Lipoprotein Lipase Gene Variants Research Articles

Uloga varijanti lipoprotein lipaze u metaboličkim poremećajima i kardiovaskularnim oboljenjima

Lipoprotein lipase (LPL) is a glycoprotein that is produced and secreted into the interstitial space in various tissues, including the cardiac muscle, adipose tissue, macrophages, and skeletal muscle. LPL activity could be affected by genetic alterations which result in changes in lipid metabolism. This review article only focuses on reporting the recent studies which mainly explain the role of the LPL gene variants in metabolic syndrome and cardiovascular diseases. There are over 100 LPL gene variants, but this review article reported rs1801177, rs118204069, rs118204057, rs118204060, rs118204068, rs268, and rs328 as the most common in metabolic syndrome patients. In cardiovascular diseases, LPL variants rs1801177, rs268 and rs328 were the most prevalent. Therefore, it is suggested that further studies should be conducted to identify the LPL gene variants in other cardiovascular diseases, including cardiac arrhythmia. This review article concludes that LPL deficiency and dysfunction are associated with many diseases, such as obesity, insulin resistance, diabetes, chylomicronemia, atherosclerosis, myocardial infarction, coronary artery disease, and stroke.

Loss-of-Function Homozygous Variant in LPL Causes Type I Hyperlipoproteinemia and Renal Lipidosis

Lipoprotein lipase (LPL) is an important enzyme in lipid metabolism, individuals with LPL gene variants could present type I hyperlipoproteinemia, lipemia retinalis, hepatosplenomegaly, and pancreatitis. To date, there are no reports of renal lipidosis induced by type I hyperlipoproteinemia due to LPL mutation. Renal biopsy was conducted to confirm the etiological factor of nephrotic syndrome in a 44-year-old Chinese man. Lipoprotein electrophoresis, apoE genotype detection, and whole-exome sequencing were performed to confirm the dyslipidemia type and genetic factor. Analysis of the 3-dimensional protein structure and invitro functional study were conducted to verify variant pathogenicity. Renal biopsy revealed numerous CD68 positive foam cells infiltrated in the glomeruli; immunoglobulin and complement staining were negative; and electron microscopy revealed numerous lipid droplets and cholesterol clefts in the cytoplasm of foam cells. Lipoprotein electrophoresis revealed that the patient fulfilled the diagnostic criteria of type I hyperlipoproteinemia. The apoE genotype of the patient was the ε3/ε3 genotype. Whole-exome sequencing revealed an LPL (c.292G > A, p.A98T) homozygous variant with α-helix instability and reduced post-heparin LPL activity but normal lipid uptake capability compared to the wild-type variant. LPL (c.292G > A, p.A98T) is a pathogenic variant that causes renal lipidosis associated with type I hyperlipoproteinemia. This study provides adequate evidence of the causal relationship between dyslipidemia and renal lesions. However, further research is needed to better understand the pathogenetic mechanism of LPL variant-related renal lesions.

The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants

Biallelic pathogenic variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome with severe hypertriglyceridemia (HTG), defined as plasma triglycerides (TG) > 10 mmol/L (> 885 mg/dL). TG levels in individuals with one copy of a pathogenic LPL gene variant is less familiar; some assume that the phenotype is intermediate between homozygotes and controls. We undertook an evaluation of the longitudinal TG phenotype of individuals heterozygous for pathogenic LPL variants. Medically stable outpatients were evaluated based on having: (1) a single copy of a rare pathogenic LPL variant; and (2) serial fasting TG measurements obtained over > 1.5 years of follow-up. Fifteen patients with a single pathogenic LPL variant were followed for a mean of 10.3 years (range 1.5 to 30.3 years). TG levels varied widely both within and between patients. One patient had normal TG levels < 2.0 mmol/L (< 175 mg/dL) continuously, while four patients had at least one normal TG level. Most patients fluctuated between mild-to-moderate and severe HTG: five patients had only mild-to-moderate HTG, with TG levels ranging from 2.0 to 9.9 mmol/L (175 to 885 mg/dL), while 6 patients had at least one instance of severe HTG. Of the 203 total TG measurements from these patients, 14.8%, 67.0% and 18.2% were in the normal, mild-to-moderate and severe HTG ranges, respectively. The heterozygous LPL deficient phenotype is highly variable both within and between patients. Heterozygosity confers susceptibility to a wide range of TG phenotypes, with severity likely depending on secondary factors.

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

BackgroundSevere hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.MethodsThe 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.ResultsThe infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.ConclusionsOur study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

Association of LPL Gene Variant and Serum LPL Level with Ischemic Stroke in Iraqi Population

Background: Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism.An increasing number of studies have suggested an association of LPL gene variants with the risk ofcardiovascular and cerebrovascular diseases.Objective: To analyze whether Hind III polymorphism of LPL gene and serum LPL level are associatedwith ischemic stroke in Iraqi population.Method: Fifty ischemic stroke patients (clinical diagnosis and x-ray CT) and fifty controls were enrolled inthis case–control study. The LPL Hind III polymorphism was determined by PCR-RFLP technique and LPLmass level was estimated using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA).Results: In the present research was not found any association between the Hindlll LPL gene polymorphismand acute ischemic stroke in the population studied; the allele and genotypic frequencies of the studiedpolymorphism was similar in cases and controls and followed the Hardy-Weinberg equilibrium. Therelationship between Hind III genotypes and the LPL mass level was analyzed using ANOVA and furtherconfirmed by Post-hoc analysis. there was no significant difference in LPL mass levels between the genotypegroups H+H+, H+H-, and H-H- (p value&gt;0.05).Conclusions: The Hind III polymorphism of LPLis not a genetic marker for the development of ischemicstroke as well as not determinants of serum LPL level in the Iraqian sample used.

The Association of a Rare Variant of -93, -53 Promoter Gene Polymorphisms of Lipoprotein Lipase Gene with Obesity and Insulin Resistance

Obesity increases the risk of numerous chronic diseases. Obesity is classified clinically using body mass index (BMI), waist-to-hip ratio, and body fat percentage. The lipoprotein lipase (LPL) gene has been linked to lipoprotein metabolism and obesity. We performed a case-control study to determine the association between LPL gene polymorphisms and obesity-associated phenotypes such as insulin resistance (IR). We examined the different LPL gene variants for association in 642 individuals segregated by BMI and IR. Genotyping of the LPL gene -93 and -53 promoter gene polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism. A substantial association was observed for -93 gene polymorphism of the LPL gene with obesity, while -53 promoter gene polymorphism showed association with IR. We found a significant association between -93 and -53 promoter gene polymorphisms of the LPL gene with obesity and associated phenotypes in the studied population.

Relationship of lipoprotein lipase gene variants and fasting triglyceride levels in a pediatric population: The CASPIAN-III study.

Lipoprotein lipase (LPL) is one of the major enzymes responsible for the hydrolysis of triglyceride (TG)-rich lipoprotein. The effects of LPL polymorphisms on serum TG are inconsistent among different populations. This study aims to assess the TG serum concentration and distributions of three LPL single nucleotide polymorphisms (SNPs), namely D9N, HINDIII and S447X, in a nationally representative sample of Iranian adolescents. We studied the associations between SNP genotypes and TG levels in a nationally representative sample of Iranian adolescents. Genotyping was performed in 750 randomly selected participants. We compared the genotypes according to different TG levels. This study comprised 746 participants, with mean ± SD age of 14.6 ± 2.5 years. The distribution of genotypes of D9N and S447X were not significantly different according to TG levels. Regarding the HINDIII polymorphism, the distribution of GG, GT, and TT genotypes were significantly different in participants with low, borderline-high, and elevated TG (p = 0.02, 0.03, and 0.01, respectively). The mean TG was not significantly different according to the genotype distribution. In this study, most of the LPL gene variants were not significantly different in adolescents with normal and elevated TG, and the mean TG was not different in participants with various genotypes. As the first evidence from the pediatric population of the region of the Middle East and North Africa (MENA), these results might be used in international comparisons. Our findings might suggest that the high prevalence of hypertriglyceridemia in Iranian adolescents is more likely to be a result of lifestyle rather than genetic factors.

Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency

Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential. We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG. Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%). In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.

Lipoprotein lipase gene variants: Association with acute myocardial infarction and lipid profiles

BackgroundStudies showed that lipid metabolism disorders are significant risk factors for myocardial infarction and coronary artery disease (CAD). Therefore, genes involved in lipid and lipoprotein metabolism pathways such as lipoprotein lipase (LPL), are proper candidates for susceptibility to CAD. AimTo investigate the possible association between LPL gene variants (HindIII (rs320) and PvuII (rs285)), acute myocardial infarction (AMI) and serum lipid levels. Subjects and methodsThe study population consisted of 211 patients with a diagnosis of premature AMI, and 203 age-matched individuals with normal coronary angiograms as controls. Genotyping of HindIII and PvuII polymorphisms was done by the PCR-RFLP technique. ResultsAlthough the H+ and P+ alleles were more observed among the patients, there were no significant differences in genotype distributions and allele frequencies of HindIII and PvuII polymorphisms between patient and control subjects (P>0.05). Triglyceride levels were found to be significantly elevated in H+H+ and P+P+ genotypes compared to others (P<0.05). However, there was no association between HindIII and PvuII genotypes and HDL-C, LDL-C and cholesterol levels. ConclusionOur findings indicate that LPL-HindIII and PvuII polymorphisms are not associated with acute myocardial infarction but with triglyceride levels.

Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia

BackgroundMonogenic hypertriglyceridemia (HTG) may result from mutations in some genes which impair the intravascular lipolysis of triglyceride (TG)-rich lipoproteins mediated by the enzyme Lipoprotein lipase (LPL). Mutations in the LPL gene are the most frequent cause of monogenic HTG (familial chylomicronemia) with recessive transmission. MethodsThe LPL gene was resequenced in 149 patients with severe HTG (TG > 10 mmol/L) and 106 patients with moderate HTG (TG > 4.5 and <10 mmol/L) referred to tertiary Lipid Clinics in Italy. ResultsIn the group of severe HTG, 26 patients (17.4%) were homozygotes, 9 patients (6%) were compound heterozygotes and 15 patients (10%) were simple heterozygotes for rare LPL gene variants. Single or multiple episodes of pancreatitis were recorded in 24 (48%) of these patients. There was no difference in plasma TG concentration between patients with or without a positive history of pancreatitis. Among moderate HTG patients, six patients (5.6%) were heterozygotes for rare LPL variants; two of them had suffered from pancreatitis. Overall 36 rare LPL variants were found, 15 of which not reported previously. Systematic analysis of close relatives of mutation carriers led to the identification of 44 simple heterozygotes (plasma TG 3.2 ± 4.1 mmol/L), none of whom had a positive history of pancreatitis. ConclusionsThe prevalence of rare LPL variants in patients with severe or moderate HTG, referred to tertiary lipid clinics, was 50/149 (33.5%) and 6/106 (5.6%), respectively. Systematic analysis of relatives of mutation carriers is an efficient way to identify heterozygotes who may develop severe HTG.

Associations of three lipoprotein lipase gene polymorphisms, lipid profiles and coronary artery disease

Lipoprotein lipase (LPL) plays a central role in lipoprotein metabolism by hydrolyzing the core triglycerides (TGs) of circulating chylomicrons and very-low-density lipoprotein (VLDL). The effects of LPL polymorphisms on lipid levels and coronary artery disease (CAD) have been inconsistent among studies and populations. To assess the lipid profiles and distributions of three LPL gene polymorphisms in Saudi patients with CAD, the HindIII, PvuII and Ser447Ter polymorphisms in the LPL gene were analyzed in 226 patients with CAD and 110 controls. Polymerase chain reaction-restriction fragment length polymorphism was used to detect LPL gene polymorphisms. The plasma lipid profiles of the patients were determined using standard enzymatic methods. Patients in the CAD group had significantly higher triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels than controls irrespective of the HindIII, PvuII or Ser447Ter genotype. Compared to the findings in controls, the HindIII TT, PvuII TC and Ser447Ter CC genotypes were associated with significantly reduced high-density lipoprotein cholesterol (HDL-C) levels in patients with CAD (P<0.0001). In summary, there are associations between LPL gene variants and high plasma TG, TC and LDL-C levels as well as low HDL-C levels.

Alipogene tiparvovec for the treatment of lipoprotein lipase deficiency

Alipogene tiparvovec is the first adeno-associated virus (AAV)-mediated gene therapy to be approved for the treatment of a metabolic disorder. Lipoprotein lipase (LPL) deficiency (LPLD) is a rare autosomal-recessive disorder in which gene mutations cause the production of a catalytically inactive enzyme required for plasma triglyceride hydrolysis. The resultant hypertriglyceridemia causes frequent abdominal pain, fatty deposits in the skin and retina, and can lead to potentially fatal pancreatitis. In addition, patients with LPLD can develop diabetes and cardiovascular disease. Past therapies to lower plasma triglycerides in these patients have been ineffective. Intramuscular injection of alipogene tiparvovec delivers a natural gain-of-function LPL gene variant, LPLS447X, to muscle tissue and has demonstrated efficacy in animal models of LPLD. In phase I/II and phase II/III clinical evaluations, alipogene tiparvovec significantly lowered plasma triglycerides and increased LPL activity, resulting in a reduction in plasma chylomicron and a decrease in the frequency of pancreatitis episodes. The therapy is well tolerated in animals and humans and produces no serious treatment-related adverse effects.

Genetic variation in MDR1, LPL and eNOS genes and the response to atorvastatin treatment in ischemic stroke

Statins reduce the risk of cardiovascular events by lowering the blood cholesterol. Many genes involved in the pharmacodynamic pathway of statins have been part of pharmacogenetic research in patients with hypercholesterolemia, with an emphasis on genes involved in the cholesterol pathway. The present study was carried out with an aim to evaluate the association between the genetic variants of lipoprotein lipase gene [HindIII (+/+)/HindIII (-/-)], multiple drug resistance gene (C3435T) and endothelial nitric oxide synthase gene (4a/4b) with clinical outcome including an increased risk of recurrent stroke or death in ischemic stroke patients on atorvastatin therapy. 525 stroke patients and 500 healthy controls were involved in the study. Follow-up telephone interviews were conducted with patients post-event to determine stroke outcome. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. A significant association of MDR1 and LPL gene variants with bad outcome in stroke patients on atorvastatin therapy was found. However, there was no significant association of 27bp VNTR polymorphism of eNOS gene with outcome. MDR analysis was carried out to analyze gene-gene interaction involving these gene variants contributing to clinical outcome of patients on stratin therapy but no significant interaction between these variants was observed. In conclusion the individuals with HindIII (-/-) genotype of LPL and CC genotype of MDR1 gene would benefit more from atorvastatin therapy.

Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial

We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPLS447X gene therapy for lipoprotein lipase deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL S447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3–12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 1011gc/kg, and cohort 3 (n=8) received 1 × 1012gc/kg. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3–12 weeks. TG subsequently returned to baseline, although sustained LPL S447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.

Association of LPL gene variant and LDL, HDL, VLDL cholesterol and triglyceride levels with ischemic stroke and its subtypes

Lipoprotein lipase (LPL) plays an important role in lipid metabolism by hydrolyzing triglycerides in chylomicrons and very low density lipoproteins. An increasing number of studies have suggested an association of LPL gene variants with the risk of cardiovascular and cerebrovascular diseases. The aim of this study was to test whether HindIII polymorphism of LPL gene is associated with ischemic stroke and its subtypes as well as plasma lipid levels in a South Indian population from Andhra Pradesh. Five hundred and twenty five ischemic stroke patients and 500 controls were enrolled in this case–control study. The LPL HindIII polymorphism was determined by PCR-RFLP technique and the lipid levels were estimated using commercially available kits. We found significant difference in the genotypic distribution between patients and controls [for HindIII (+/+) vs. HindIII (−/−), χ2=4.916; p=0.02; Odds ratio=1.59 (95%CI; 1.054–2.413); HindIII (+/+) vs. HindIII (−/−) and HindIII (+/−), χ2=5.25; p=0.02; Odds ratio=1.24 (95%CI; 1.03–1.503)]. A stepwise multiple logistic regression analysis confirmedthese findings. The relationship between HindIII genotypes and plasma levels of HDL, LDL, VLDL and triglycerides was analyzed using ANOVA and further confirmed by Post-hoc analysis. The levels of triglycerides were found to be elevated in individuals bearing HindIII (+/+) genotype in comparison with HindIII (−/−) genotype. HDL levels were found to be significantly reduced and triglyceride levels significantly elevated in HindIII (+/+) genotype in comparison with HindIII (−/−). However, there was no difference in the levels of LDL and VLDL between the two genotypes. Examining the association of LPL gene HindIII polymorphism with stroke subtypes, we found significant association of HindIII polymorphism with Intracranial large artery atherosclerosis [Odds ratio=2.12 955CI (1.656–2.848); p=0.009]. Our results suggest that the HindIII polymorphism of LPL is significantly associated with ischemic stroke risk and elevated levels of plasma triglycerides and reduced HDL levels. Further, this polymorphism is significantly associated with intracranial large artery atherosclerosis which is the most frequent subtype in our region.

LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia

ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants (n = 1,250) in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Multivariate linear regression and two-way ANOVA for percent change in apoC-III level were performed. SNPs in the lipoprotein lipase (LPL) gene region, rs1801177 (P = 4.7 × 10(-8)), rs7016529 (P = 1.2 × 10(-6)), and rs249 (P = 4.1 × 10(-5)), were associated with apoC-III response to combination therapy. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoC-III increase in response to statins and FA. This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy.

Contribution of adiponectin to the cardiometabolic risk of postmenopausal women with loss-of-function lipoprotein lipase gene mutations

Cardiovascular risk significantly increases after menopause. Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG)-rich lipoproteins, which contributes to cardiometabolic homeostasis. Adiponectin is an adipocytokine, which also influences the cardiometabolic status. The objective of this study was to evaluate the contribution of plasma adiponectin to the cardiometabolic status of women with loss-of-function LPL gene variants (LPLD). A total of 568 white women (127 women with partial LPL deficiency and 441 controls) were included. The association of plasma adiponectin with LPLD was assessed using multiple regression models. Cardiometabolic covariates included anthropometrics, lipids (TG, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B), fasting glucose, and smoking status. Plasma adiponectin concentration was significantly lower in women with LPLD (8.69 ± 5.13 vs 6.50 ± 4.66 μg/mL; P < 0.001). Women with LPLD also presented a significantly higher risk of coronary artery disease (P = 0.013). After menopause, adiponectin explained a significant (P < 0.01) proportion of the variance in cardiometabolic covariates in both groups. This effect was more pronounced in women with LPLD: 13% versus 8% for high-density lipoprotein cholesterol, 8% versus 4% for waist circumference, 9% versus 5% for fasting TG, and 6% versus 2% for fasting glucose. When controlling for cardiometabolic covariates, low adiponectin values independently contributed to the clinical expression of LPLD in postmenopausal women (odds ratio, 5.55; 95% CI, 0.04-0.81; P = 0.025). In conclusion, these results suggest that a low plasma adiponectin level significantly contributes to the cardiometabolic risk profile of postmenopausal women with LPLD, independently of anthropometrics, lipids, and other covariates.

Common sequence variant in lipoprotein lipase gene conferring triglyceride response to fibrate treatment

Little is known about whether the variations in the lipoprotein lipase (LPL) and apolipoprotein gene cluster (APOA1/C3/A5) confer appreciable triglyceride lowering after fibrate treatment among patients with hypertriglyceridemia. We investigated whether variations in these genes confer a triglyceride lowering response after fibrate treatment among 145 patients with hypertriglyceridemia receiving 6 months of fibrate treatment. Overall triglycerides decreased from 746.2 mg/dl to 465.9 mg/dl and the mean percentage of triglyceride lowering was 50.7 +/- 38.6%. A total of two polymorphisms, LPL IVS8 +483T>G and APOA1 +2169G>C, were associated with a significant percentage of triglyceride lowering. Common haplotype effects of LPL on the triglyceride lowering percentage were significant (p = 0.002) and the percentage of variance explained by the LPL haplotype was 7.5%. One common LPL haplotype encompassing three polymorphisms was associated with a -45.40% change (p < 0.001) and risk of a 5.9-fold risk for developing a poor response (95% confidence interval: 1.11-31, p = 0.037), compared with the most frequent LPL haplotype. Our results indicate that the LPL gene variant may cause triglyceride lowering after fibrate treatment among patients with hypertriglyceridemia.

Lipoprotein lipase variants associated with an endophenotype of hypertension: hypertension combined with elevated triglycerides

Previously, we observed that young-onset hypertension was independently associated with elevated plasma triglyceride(s) (TG) levels to a greater extent than other metabolic risk factors. Thus, focusing on the endophenotype--hypertension combined with elevated TG--we designed a family-based haplotype association study to explore its genetic connection with novel genetic variants of lipoprotein lipase gene (LPL), which encodes a major lipid metabolizing enzyme. Young-onset hypertension probands and their families were recruited, numbering 1,002 individuals from 345 families. Single-nucleotide polymorphism discovery for LPL, linkage disequilibrium (LD) analysis, transmission disequilibrium tests (TDT), bin construction, haplotype TDT association and logistic regression analysis were performed. We found that the CC- haplotype (i) spanning from intron 2 to intron 4 and the ACATT haplotype (ii) spanning from intron 5 to intron 6 were significantly associated with hypertension-related phenotypes: hypertension (ii, P=0.05), elevated TG (i, P=0.01), and hypertension combined with elevated TG (i, P=0.001; ii, P<0.0001), according to TDT. The risk of this hypertension subtype increased with the number of risk haplotypes in the two loci, using logistic regression model after adjusting within-family correlation. The relationships between LPL variants and hypertension-related disorders were also confirmed by an independent association study. Finally, we showed a trend that individuals with homozygous risk haplotypes had decreased LPL expression after a fatty meal, as opposed to those with protective haplotypes. In conclusion, this study strongly suggests that two LPL intronic variants may be associated with development of the hypertension endophenotype with elevated TG.

Apolipoprotein E and lipoprotein lipase gene polymorphisms interaction on the atherogenic combined expression of hypertriglyceridemia and hyperapobetalipoproteinemia phenotypes

The combination of hypertriglyceridemia (hyperTG) and hyperapobetalipoproteinemia (hyperapoB) is associated with an increased coronary artery disease (CAD) risk. Apolipoprotein (apo) E and lipoprotein lipase (LPL) genes are involved in the catabolism of triglycerides (TG)-rich apoB-containing lipoproteins (VLDL). Several apoE and LPL gene variants affecting CAD risk, plasma TG or apoB concentrations have an allelic frequency of >5% in the general population. This study examined the combined effect of frequent apoE and LPL gene polymorphisms on the expression of hyperTG and hyperapoB. ApoE (E2, E3, and E4) and LPL (D9N, N291S, G188E, and P207L) were genotyped and fasting lipid profiles were assessed among 1,441 French-Canadian subjects. Multivariate analyses were performed to estimate the relationship between apoE and LPL gene variants and the risk of hyperTG (TG>1.7 mmol/l) and hyperapoB (apoB>0.9 g/l). Compared to apoE3 carriers, the apoE4 allele significantly increased the risk of expressing the "hyperTG/hyperapoB" phenotype [odds ratio (OR)=1.95; p=0.014]. This risk was significantly exacerbated (OR=4.69; p=0.017) by the presence of frequent deleterious LPL gene variants in this population. The apoE2 allele was negatively associated with hyperTG/hyperapoB (OR=0.49; p=0.002) in the absence of a deleterious LPL gene variant. These results suggest that epistasis is a phenomenon to consider while assessing the CAD risk associated with gene variants or the effect of frequent alleles on high-risk lipid profiles.