S447X variant of the lipoprotein lipase gene, lipids, and risk of coronary heart disease in 3 prospective cohort studies

Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
American heart journal (Impact Factor: 4.46). 03/2009; 157(2):384-90. DOI: 10.1016/j.ahj.2008.10.008
Source: PubMed


Lipoprotein lipase (LPL) has a prominent role in the metabolism of triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C) and is a potential interesting target for the development of antiatherogenic treatment. To provide deeper insight into the role of natural variation in this gene, we investigated the association between the LPL S447X variant with lipids and risk of coronary heart disease (CHD) in 3 independent, prospective studies.
The S447X variant was genotyped in case-control studies of incident CHD nested within the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Danish Diet, Cancer and Health (DCH) study, totaling 245, 258, and 962 cases, respectively.
S447X carriers tended to have lower TG and higher HDL-C concentrations than noncarriers. The S447X variant was associated with a lower risk of CHD in the NHS; the association was weaker in the HPFS and not statistically significant in the DCH women and men. The pooled relative risk per minor allele was 0.74 (0.56-1.00). There was a suggestion that the associations of the S447X variant with plasma lipids and CHD risk were more pronounced in obese individuals in the NHS study, but this finding was not consistent across the studies.
The LPL S447X variant tended to be associated with lower TG and higher HDL-C levels, and lower risk of CHD in all 3 cohorts. Lipoprotein lipase is an attractive target for clinical intervention, but studies are needed to clarify whether greater benefit from this variant may be conferred in some subgroups.

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    • "Total missense, and nonsense mutations lead to type I hyperlipoproteinemia characterized by the accumulation of chylomicrons in the circulation [8]. The validity of our findings is emphazied by previous associations of the S447X variant with a number of lipid parameters [6,9,10], and also the presence of the MetS [10], and associations with peak LDL particle size [11]. However, this is the first study, to our knowledge, to associate variants with a pattern of particle sizes created using information from all three fractions of lipoprotein, which associates with the highest IR within the MetS. "
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    • "It permits us to use one large, randomly selected comparison group as comparison group for several nested studies within the Diet, Cancer and Health cohort, saving resources and valuable DNA, and the obtained risk estimates can be related directly to the cohort, which is population-based. We have previously used the same design in other studies of colorectal cancer [17,19,20,39,51], lung cancer [52-55], and coronary heart disease [56-59]. "
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    • "A case-cohort study was designed using incident ACS, which includes unstable angina pectoris, fatal and non-fatal myocardial infarction as the outcome [14,15]. Information on the disease endpoint was obtained by linkage with central Danish registries via the unique identification number assigned to all Danish citizens. "
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