Ischemic Heart Disease Not Associated With Low HDL Levels From Gene Variation

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Main Category: Heart Disease
Also Included In: Genetics;  Cholesterol
Article Date: 03 Jun 2008 - 13:00 PDT

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A paper published in the June 4 issue of JAMA has shown that patients who have lower levels of high-density lipoprotein (HDL) cholesterol due to a gene mutation do not have an increased risk of ischemic heart disease.

Low plasma levels of HDL - also known as the "good" cholesterol - have been linked to an increased risk of ischemic heart disease (IHD) in several previous studies. It is unclear, however, if HDL cholesterol is a primary factor in the development of the disease that starves the heart muscle of blood. This is because there are several other factors (such as plasma triglycerides) that are related to low HDL cholesterol levels, and these factors may have independent contributions to the occurrence of cardiovascular events. The authors note that, "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 study, conducted by Ruth Frikke-Schmidt, M.D., Ph.D. (University of Copenhagen, Denmark) and colleagues, analyzed mutations in the gene ABCA1 to see if they were associated with an increased risk of IHD. These gene mutations was selected because they genetically reduce HDL cholesterol levels but do not increase plasma triglyceride levels, thus removing the confounding factor in previous studies. The researchers analyzed data from three studies out of Copenhagen that contained heterozygotes - or persons who have two different forms of a gene, where one is inherited from each parent:

1. Copenhagen City Heart Study (CCHS), a 31-year general population study with 9,022 participants and 28 heterozygotes
2. Copenhagen General Population Study (CGPS), with 31,241 participants and 76 heterozygotes
3. Copenhagen Ischemic Heart Disease Study (CIHDS), with 16,623 participants and 44 heterozygotes

The researchers collected data from January 1976 through July 2007 pertaining to HDL cholesterol levels and other information that could aid in examining the association between IHD and HDL cholesterol and genotype.

Results indicated that in four ABCA1 mutations (P1065S, G1216V, N1800H, R2144X), heterozygotes had HDL levels of 41 mg/dL and noncarriers had HDL levels of 58 mg/dL, a reduction of 17 mg/dL for carriers. In the CCHS, a 17 mg/dL lower HDL cholesterol level was linked to a 70% higher risk of IHD. However, the researchers found that heterozygotes had a 33% lower risk of IHD than noncarriers in the CCHS, an 18% lower risk in the CGPS, and a 14% lower risk in the CIHDS. Combining the studies allowed an analysis of 41,961 participants, 6,666 cases of IHD, and 109 heterozygotes, and the researchers were unable to find a statistical association between heterozygotes and a higher risk of IHD.

The authors conclude that, "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 [capable of producing a type of plaque in arteries] remnant lipoproteins, did not predict an increased risk of IHD."

Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease
Ruth Frikke-Schmidt; Børge G. Nordestgaard; Maria C. A. Stene; Amar A. Sethi; Alan T. Remaley; Peter Schnohr; Peer Grande; Anne Tybjærg-Hansen
JAMA (2008). 299[21]:2524-2532.
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Written by: Peter M Crosta
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