CVRI Investigator

 

Mary J. Malloy M.D.
Senate Emeritus
CVRI Emeritus Investigator
Website
mary.malloy at ucsf.edu

Research Interests:
Molecular mechanisms in lipoprotein metabolism; genetic basis of metabolic disorders of lipoproteins and of arteriosclerosis

Program Areas
Prediction and Prevention of Cardiovascular Disease
Metabolism, Obesity, and Metabolic Disease
Research Summary
The longitudinal focus of my research has been the elucidation of previously unknown disorders of lipid metabolism and transport. In addition to their clinical importance, they are highly informative with respect to metabolic pathways. The first of these was normotriglyceridemic abetalipoproteinemia, a disorder characterized by absence of low density lipoproteins. Unlike classical abetalipoproteinemia, triglyceride-rich lipoproteins are preserved. Investigation of the molecular basis of this disorder revealed a truncation of the apo B protein, elucidating domain-specific functional activities. This was followed by the discovery of mutations in apo C-II, C-III, and A-I that were then linked to clinical and biochemical phenotypes. Subsequently, we discovered cholesterol 7-alpha hydroxylase deficiency, that proved to have a complex and informative phenotype linking metabolic control of hepatic lipid metabolism with bile acids. It is estimated that at least 100,000 Americans carry one allele for this disorder. More recently, we have been exploring the role of apo A-V in triglyceride metabolism and have reported a polymorphism found in North Asians that is associated with marked elevations in plasma triglyceride levels. We have just reported another disorder, LMF-1 deficiency, that presents a unique clinical and biochemical phenotype. It involves simultaneous deficiency of hepatic and lipoprotein lipases. This was linked to a third locus that would be predicted to be a chaperone. The clinical phenotype included recurrent acute pancreatitis and coronary arteriosclerosis, and probably involves the pathophysiology of the endoplasmic reticulum stress syndrome attributable to the accumulation of misfolded lipase proteins in liver. The discovery of this disorder has opened a broad collaboration with the UCSF Department of Biochemistry and with UCLA to find other targets for the chaperone, including a phospholipase now associated with platelets.

The discovery of informative genetic disorders and genome-wide studies of coronary disease and stroke have depended heavily on our development of a large, deeply annotated collection of human DNA and plasma samples, The Genomic Resource In Arteriosclerosis and Metabolic Disease. I am Co-Director of the Resource and have had a major role in its assembly. This collection now includes > 26,000 specimens and provides the basis for collaboration between our group and investigators in Europe and the United States. Through my role in the Genomic Resource, I have participated in a number of allele-association and genome-wide studies that have resulted in the discovery of about 20 gene loci associated with risk of coronary artery disease or atherothrombic stroke. Several of the associations we have discovered are emerging as useful guides in clinical practice. As Co-Director of the UCSF Adult Lipid Clinic and Director of the Pediatric Lipid Clinic, I am actively translating advances in the understanding of lipid transport and metabolism into improved regimens for management of dyslipidemias and for prevention of coronary and cerebral atherosclerosis.
 
Publications