the most common major birth defect, scientists have not previously identified the genes that give rise to it. Now genetics and cardiology researchers have discovered it.
"This gene, ISL1, plays a key role in regulating early cardiac development, so there is a compelling biological reason for investigating it as a genetic risk factor for CHD," said study leader Peter J. Gruber, M.D., Ph.D., a cardiothoracic surgeon and developmental biologist at The Children's Hospital of Philadelphia. Gruber collaborated with his brother, Stephen B. Gruber, M.D., Ph.D., a geneticist and epidemiologist at the University of Michigan Medical School.
The study appeared online today in the journal PLoS ONE.
CHD ranges widely in severity, from tiny holes between heart chambers that close naturally, to life-threatening abnormal structures such as hypoplastic left-heart syndrome that require a series of complicated surgeries.
CHD can affect a variety of different structures in the heart, but the researchers decided to focus on the earliest period of the organ's development. "Instead of assuming separate genes would govern each specific defect, we formed the hypothesis that a common gene variant operates early in the biological pathway of heart formation, thus affecting multiple subtypes of congenital heart disease," said Peter Gruber.
In Peter Gruber's previous research in human cardiac stem cells, he found that a gene called ISL1 was crucial in regulating the development of early cardiac progenitor cells. Suspecting that ISL1 was a likely candidate gene involved in human CHD, he designed a study in collaboration with two genetics teams, one in Philadelphia, the other in Michigan.
At the Children's Hospital of Philadelphia, he worked with Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics, one of the world's largest centers for pediatric genotyping.
Gruber collected DNA samples from 300 children with CHD at the hospital's comprehensive Cardiac Center, and from 2,200 healthy children at the Center for Applied Genomics. Hakonarson's team did the initial genotyping-looking for gene variants (mutations) in the DNA of genes in or near the ISL1 gene. When combined with results from the genetics team at the University of Michigan, the researchers found eight of these alternative spellings in DNA bases (single-nucleotide polymorphisms, or SNPs) raised the risk of CHD.
Stephen Gruber and colleagues at the University of Michigan performed second-stage studies on the initial data, analyzing specific DNA sequences and performing "fine mapping" research-focusing in sharper detail on the gene regions of interest. "It was challenging to analyze how genetic variation contributes to complex congenital heart disease," Stephen Gruber said. "We combined expertise in cardiology, epidemiology, genetics and developmental biology that led to an interesting discovery."
Adding DNA from medical programs in Canada and the Netherlands to the U.S. samples, the researchers studied genes from a total of 1,344 children with CHD and 6,135 healthy controls, and confirmed in replication studies that variants in the ISL1 gene had strong associations with CHD. Within that gene, they found that one SNP raised the risk for white children, and a different SNP increased the risk for African American children.