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, MD, PhD; Børge G. Nordestgaard, MD, DMSc; Maria C. A. Stene, MSc, PhD; Amar A. Sethi, MD, PhD; Alan T. Remaley, MD, PhD; Peter Schnohr, MD; Peer Grande, MD, DMSc; Anne Tybjærg-Hansen, MD, DMSc
JAMA. 2008;299(21):2524-2532.
Context Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear.
Objective To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD).
Design, Setting, and Participants Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31 241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16 623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007.
Main Outcome Measures Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype.
Results Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41 961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62).
Conclusion Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.
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Study Questions Drugmakers' Hunt for `Good' Cholesterol Booster
By Shannon Pettypiece
June 4 (Bloomberg) -- Researchers are raising doubts about a theory drugmakers have spent more than $1 billion pursuing after a study showed so-called good cholesterol didn't reduce the risk of heart attacks.
People with a genetic condition that causes them to produce very low levels of HDL cholesterol were no more likely to have a heart attack than those with normal levels, according to a study in the Journal of the American Medical Association. Previous studies showed HDL cholesterol helped ferry artery-clogging plaque from the body, leading researchers to expect these patients with low levels of the beneficial cholesterol to have twice the risk of a heart attack.
Pfizer Inc., Merck & Co. and Roche Holdings AG have spent years developing drugs that increase production of HDL cholesterol. The new research throws that strategy into question and shows HDL plays no role in preventing heart attacks, said Anne Tybjaerg-Hansen, a study author and clinical biochemistry researcher at Copenhagen University Hospital.
``There is really no evidence that this method is going to work,'' said Tybjaerg-Hansen in a telephone interview. ``This theory has been around for a long time, but this study just doesn't support it.''
The reason may be that other HDL cholesterol research examined patients with high levels of triglycerides, the chemical form of fat. Triglycerides, not patients' low HDL levels, may have caused their increased heart risk, Tybjaerg-Hansen said.
Why Pfizer Flopped
This may explain why the experimental drug torcetrapib, which New York-based Pfizer spent more than $1 billion developing, raised HDL levels without providing heart benefits, the study said. Analysts had expected torcetrapib would have more than $14 billion in annual sales. Pfizer quit developing it in 2006 because it increased deaths. Whitehouse Station, New Jersey- based Merck and Basel, Switzerland-based Roche also are developing drugs aimed at raising HDL levels.
Yale Mitchel, Merck vice president of cardiovascular disease research, said the study, which was small and in a rare patient population, won't persuade the company to change its plans for an HDL-raising drug given the large body of data suggesting HDL provides a benefit.
Merck has spent five years developing a drug called anacetrapib, which raises HDL by blocking the cholesterol ester transfer protein. The drug is in the third and final stage of testing necessary to gain regulatory approval.
`Too Attractive'
``The hypothesis on whether CETP inhibition is a benefit or not hasn't been tested and it is too attractive a mechanism to disregard right now,'' said Mitchel. ``We have to be careful about not over interpreting it at this point. There is a large contextual database that suggests low HDL levels are associated with an increased risk.''
Pfizer has said the company's HDL-raising research is temporarily on hold. Roche said its drug is in the final stages of testing and it will file for U.S. regulatory approval after 2011.
``We haven't had an opportunity to evaluate this study yet, but epidemiological data does show there is a strong inverse relationship between HDL and cardiovascular risk,'' said Roche spokesman Terence Hurley.
The idea that HDL helps purge artery plaque is based mostly on animal studies, which Tybjaerg-Hansen said are sometimes difficult to understand and apply to humans.
The new study looked at data collected from almost 57,000 Danish patients between 1976 and 2007, of which 148 had a rare genetic condition called Tangier disease that caused them to produce very low levels of HDL cholesterol.
The study adjusted for age and other factors that could raise the risk of a heart attack.
To contact the reporter on this story: Shannon Pettypiece in New York at spettypiece@bloomberg.net |
