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Susceptibility mutations for ischemic heart disease
B G Nordestgaard1, A Tybjaerg-Hansen
1Herlev University Hospitals and The Copenhagen City Heart Study, Copenhagen, Denmark.
Insights
Genetic variations in apolipoprotein B, lipoprotein lipase, and angiotensin converting enzyme impact cholesterol and triglyceride levels, influencing ischemic heart disease risk. These genetic factors contribute to a small but significant portion of heart disease in the population.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Population Health
Background:
- Genetic polymorphisms are increasingly recognized as determinants of cardiovascular disease risk.
- Specific gene variants, including those in apolipoprotein B (APOB), lipoprotein lipase (LPL), and angiotensin converting enzyme (ACE), have been associated with lipid metabolism and cardiovascular outcomes.
- Understanding the population-level impact of these variants is crucial for public health strategies.
Purpose of the Study:
- To investigate the association between specific genetic mutations in APOB, LPL, and ACE and their impact on plasma lipid levels (cholesterol and triglycerides) and the risk of ischemic heart disease (IHD).
- To quantify the population-attributable fraction of IHD associated with these genetic variants compared to diabetes mellitus.
Main Methods:
- Analysis of genetic variants (APOB Arg3500Gln, APOB Arg3531Cys, LPL Gly188Glu, LPL Asn291Ser, LPL Asp9Asn, ACE DD) within The Copenhagen City Heart Study cohort.
- Measurement of plasma lipid levels (cholesterol and triglycerides) and angiotensin converting enzyme (ACE) activity.
- Calculation of odds ratios for IHD associated with each genotype and estimation of population-attributable fractions.
Main Results:
- APOB Arg3500Gln significantly increased plasma cholesterol by 41%, associated with a sevenfold increased IHD risk.
- LPL Gly188Glu increased plasma triglycerides by 42% (sevenfold IHD risk), LPL Asn291Ser by 13% (twofold IHD risk in women), and LPL Asp9Asn by 13% (twofold IHD risk in men).
- ACE DD increased plasma ACE activity by 57% but was not associated with increased IHD risk; diabetes mellitus conferred a threefold IHD risk and accounted for 7% of population-attributable IHD.
Conclusions:
- Specific mutations in APOB and LPL are significant risk factors for elevated plasma lipids and increase the risk of ischemic heart disease.
- While these genetic variants contribute to IHD, their overall population-attributable fraction is modest compared to conditions like diabetes mellitus.
- Genetic screening for these variants may offer insights into individual cardiovascular risk, but population-level interventions targeting major risk factors like diabetes remain paramount.
Abstract:
In The Copenhagen City Heart Study, apolipoprotein B Arg3500Gln and Arg3531Cys increased plasma cholesterol 41% and 0%, lipoprotein lipase Gly188Glu, Asn291Ser, and Asp9Asn increased plasma triglycerides 42%, 13% (women only), and 13% (men only), and angiotensin converting enzyme DD increased plasma ACE activity 57%. Risk of ischemic heart disease for these mutations was sevenfold, unchanged, fivefold, twofold (women only), twofold (men only), and unchanged, respectively, compared with threefold for diabetes mellitus. The fraction of ischemic heart disease in the population at large attributed to these mutations was 0.5%, 0%, 0.3%, 5% (women only), 3% (men only), and 0%, respectively, compared with 7% for diabetes mellitus.