Thrombospondin Gene Variants Associated With familial Premature CAD

Multiple novel variants in the thrombospondin gene family appear to be associated with familial premature coronary artery disease, investigators report in a rapid communication in the November 27th issue of Circulation.

Dr. Eric J. Topol of the Cleveland Clinic Foundation and associates enrolled a total of 352 cases. Enrollment required myocardial infarction, coronary revascularization, or a significant coronary artery lesion diagnosed before age 45 years in men or 50 years in women and at least one affected sibling.

Using high-throughput genomics technology, the investigators compared the genotypes of the cases with those of 418 control subjects. They found that variants in three related members of the thrombospondin protein family were associated with premature CAD, primarily myocardial infarction.

Dr. Topol’s group notes that thrombospondins are present in atherosclerotic plaque and that these matrix glycoproteins modulate vascular injury, coagulation and angiogenesis.

“The coincidence of finding an association with three distinct single-nucleotide polymorphisms in thrombospondin family members and the functional correlation of low plasma levels with the highest risk genotype for thrombospondin-1 strengthens the hypothesis of a potential biological link between thrombospondin variation and early-onset CAD,” the investigators write.

In expanding on his group’s findings, Dr. Topol told Reuters Health, “One variant in thrombospondin-1 led to a 10-fold increased risk of heart attack. A patient homozygous for this variant had already had a couple of heart attacks. We found that his platelets were very hyperactive. This suggests that for similar patients, we may want to consider aspirin early in life and even a second anti-platelet medication.”

“Other proteins encoded by these variants have different functions,” he added. “For example, they may line blood vessels or be present in endothelial cells or myocytes.”

“Every week new genetic information is reported for cancer or neural science, Alzheimer’s disease or Parkinson’s,” Dr. Topol said. “It’s about time that we gain some important insight into one of the most common causes of death in human beings.”