JAMA paper describes research on loss-of-function mutations in ABCA1, which decreases HDL but not plasma triglycerides or certain lipoproteins.
Lower levels of HDL cholesterol due to a gene mutation are not associated with an elevated risk of ischemic heart disease (IHD) unlike previously thought, according to a group of researchers.
“The principal finding of this study is that heterozygosity for loss-of-function mutations in ABCA1 associated with substantial, lifelong lowering of plasma levels of HDL cholesterol, but not with corresponding higher levels of plasma triglycerides or atherogenic remnant lipoproteins, did not predict an increased risk of IHD,” the authors write in the June 4 issue of the Journal of the American Medical Association.
Despite the implications from earlier studies, whether HDL cholesterol is a primary factor in the development of IHD is not clear, the scientists note. This is partly because of other factors related to low HDL cholesterol levels, such as plasma triglycerides, which may contribute independently to increases in cardiovascular events.
“Studies of genetic disorders that lower HDL cholesterol without increases in plasma triglycerides and remnant lipoproteins provide an ideal system in which to assess the consequences of isolated, lifelong low HDL cholesterol levels,” the investigators note.
Ruth Frikke-Schmidt, M.D., Ph.D., of the University of Copenhagen, Denmark, and colleagues examined mutations in the gene ABCA1, which genetically reduces HDL cholesterol levels but does not increase plasma triglyceride levels. Three studies were used: the Copenhagen City Heart Study (CCHS), a 31-year general population study, the Copenhagen General Population Study (CGPS), and the the Copenhagen Ischemic Heart Disease Study (CIHDS). These studies covered a total of 56,886 people with 148 heterozygotes. Data from these studies were collected during January 1976 to July 2007.
The researchers found that heterozygotes versus noncarriers for four ABCA1 mutations, P1065S, G1216V, N1800H, and R2144X, had HDL cholesterol levels of 41 mg/dL versus 58 mg/dL. A 17 mg/dL lower HDL cholesterol level in the CCHS was associated with a 70% higher risk for IHD. For IHD in heterozygotes versus noncarriers, however, the risk was 33% lower in the CCHS, 18% lower in the CGPS, and 14% lower in the CIHDS.
“These statements seemingly contradict each other, but that’s the whole point of the paper,” points out Anne Tybjærg-Hansen, M.D., chief physician and associate professor at the department of clinical biochemistry, University of Copenhagen. “The 17 mg/dL decrease in HDL cholesterol in the population at large predicts a 70% increase in risk of IHD. However, the low HDL cholesterol is most often found in individuals with high triglycerides and atherogenic remnant lipoproteins, which likely drives this association, rather than the low HDL cholesterol in itself.
“In contrast, we looked at people with genetically isolated low HDL cholesterol without elevated triglycerides and remnant lipoproteins, and these individuals do not have the predicted increased risk of IHD, but rather a trend (33% lower) towards lower risk of IHD. This suggests that low HDL cholesterol in itself is not causally related to risk of IHD.”
