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.

Full-text preview

Available from:
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), ~75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P < .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328). Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04). This was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.
    Full-text · Article · Aug 2011 · Lipids in Health and Disease
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transcription factors and nuclear receptors constitute a link between exposure to heterocyclic amines and polycyclic aromatic hydrocarbons from meat and tobacco smoke and colorectal cancer (CRC) risk. The aim of this study was to investigate if polymorphisms in nuclear factor kappa-B, pregnane X receptor, and liver X receptor were associated with risk of CRC, and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. The polymorphisms nuclear factor kappa-B (NFkB, NFKB1) -94 insertion/deletion ATTG (rs28362491), pregnane X receptor (PXR, NR1I2) A-24381C (rs1523127), C8055T (rs2276707), A7635G (rs6785049), liver X receptor (LXR-β, NR1H3) C-rs1405655T, T-rs2695121C were assessed together with lifestyle factors in a nested case-cohort study of 378 CRC cases and 756 random participants from the Danish prospective Diet, Cancer and Health study of 57,053 persons. Carriers of NFkB -94deletion were at 1.45-fold higher risk of CRC than homozygous carriers of the insertion allele (incidence rate ratio (IRR) = 1.45, 95% confidence interval (95% CI): 1.10-1.92). There was interaction between this polymorphism and intake of red and processed meat in relation to CRC risk. Carriers of NFkB -94deletion were at 3% increased risk pr 25 gram meat per day (95% CI: 0.98-1.09) whereas homozygous carriers of the insertion were not at increased risk (p for interaction = 0.03). PXR and LXR polymorphisms were not associated with CRC risk. There was no interaction between use of nonsteroid antiinflammatory drugs (NSAID) or smoking status and NFkB, PXR or LXR polymorphisms. A polymorphism in NFkB was associated with CRC risk and there was interaction between this polymorphism and meat intake in relation to CRC risk. This study suggests a role for NFkB in CRC aetiology.
    Full-text · Article · Sep 2010 · BMC Cancer
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the western world. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of the energy balance, adipocyte differentiation and lipid biosynthesis. The aim was to investigate if the polymorphism PPARgamma2 Pro12Ala, which encodes a less efficient transcription factor, was associated with risk of acute coronary disease and if there were interactions between this polymorphism and factors that modify PPARgamma activity, such as alcohol intake, smoking, and use of non-steroidal anti-inflammatory medicine. A case-cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals. Homozygous male variant allele carriers of PPARgamma2 Pro12Ala were at higher risk of ACS (HR = 2.12, 95% CI: 1.00-4.48) than homozygous carriers of the Pro-allele. Among men, there was a statistically significant interaction between genotypes and alcohol intake such that homozygous variant allele carriers with a low alcohol intake were at higher risk of ACS (HR = 25.3, CI: 16.5-38.7) compared to homozygous common allele carriers (p for interaction < 0.0001). Overall, the association was only observed among homozygous variant allele carriers. Thus, all the observed associations were obtained in subgroups including small numbers of cases. It is therefore possible that the observed associations were due to chance. In the present study, there were no consistent associations between PPARgamma Pro12Ala and risk of ACS, and no consistent interaction with alcohol, BMI, NSAID or smoking in relation to ACS.
    Full-text · Article · Jun 2009 · BMC Medical Genetics
Show more