Arya Mani, MD, FACC

Associate Professor of Medicine (Cardiology) and of Genetics; Director, Cardiovascular Genetics Program

Research Organizations

Internal Medicine: Cardiovascular Medicine

Research Summary

Despite our recent advances in Cardiovascular Medicine, the cardiovascular disease remains the leading cause of death in the world. With the break through brought about by The Human Genome project, we are now in a unique position to dissect the genetic causes of cardiovascular diseases to better understand the pathways that lead to disease in human and subsequently try to find therapies tailored to the specific genetic abnormality.

My interest is to identify cardiovascular disorders that have strong familial pattern. We identify kindreds with these disorders and collect DNA samples from the extended family members to proceed with the technique of positional cloning to identify the disease-causing genes.

Thus far, I, and my colleagues have mapped and identified several gene mutation for congenital heart diseases including patent ductus arteriosus and bicuspid aortic valve. Recently my group identified a gene mutation in LRP6, a co-receptor for Wnt, in a kindred with coronary artery disease and several metabolic phenotypes. We have shown that the mutation impairs a signaling pathway known as Wnt. We have created knockin and knockout mouse models of this gene and are conducting in vivo and in vitro functional studies using human cells, in vitro transfection models, human clinical studies as well as studies on lipid and glucose metabolism in mice in collaboration with Dr. Gerald Shulman, The GCRC, and The Mouse Metabolic Phenotyping Center. We are also investigating the genetic causes of premature coronary artery disease in South Asians. South Asians suffer largely from coronary artery disease in young ages and have high risk for developing diabetes, a constellation of phenotypes commonly referred to as metabolic syndrome. Our preliminary data suggests, that we have identified at least one gene locus for this disorder. We are currently collaborating with several medical centers across the world and in India to recruit new families and individuals with premature coronary artery disease with or without metabolic syndrome to refine the mapped region and identify the gene mutation.

We use several different techniques in our laboratory, which includes positional cloning using DNA microarrays, techniques used for protein chemistry, subcloning, tissue culture, confocal microscopy, FACS, real time PCR and animal model.

Extensive Research Description

My laboratory’s major focus is the identification of genetic causes of major cardiovascular disorders and the elucidation of their pathophysiology. To achieve this, we have built strong ties at national and international levels with major cardiovascular centers. The goal is to identify and recruit patients and families with diverse cardiovascular disorders that have strong genetic components. Through collaborative efforts with physicians and scientist across the world we have recruited large populations of patients and families with early onset coronary artery disease and metabolic syndrome and have successfully mapped and identified number of genes for these diseases. An ongoing effort in the laboratory is to understand the function of these genes and how the mutations affect the phenotype.

In addition my laboratory studies the genetic studies of congenital heart disease. We have mapped and identified disease genes for syndromic and nonsyndromic, autosomal dominant and recessive patent ductus arteriosus and have identified number of novel copy number variations for the bicuspid aortic valve.

My lab has identified one of the first disease genes for early onset coronary artery disease and metabolic syndrome. The mutation (R611C) resides at a highly conserved residue of the second EGF-like domain in the LDL receptor like protein (LRP6), which encodes a co-receptor in the Wnt signaling pathway. Genotype phenotype correlation showed that the mutation impacts number of the metabolic phenotypes that are present in the affected members of the kindred. These findings have established a causal link between Wnt signaling impairment caused by LRP6 mutation and coronary artery/metabolic syndrome and raise the possibility of complex downstream effects of the mutation, which has motivated further investigation.

Having unique access to the genetic study population, we have had the opportunity to carry out clinical studies to investigate the disease mechanisms and have made numerous novel discoveries, published in top ranked journals. We have shown that Wnt signaling regulates the insulin receptor transcription and its reduced expression in human causes diabetes. We have also generated a mouse model of the disease and have shown that Wnt signaling is a nutrient sensing pathway that regulates insulin signaling, glucose metabolism and cholesterol synthesis and, lipogenesis and VLDL secretion. Through investigation of heterozygote mice with we have understood how adipose tissue and liver communicate through leptin receptors to adjust the hepatic gluconogenesis. Hyperinsulinemic clamps are used to examine the contribution of different insulin sensitive tissues to glucose homeostasis.

We have also shown that LRP6 is required for normal function of the LDLR and LDL uptake. This was the first demonstration of LRP6 as an endocytic molecule.

The most exciting development in our lab was the generation of a novel atherosclerotic mouse model. Mouse with mutant LRP6 mutation have diffuse atherosclerosis that could be recued by Wnt3a therapy. In addition we have recently identified 2 novel genes for CAD that are being currently studied for their function.

Selected Publications

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Contact Info

Arya Mani, MD, FACC
Patient Care Locations
Yale CardiologyYale Physicians Building
800 Howard Avenue, Ste 2nd floor

New Haven, CT 06519
Yale-New Haven Hospital
20 York Street

New Haven, CT 06510
Lab Location
Mani's Lab300 George Street, Ste 759
New Haven, CT 06511
Mailing Address
Internal MedicinePO Box 208056
333 Cedar Street

New Haven, CT 06520-8056

Curriculum Vitae