RARE ABCA1 VARIANTS FOUND ONLY IN AFRICAN AMERICANS AND HOW THEY AFFECT LIPID EFFLUX AND NASCENT HDL FORMATION

Discovery of Tangier disease and subsequent discovery of ATP binding cassette transporter A1 (ABCA1) as the gene responsible for the disease has changed the study of lipoproteins due to almost non-existent levels of HDL-C and increased atherosclerosis in these subjects. The idea that HDL-C and atherosclerosis are inversely correlated provides evidence for the benefit of these anti-atherogenic particles. However, African Americans generally have higher HDL-C, yet are at greater risk for heart disease. Epidemiologic studies have shown that drugs which increase HDL-C do not necessarily improve measures of coronary heart disease, prompting the idea that HDL function may be more important than HDL concentration. About 10-20% of individuals with low HDL-C harbor mutations of ABCA1. Using exome sequencing, we have identified rare ABCA1 coding sequence variants present in African American populations are associated with decreased plasma HDL-C. These mutations are predicted to be damaging and are largely absent in European American populations. We predict these ABCA1 mutations will be defective in lipid efflux, nHDL formation, and result in plasma HDL with defective macrophage free cholesterol efflux potential. Our results show that these mutations are able to impact cellular cholesterol efflux, a measure of HDL function, leading us to believe that these mutations to ABCA1 do, in fact, result in functional consequences.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2017

Author dc:creator

• Martinez, John

• ABCA1

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/82208

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/82208