Lipoprotein Receptor Mutation Linked to Increased Coronary Heart Disease Risk

A mutation caused by a single nucleotide polymorphism (SNP) in a cell membrane lipoprotein receptor has been linked to a significantly higher risk for developing coronary heart disease (CHD).

The lipoprotein receptor SR-BI (scavenger receptor class B, type I), which is encoded by the SCARB1 gene, is an integral membrane protein found in numerous cell types and tissues, including the liver and adrenal. It is best known for its role in facilitating the uptake of cholesteryl esters from high-density lipoproteins (HDL) in the liver. This process drives the movement of cholesterol from peripheral tissues towards the liver for excretion. This movement of cholesterol is known as reverse cholesterol transport and is a protective mechanism against the development of atherosclerosis, which is the principal cause of heart disease and stroke.

Investigators at the University of Connecticut (Farmington, USA) examined the association of the SCARB1 rs4238001 missense SNP with incidents of CHD. For this work incidences of CHD were identified in a population of 2,319 White, 1,570 African-American, and 1,292 Hispanic-American participants in the 2000–2002 Multi-Ethnic Study of Atherosclerosis in Major American Cities study. The association of rs4238001 with incident CHD was determined after adjustments for age, sex, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education, and smoking exposure.

Results published in the May 20, 2015, online edition of the journal PLOS ONE revealed that subjects who were carriers of the risk T allele for rs4238001 had significantly lower SR-BI protein levels as compared with carriers of the normal allele. Moreover, in vitro experiments showed that the rs4238001 variant was significantly associated with increased degradation of SR-BI protein and reduced function as measured by decreased specific cholesteryl ester uptake from HDL.

The clinical study showed that the SCARB1 missense SNP rs4238001 was statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups. In particular men with the variant had a 29% higher risk than a comparable group of men without. African-American males fared even worse, with 49% increase risk, as compared to white males.

"We want to go deep in the cell, and figure out how to repair it," said senior author Dr. Annabelle Rodriguez-Oquendo, professor of cell biology at the University of Connecticut. "We are really interested in understanding more about how this protein gets chewed up and degraded faster."

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