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Rare Mutation Causes Early Heart Disease and Metabolic Syndrome

Yale School of Medicine researchers have identified a rare defect in a single gene that poses a substantial risk for metabolic syndrome and early heart disease, the leading// cause of death worldwide.

The international study, led by Arya Mani, M.D., assistant professor of cardiology, and Richard Lifton, M.D., chair of genetics at Yale, identifies a new pathway implicated in heart disease. Even though the genetic mutation is very rare, these findings point to new approaches for improving this aspect of health.

“These findings indicate that altered activity of a well-known signaling pathway, Wnt, has large effects on multiple metabolic pathways that contribute to cardiovascular disease,” said Mani.

Coronary artery disease (CAD) is commonly caused by metabolic syndrome, which includes a constellation of risk factors such as high low-density lipoprotein (LDL) cholesterol, high triglycerides, low high-density lipoprotein (HDL) cholesterol, hypertension and diabetes.

This study was based on a large family of Iranian ancestry that had an extraordinary prevalence of early CAD. Among 58 blood relatives, 28 were diagnosed with early CAD at or before age 50 for the men, and 55 for the women. Twenty-three of the 28 died from CAD at young ages. In contrast, relatives without early CAD died at an average age of 81. The relatives with CAD had high LDL, high triglycerides, hypertension, and diabetes, while their unaffected relatives did not. The relatives with CAD also were predisposed to osteoporosis, which is particularly interesting given recent evidence of association of osteoporosis with CAD.

By comparing the inheritance of CAD to the inheritance of each chromosome segment in the pedigree, the team narrowed the location of the disease-causing gene to a short segment of chromosome 12. In this region, they found a single mutation in a gene called LRP6, which acts in the Wnt signaling pathway and which was previously kno
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