Lipoprotein Lipase D9N Research Articles

Associations between LPL gene polymorphisms and coronary artery disease: evidence based on an updated and cumulative meta-analysis.

Lipoprotein lipase (LPL) is widely linked to lipid and lipoprotein metabolism, but its effects on coronary artery disease (CAD) are not clearly elucidated. The aim of the present study was to clarify the association between LPL gene polymorphisms and CAD susceptibility. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of the relationship between LPL gene polymorphisms and CAD risk. Comprehensive electronic databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library, were systematically searched. A total of 45 records containing 80 eligible studies were analyzed. The results indicated an increased risk between the LPL D9N polymorphism and susceptibility to CAD in the dominant genetic model (AA + GA vs. GG: OR = 1.46, 95% CI = 1.14–1.87), whereas the LPL HindIII polymorphism showed a protective effect against CAD under all tested models (GG + GT vs. TT: OR = 0.85, 95% CI = 0.75–0.97; GG vs. TT + TG: OR = 0.62, 95% CI = 0.47–0.83; G vs. T: OR = 0.81, 95% CI = 0.71–0.92). No significant association was identified for the LPL N291S and PvuII polymorphisms. Stratification analysis by ethnicity suggested a significant correlation between the LPL S447X polymorphism and CAD susceptibility in Caucasians under the dominant and allele genetic models. In summary, our meta-analysis indicated that the LPL D9N polymorphism was associated with an increased risk of CAD, whereas the S447X and HindIII polymorphisms showed protective effects. There was no association observed between the N291S and PvuII polymorphisms and CAD risk.

Diagnostic value of post-heparin lipase testing in detecting common genetic variants in the LPL and LIPC genes

Post-heparin lipoprotein lipase and hepatic lipase activities are used to identify primary disorders of triglyceride and HDL-cholesterol metabolism. Their ability to identify common variants in the lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes is unclear. To investigate the ability of lipase testing to detect common lipase gene variants, we included 183 patients who had undergone post-heparin lipase testing and genotyped the LPL D9N, N291S, PvuII, HindIII, and S447X and the LIPC-514CT, V73M, V133V, and N193S polymorphisms. Allele frequencies were compared with 163 controls. Polymorphisms with different allele frequencies in patients and controls or influencing lipids, were analyzed further. The diagnostic value of post-heparin lipase testing was assessed using logistic regression and receiver operating characteristic curves. We found that lipase activities did not predict the LPL D9N and N291S polymorphisms, but predicted the LPL S447X and LIPC-514CT polymorphisms. Adjusted for covariates, the area under the receiver operating characteristic curves was 0.643, 0.478, 0.686, and 0.657 for LPL D9N, N291S S447X and LIPC-514CT, respectively. On the basis of these findings, we conclude that high-LPL and low-HL activities associate with the LPL S447X and LIPC-514CT polymorphisms, but low-LPL activity was not related to LPL polymorphisms. Overall, the discriminative ability of post-heparin lipase tests in identifying carriers of common variants in the LPL and LIPC genes was limited. This indicates that conclusions on the genetic causes of lipase activities outside of the normal range should be drawn with caution.

Subsets of SNPs define rare genotype classes that predict ischemic heart disease

Single nucleotide polymorphisms (SNPs) are hypothesized to explain the genetic predisposition to ischemic heart disease (IHD) in the general population. Lack of evidence for a role of such variation is fostering pessimism about the utility of genetic information in the practice of medicine. In this study we determined the utility of exonic and 5' SNPs in apolipoprotein E (APOE) and lipoprotein lipase (LPL) when considered singly and in combination for predicting incidence of IHD in 8,456 individuals from the general population during 24 years of follow-up. In men, LPL D9N improved prediction of IHD (P = 0.03) beyond smoking, diabetes and hypertension. The group of men heterozygous and homozygous for the rare D9N variant had a hazard ratio (HR) of 1.69 (95% confidence interval = 1.10-2.58) relative to the most common genotype. Pairwise combinations of D9N with -219G > T in APOE and N291S and S447X in LPL significantly improved the prediction of IHD (P = 0.05 in women, P = 0.04 in men, P = 0.03 in men, respectively) beyond smoking, diabetes and hypertension, and identified subgroups of individuals (n = 6-94) with highly significant HRs of 1.92-4.35. These results were validated in a case-control study (n = 8,806). In conclusion, we present evidence that combinations of SNPs in APOE and LPL identify subgroups of individuals at substantially increased risk of IHD beyond that associated with smoking, diabetes and hypertension.

Lipoprotein lipase D9N, N291S and S447X polymorphisms: their influence on premature coronary heart disease and plasma lipids

Lipoprotein lipase (LPL) plays a pivotal role in lipoprotein metabolism. Three recently described exonic polymorphisms of the gene, D9N, N291S and S447X, have been variably found to influence plasma lipids while effects on coronary heart disease (CHD) are less well documented. Two predominantly Caucasian groups were studied: CHD patients <50 years of age, with angiographically documented CHD; and a randomly recruited community control group without a history of heart disease. The 9N allele of the D9N polymorphism was present in 25 of 428 (5.8%) of Caucasian males with CHD and in seven of 291 (2.4%) of corresponding community subjects (odds ratio, 2.5; 95% confidence interval (CI), 1.1–5.9; P=0.03) and was also significantly over-represented in the Caucasian males with myocardial infarction (MI) (21 of 308 or 6.8%; odds ratio, 2.6; 95% CI, 1.1–5.9; P=0.01). The distributions of the other two polymorphisms were similar in the CHD and community groups. In multivariate models adjusted for age, sex, diabetes, body mass index, smoking, lipid levels and race, the D9N polymorphism remained significantly related to both CHD and MI, with an odds ratio >2. There were, generally, trends to more adverse fasting plasma high-density lipoprotein (HDL) cholesterol and triglycerides in carriers of the 291S and 9N alleles, and the opposite trends for triglycerides in 447X carriers. In the community group, male carriers of 291S ( n=13) had significantly (20%) lower HDL cholesterol than corresponding non-carriers ( n=323), 0.98±0.07 mmol/l (mean±S.E.) versus 1.22±0.02 mmol/l ( P<0.005), while HDL cholesterol was not different in male carriers ( n=8) and non-carriers ( n=296) of 9N (1.23±0.13 mmol/l versus 1.22±0.02 mmol/l). Multivariate analysis confirmed that the 291S allele carrier status conferred a significantly lower HDL cholesterol ( P=0.001) and the 447X allele lower triglyceride ( P<0.01) in the community group. In conclusion, LPL 9N carrier status was unequivocally related to premature CHD and to MI in males, strongly supporting recent results in older aged males. The somewhat different effects of the D9N and N291S polymorphisms on plasma lipids, and the absence of a clear effect of the N291S on CHD, raise the possibility that the effect of 9N carrier status might be mediated through effects on LPL function in addition to those influencing fasting plasma lipids.

Parental history of myocardial infarction: lipid traits, gene polymorphisms and lifestyle

To investigate the relationship between parental history of myocardial infarction (MI), lipid traits and gene polymorphisms involved in lipid metabolism, we examined Dutch men and women, who were selected from a large population-based study. Subjects whose father ( n=112), mother ( n=115) or both parents ( n=115) suffered from a premature MI presented with significantly higher apolipoprotein B (apo B) levels than subjects without a parental history ( n=114). Genetic analyses revealed that the apo E4 isoform and the D9N mutation of lipoprotein lipase (LPL) were more frequent among subjects with a parental history ( P≤0.05). A similar trend was found for the LPL N291S mutation. In contrast, the LPL S447X mutation and polymorphisms at the cholesteryl ester transfer protein (TaqIB) and apo CIII (SstI) loci proved to be noninformative. Body mass index and lifestyle could not explain differences in apo B levels between parental history groups. In contrast, the apo E polymorphism and the LPL D9N mutation accounted for some, but not all, of the higher apo B levels in subjects with a parental history. Therefore, other genetic or lifestyle-related factors must be responsible for the increased levels of apo B in individuals with a family history of myocardial infarction.

The common mutations in the lipoprotein lipase gene in Italy: effects on plasma lipids and angiographically assessed coronary atherosclerosis.

The present study evaluated the role of the common lipoprotein lipase (LPL) mutations on the risk of dyslipidemia and coronary atherosclerosis in an Italian population. Cohorts of 632 patients undergoing coronary angiography, as well as 191 healthy controls, were screened by a combination of PCR and restriction enzyme digestion. In the pooled population, the frequencies of LPL D9N and N291S were 4.1%, with no homozygous carriers, whereas that of LPL S447X was 21% with 19.6% heterozygous and 1.4% homozygous carriers. Compared to non-carriers, LPL N291S carriers showed higher plasma triglycerides (TG) (p < 0.03) and increased risk of high TG phenotype (odds ratio [OR] 2.49, 95% Cl 1.06-5.81; p < 0.03). When this LPL mutation was associated with high body mass index (BMI) ( > 25 Kg/m2) or fasting, plasma insulin (> 10.6 mU ml(-1)) significantly reduced HDL-C levels were also observed. Carriers of the S447X mutation presented with higher HDL-C concentrations (p < 0.05) as compared to non-carriers; they also showed a significantly reduced risk of high TG/low HDL-C dyslipidemia (OR 0.34, 95%, Cl 0.12-0.99; p < 0.05). The favourable effect of the LPL S447X variant was even more pronounced in lean subjects and in those with low insulin levels. No significant influence on plasma lipids by the LPL D9N was observed. None of LPL variants was a significant predictor of angiographically assessed coronary atherosclerosis. At most, the risk was borderline, increased in N291S carriers and possibly decreased in S447X carriers.

Functional variants in the lipoprotein lipase gene and risk cardiovascular disease.

The current report is a quantitative review of the relationship between lipoprotein lipase gene variants and cardiovascular disease based on published population-based studies. Sixteen studies, representing 17,630 individuals, report allelic distribution for lipoprotein lipase gene variants among patients and control individuals. Patient outcomes included clinical cardiovascular disease events, documented coronary disease based on angiography, or intimal media thickening by B-mode ultrasonography. Mantel-Haenszel stratified analysis was used to compute a summary odds ratio and 95% confidence intervals for the association between rare allele in the lipoprotein lipase gene and disease status. Because of potential differing effects associated with different lipoprotein lipase variants, each lipoprotein lipase mutant allele was considered separately. The lipoprotein lipase D9N/-93G to T allele has a summary odds ratio of 2.03 (95% confidence interval 1.30-3.18), indicating a twofold increase in risk of coronary disease for carriers with this allelic variant. The summary odds ratio for the relationship of the rare lipoprotein lipase G188E variant with cardiovascular disease is 5.25 (95% confidence interval 1.54-24.29). The lipoprotein lipase N291S allele is associated with a marginal increase in cardiovascular disease (summary odds ratio 1.25, 95% confidence interval 0.99-1.60, P = 0.07). However, there is stronger evidence for a positive association in certain populations. The summary odds ratio for lipoprotein lipase S447X allele is 0.81 (95% confidence interval 0.65-1.0), which indicates a cardioprotective effect of this lipoprotein lipase gene variant. Thus, lipoprotein lipase gene variants are associated with differential susceptibility to cardiovascular disease.

Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia.

The role of the lipoprotein lipase (LPL) gene in familial combined hyperlipidaemia (FCH) is unclear at present. We screened a group of 28 probands with familial combined hyperlipidaemia and a group of 91 population controls for two LPL gene mutations, D9N and N291S. LPL-D9N was found in two probands and one normolipidaemic population control. LPL-N291S was found in four probands and four population controls. Subsequently, two pedigrees from probands with the D9N mutation and two pedigrees from probands with the N291S mutation were studied, representing a total of 24 subjects. Both LPL gene mutations were associated with a significant effect on plasma lipids and apolipoproteins. Presence of the D9N mutation (n = 7) was associated with hypertriglyceridaemia [2.69 +/- 1.43 (SD) mmol L-1] and reduced plasma high-density lipoprotein cholesterol (HDL-C) concentrations (0.92 +/- 0.21 mmol L-1) compared with 11 non-carriers (triglyceride 1.75 +/- 0.64 mmol L-1; HDL-C 1.23 +/- 0.30 mmol L-1, P = 0.03 and P = 0.025 respectively). LPL-D9N carriers had higher diastolic blood pressures than non-carriers. LPL-N291S carriers (n = 6) showed significantly higher (26%) apo B plasma concentrations (174 +/- 26 mg dL-1) than non-carriers (138 +/- 26 mg dL-1; P = 0.023), with normal post-heparin plasma LPL activities. Linkage analysis revealed no significant relationship between the D9N or N291S LPL gene mutations and the FCH phenotype (hypertriglyceridaemia, hypercholesterolaemia or increased apo B concentrations). It is concluded that the LPL gene did not represent the major single gene causing familial combined hyperlipidaemia in the four pedigrees studied, but that the LPL-D9N and LPL-N291S mutations had significant additional effects on lipid and apolipoprotein phenotype.