In 1998 Arya Mani, M.D., HS ’97, FW ’01, assistant professor of medicine (cardiology), returned to his native Iran to embark on a research project that linked modern genomics with his country’s patterns of intermarriage [See “Journey of the Heart,” Yale Medicine, Spring 2004]. Working with Richard P. Lifton, M.D., Ph.D., chair of genetics, Mani sought a genetic component to heart disease. He also believed that genetic mutations would be more prevalent in families where relatives intermarried.Although their initial research focused on patent ductus arteriosis (PDA), in March the journal Science published Mani and Lifton’s research on metabolic disease, also involving coronary and carotid arteries. They identified a rare defect in a single gene that causes metabolic syndrome—a cluster of risk factors that include high LDL cholesterol, low HDL cholesterol, high triglycerides, hypertension and diabetes—and early heart disease. The paper relied on a study of an Iranian family with high rates of coronary artery disease (CAD). Among 58 blood relatives, 28 were diagnosed with early CAD—before the age of 50 for men and 55 for women—and 23 of the 28 died at young ages. Relatives without CAD died at an average age of 81.Mani and Lifton traced the mutation to a section of chromosome 12. There they found a mutation in a gene called LRP6. One change in an amino acid altered the activity of the protein encoded by the gene, which acts in the Wnt signaling pathway, a network of proteins that is involved in development and is altered in certain malignant tumors.“The main finding is the role of Wnt signaling in development of metabolic syndrome and CAD; that is where science has to focus on now to understand the basic molecular mechanism of the disease,” Mani said.“We expect that studies of the Wnt signaling pathway in patients with early CAD and metabolic syndrome will provide new insight into the basic biology of disease causation and allow new approaches to disease prevention,” Lifton said.