Title: Lipoprotein-associated phospholipase A2 activity and incident coronary heart disease among men and women with type 2 diabetes Hatoum IJ, Hu FB, Nelson JJ, Rimm EB Ref: Diabetes, 59:1239, 2010 : PubMed
OBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been shown to be associated with increased risk of coronary heart disease (CHD) in general adult populations. Because men and women with type 2 diabetes are at particularly high risk for CHD, the aim of this study was to assess the association of Lp-PLA(2) with future coronary events among diabetic men and women. RESEARCH DESIGN AND METHODS: We measured Lp-PLA(2) activity among 740 men and 777 women with confirmed diabetes enrolled in the Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS). Participants were free of all cardiovascular disease and cancer at baseline. RESULTS: During 10 years of follow-up among men and 14 years among women, we documented 178 and 146 cases of CHD, respectively. We defined CHD as coronary artery bypass graft, angioplasty, nonfatal myocardial infarction, and fatal CHD. After adjustment for age, smoking, medical history, and biomarkers including C-reactive protein, HDL, and LDL, the relative risk of total CHD comparing extreme tertiles of Lp-PLA(2) was 1.39 (95% CI 1.01-1.90; P trend = 0.03). When we restricted analyses to only nonfatal myocardial infarction and fatal CHD, the relative risk was 1.75 (95% CI 1.05-2.92; P for trend = 0.001). LDL, HDL, C-reactive protein, hormone replacement therapy use, and diabetes duration did not modify these relationships. CONCLUSIONS: Levels of Lp-PLA(2) activity were significantly associated with incident CHD among men and women with type 2 diabetes, independent of traditional and inflammatory risk factors. This positive association was strongest for more severe clinical end points.
Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
AIMS: Endothelial lipase (LIPG) is implicated in the metabolism of high-density lipoprotein cholesterol (HDL-C). Small studies in selected populations have reported higher HDL-C levels among carriers of the common T111I variant in LIPG, but whether this variant is associated with plasma lipids and risk of coronary heart disease (CHD) in the general population is unclear. The objective of this study was to address the associations of the T111I variant with plasma lipids and risk of CHD in three independent prospective studies of generally healthy men and women. METHODS AND RESULTS: The T111I variant was genotyped in case-control studies of CHD nested within the Diet, Cancer, and Health study with 998 cases, Nurses' Health Study with 241 cases, and Health Professionals Follow-up Study with 262 cases. The minor allele frequency in the combined pool of controls was 0.29. The T111I variant was not associated with HDL-C or any other lipid and lipoprotein measures. Compared with wildtype homozygotes, the pooled estimate for risk of CHD was 0.95 (0.85-1.06) per T111I allele. CONCLUSION: Our analysis among healthy Caucasian men and women from three independent studies does not support an association between the T111I variant and HDL-C, other plasma lipids, or risk of CHD.
Title: Interactions between the -514C->T polymorphism of the hepatic lipase gene and lifestyle factors in relation to HDL concentrations among US diabetic men Zhang C, Lopez-Ridaura R, Rimm EB, Rifai N, Hunter DJ, Hu FB Ref: Am J Clin Nutr, 81:1429, 2005 : PubMed
BACKGROUND: Low plasma HDL-cholesterol concentrations are a hallmark of diabetic dyslipidemia. A common polymorphism (-514C-->T) of the hepatic lipase gene (LIPC), which accounts for up to 30% of the variation in hepatic lipase activity, has been associated with low hepatic lipase activity and high HDL-cholesterol concentrations. OBJECTIVE: We examined the association between this polymorphism and plasma HDL-cholesterol concentrations and evaluated whether this association was modified by adiposity and dietary fat intake. DESIGN: We followed men aged 40-75 y who participated in the Health Professionals Follow-Up Study in 1986. Among 18 159 men who returned blood samples by 1994, 780 had confirmed type 2 diabetes at blood drawing or during follow-up to 1998 and were free of cardiovascular disease at blood drawing. RESULTS: After adjustment for age, smoking, alcohol consumption, fasting status, glycated hemoglobin concentration, physical activity, and body mass index, HDL-cholesterol concentrations were significantly higher in men with the C/T or T/T genotype than in those with the C/C genotype (adjusted x: 40.9 and 38.8 mg/dL, respectively; P = 0.01). We observed significant LIPC -514 polymorphism x body mass index and LIPC -514 polymorphism x saturated fat intake interactions for HDL-cholesterol concentrations (P = 0.003 for both). The T allele was associated with higher HDL-cholesterol concentrations only in men who were not overweight or who had higher saturated fat intake. CONCLUSION: Our study suggests that the effects of -514C-->T of the LIPC gene on HDL concentrations were modified by saturated fat intake and obesity.
