Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden

doi:10.1016/0021-9150(92)90130-9

Atherosclerosis

Volume 97, Issues 2–3, December 1992, Pages 171-185

https://doi.org/10.1016/0021-9150(92)90130-9 Get rights and content

Abstract

Association studies were carried out on a sample of 87 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms (PvuII, HindIII and Serine₄₄₇-Stop) at the lipoprotein lipase (LPL) gene locus on among-individual differences in plasma lipid traits and progression of atherosclerosis. Significant linkage dis-equilibrium was detected between any two of these polymorphisms, with the Stop₄₄₇ allele being only found on the same chromosome as the rare alleles (no cutting sites) of the PvuII and HindIII polymorphisms. In the healthy individuals, weak associations were found between genotypes of the HindIII polymorphism and triglycerides and the PvuII polymorphism and high density lipoprotein cholesterol explaining 7.4% and 5.6% of sample variance (P = 0.03 and 0.09), respectively. No associations were found between these traits and genotypes of the Serine₄₄₇-Stop substitution, and thus it is unlikely to be the cause of the associations seen with the Pvull and HindIII polymorphisms even though it truncates the enzyme amino acid sequence. The presence of the rare allele, H⁻, of the HindIII polymorphism was associated with a smaller variance in triglycerides and both cholesterol and triglycerides in the very low density lipoprotein fraction, and with larger interdependent variation between these lipid traits, and also between LPL activity and these lipid traits. This implies that the H⁻ allele, rather than the Stop₄₄₇ allele, hasthe major impact on interdependence between traits which are directly orindirectly influenced by LPL activity. In the healthy individuals who were carriers of the apolipoprotein E2 allele, the inter-dependence between LPL activity and lipid traits was significantly smaller, and that between high density lipoprotein cholesterol and both cholesterol and triglycerides in the very low density lipoprotein fraction was much larger compared with non-carriers (P < 0.05). No significant associations were found between lipid traits or lipase activity and genotypes of the Serine₄₄₇-Stop substitution. However, in the patients, global severity of coronary atherosclerosis at the first angiography was significantly associated with haplotype combinations of the HindIII and the Serine₄₄₇-Stop polymorphisms, with the H⁻Stop haplotype being associated with the highest median score (P = 0.02). The data suggest that variation at the LPL gene locus is assoicated with a pleiotropic effect, that is not directly mediated by changes in lipids, on severity of coronary atherosclerosis.

References (49)

R.L. Jackson
Lipoprotein lipase and hepatic lipase
M.R. Taskinen et al.
Enzymes involved in triglyceride hydrolysis
K. Shirai et al.
Hydrolysis of human plasma high density lipoproteins₂ phospholipids and triglycerides by hepatic lipase
Biochem. Biophys. Res. Commun.
(1981)
R.S. Sparkes et al.
Human genes involved in lipolysis of plasma lipoproteins: Mapping of loci for lipoprotein lipase to 8p22 and hepatic lipase to 15821
Genomics.
(1987)
T.G. Kirchgessner et al.
The sequence of cDNA encoding lipoprotein lipase
J. Biol. Chem.
(1987)
K. Oka et al.
Structure and polymorphic map of human lipoprotein lipase gene
Biochim. Biophys. Acta
(1990)
F. Faustinella et al.
Catalytic triad residue mutation (Asp 156 to Gly) causing familial lipoprotein lipase deficiency
J. Biol. Chem.
(1991)
F. Faustinella et al.
Catalytic triad residue mutation (Asp 156 to Gly) causing familial lipoprotein lipase deficiency
J. Biol. Chem.
(1992)
T. Gotoda et al.
Gene polymorphism idenified by Pvull in familial lipoprotein lipase deficiency
Biochem. Biophys. Res. Commun.
(1989)
J.A. Thorn et al.
Lipoprotein and hepatic gene variants in coronary atherosclerosis
Atherosclerosis
(1990)
A. Hamsten et al.
Serum lipoproteins and apolipoproteins in young male survivors of myocardial infarction
Atherosclerosis
(1986)

A. Hamsten et al.

Plasminogen activatior inhibitor in plasma; risk factor for recurrent myocardial infarction

Lancet

(1987)

R. Peacock et al.

Apolipoprotein B gene polymorphisms, lipoproteins and coronary athero sclerosis: A study of young myocardial infarction survivors and healthy population-based individuals

Atherosclerosis

(1992)

A. Hamsten et al.

Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction

Circulation

(1986)

P. Nilsson-Ehle et al.

Rapid, simple and specific assays for lipoprotein lipase and hepatic lipase

Artery

(1977)

J.E. Hixson et al.

Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI

J. Lipid Res.

(1990)

N.B. Myant et al.

Clinical signs of familial hyper cholesterolaemia in patients with familial defective apolipoprotein B-100 and normal low density lipoprotein receptor function

Atheroscler. Thromb.

(1991)

J.R. Patsch

Postprandial lipaemia

J. Kobayashi et al.

A heterozygous mutation (the codon for Ser⁴⁴⁷ to a stop codon) in lipoprotein lipase contributes to a defect in lipid interface recognition in a case with type I hyperlipidaemia

Biochem. Biophys. Res. Commun.

(1992)

N.V. Federoff

K.L. Wion et al.

Human lipoprotein lipase complementary DNA sequence

Science

(1987)

J.R. Patsch et al.

Postprandial lipaemia; a key for the conversion of high density lipoprotein₂ into high density lipoprotein₃ by hepatic lipase

J. Clin. Invest.

(1984)

S.S. Deeb et al.

Structure of the human lipoprotein lipase gene

Biochemistry

(1989)

T.G. Kirchgessner et al.

Organization of the lipoprotein lipase gene and evolution of the lipase gene family

O.U. Beg et al.

Lipoprotein lipase_Beihesda: a single amino acid substitution (Ala-176 to Thr) leads to abnormal heparin binding and loss of enzyme activity

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The association between the genes LPL Ser447Ter, CMA1-1903A > G, FTO rs9939609 and obesity in the Rostov region from Russia
2021, Gene Reports
Due to the high prevalence of diseases associated with obesity. There are several factors, including the genetic factors, it is known that the genes Fat mass and obesity-associated FTO rs9939609, the lipoprotein lipase (LPL) Ser447Ter, and the chymase 1 (CMA1) -1903A > G are associated with lipoprotein metabolism. The aim of the present investigation was to study the association of the FTO, LPL, and CMA1 genes with obesity in the children and adolescents population of the Rostov region, Russia.
In a case-control study involving 500 children and adolescents aged from 3 to 17 years, the association between the genetic polymorphisms of the FTO rs9939609, LPL Ser447Ter (rs328) and CMA1 -1903A > G (rs1800875) with the obesity was studied. The obese patients' group consisted of 300 obese children and adolescents, while the control group consisted of 200 non-obese children and adolescents. The genotyping polymorphisms for these genes was performed using PCR amplified fragments. Genetic polymorphisms in DNA samples were typed using commercial test systems NPF Liteh (Russia) with electrophoretic detection.
Significant differences (P < 0.05) were found in the frequency distribution of the AA genotype (P = 0.008; OR: 0.60; 95% CI: 0.41–0.87) and the A allele (P = 0.025; OR: 1.35; 95% CI: 1.05–1.75) of the FTO gene polymorphism rs9939609, as well as the distribution of the AA genotype (P = 0.021; OR: 1.76; 95% CI: 1.09–2.83) of the CMA1 gene polymorphism -1903A > G in the obese and control groups. A combination of FTO rs9939609, CMA1 -1903A > G of genotypes increased risks has been identified and LPL Ser447Ter of genotypes which decreased risks according to the nature of the association between the dominant and recessive models of obesity in children and adolescents.
An interrelation was revealed between the gene FTO rs9939609 polymorphism and the obesity, while the effect of the CMA1 -1903A > G gene on obesity is unknown, although there was a significant effect on the AA genotype of obesity among the Rostov on-don population.
Prediction of dyslipidemia using gene mutations, family history of diseases and anthropometric indicators in children and adolescents: The CASPIAN-III study
2018, Computational and Structural Biotechnology Journal
Citation Excerpt :
Thus, the sample size of 725 (ncontrols = 418, ncase = 307), sufficed. Single nucleotide polymorphisms (SNPs) of lipoprotein lipase LPL (D9N [rs1801177]), cholesteryl ester transfer protein CETP (TaqIB [rs708272]) [30], LPL (HindIII [rs320]), LPL (S447X [rs328]) [31], ATP-binding cassette transporter-1 ABCA1 (V771M [rs2066718]), ABCA1 (R1587K [rs2230808]) [32], CETP (A373P [rs5880]) [33,34], apolipoprotein C-3 APOC3 (SstI [rs5128]) [35], apolipoprotein A-1 APOA1 (MspI [rs2893157]) [36], apolipoprotein A-5 APOA5 (C-1131T [rs662799]) [37] and apolipoprotein-E ApoE genes [38,39], appearing to relate to lipid profile disorders and (or) cardiovascular diseases, were investigated [3,40]. Subjects' peripheral blood was analyzed using the QIAamp DNA Blood Mini kit (Qiagen, Germany) and DNA was extracted following the manufacturer's protocol [41].
Dyslipidemia, the disorder of lipoprotein metabolism resulting in high lipid profile, is an important modifiable risk factor for coronary heart diseases. It is associated with more than four million worldwide deaths per year. Half of the children with dyslipidemia have hyperlipidemia during adulthood, and its prediction and screening are thus critical. We designed a new dyslipidemia diagnosis system. The sample size of 725 subjects (age 14.66 ± 2.61 years; 48% male; dyslipidemia prevalence of 42%) was selected by multistage random cluster sampling in Iran. Single nucleotide polymorphisms (rs1801177, rs708272, rs320, rs328, rs2066718, rs2230808, rs5880, rs5128, rs2893157, rs662799, and Apolipoprotein-E2/E3/E4), and anthropometric, life-style attributes, and family history of diseases were analyzed. A framework for classifying mixed-type data in imbalanced datasets was proposed. It included internal feature mapping and selection, re-sampling, optimized group method of data handling using convex and stochastic optimizations, a new cost function for imbalanced data and an internal validation. Its performance was assessed using hold-out and 4-foldcross-validation. Four other classifiers namely as supported vector machines, decision tree, and multilayer perceptron neural network and multiple logistic regression were also used. The average sensitivity, specificity, precision and accuracy of the proposed system were 93%, 94%, 94% and 92%, respectively in cross validation. It significantly outperformed the other classifiers and also showed excellent agreement and high correlation with the gold standard. A non-invasive economical version of the algorithm was also implemented suitable for low- and middle-income countries. It is thus a promising new tool for the prediction of dyslipidemia.
Meta-analyses of four polymorphisms of lipoprotein lipase associated with the risk of Alzheimer's disease
2016, Neuroscience Letters
We evaluated the contributions of four polymorphisms of the lipoprotein lipase (LPL) gene to the risk of Alzheimer’s disease (AD).
Through a comprehensive literature search for genetic variants of LPL involved in AD association studies, we found four polymorphisms for the current meta-analyses. These polymorphisms were Asn291Ser(rs268), PvuII(rs285), HindIII(rs320) and Ser447Ter(rs328).
In total, eight studies with 5064 cases and 5016 controls were retrieved for the meta-analyses of the four genetic variants. The analyses showed that Asn291Ser(rs268) (OR = 2.34, 95% CI = 1.05–5.25, P = 0.04), HindIII(rs320) (OR = 1.44, 95% CI = 1.17–1.78, P = 0.0006), and Ser447Ter(rs328) (OR = 0.80, 95% CI = 0.66–0.98, P = 0.03) were significantly associated with a risk of AD. No association was found between the PvuII(rs285) polymorphism and the risk of AD.
Our results showed that Asn291Ser(rs268), HindIII(rs320) and Ser447Ter(rs328) polymorphisms of LPL were associated with a risk of AD. Asn291Ser(rs268) and HindIII(rs320) were predisposing factors of AD, whereas Ser447Ter(rs328) showed a protective effect for AD.
Lipoprotein lipase gene HindIII polymorphism and risk of myocardial infarction in South Indian population
2013, Indian Heart Journal
Citation Excerpt :
It is an intronic base transition of thymine (T) to guanine (G) at position +495, which abolishes the restriction site for the enzyme HindIII. Several studies have shown that the common allele (H+) is significantly associated with high triglycerides (TG) levels and low HDL levels compared to the rare allele (H−).10–16 The LPL H+ H+ genotype presented elevated TG levels.17
Studies have reported an association between lipoprotein lipase (LPL) gene and myocardial infarction in some populations. Therefore, the present study aimed to investigate the association of the HindIII polymorphism of the (LPL) gene with myocardial infarction and to explore its potential role in susceptibility in a South Indian population.
We included a total of 412 subjects (202 myocardial infarction patients and 210 age- and sex-matched controls). Demographic and clinical characteristics were collected. Lipid profiles were estimated. DNA was isolated and the LPL gene HindIII polymorphism was determined by polymerase chain reaction.
Comparison of the lipid profiles between patients and controls showed that patients had statistically high significant values (p = 0.0001). The H⁺ H⁺ genotype of the LPL gene is associated with myocardial infarction. H⁺ H⁺ vs. H⁻ H⁻ was χ2 = 19.4, OR 3.1, CI 95% 1.8–5.2, p < 0.0001.
Our study strongly suggests that the LPL gene HindIII Hþ Hþ genotype is an independent risk factor for first MI.
Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease
2008, Atherosclerosis
Citation Excerpt :
In association studies, although the X447 allele has been reported to be associated with a favorable lipid profile in some studies [7–8,22] the results have not been confirmed in other studies [15]. Similarly, the association of the S447X polymorphism with CAD is inconsistent [10–18]. In a meta analysis the association of the S447X polymorphism with TG/HDL-C and CAD was found to be small compared to three other LPL amino acid polymorphisms examined [12] or it was gender-specific [23].
Lipoprotein lipase (LPL) plays a pivotal role in lipid metabolism by hydrolyzing triglyceride (TG)-rich lipoprotein particles. Abnormalities in normal LPL function are associated with the risk of coronary artery disease (CAD). A number of genetic variants have been identified in the LPL gene that affects different functions of the LPL protein. A common HindIII polymorphism in intron 8 (T/G) of the LPL gene has been found to be associated with altered plasma TG and HDL-cholesterol, and CAD risk in several studies, but its functional significance is unknown. It has been shown that certain intronic sequence contain regulatory elements that are important for transcription and translational regulation of a gene. In this study we tested the hypothesis that this polymorphism affects the binding site of a transcription factor that regulates the transcription of LPL gene. Electrophoretic mobility shift assays (EMSAs) revealed that the HindIII site binds to a transcription factor and that the mutant allele has lower binding affinity than the wild type allele. Transcription assays containing the entire intron 8 sequence along with full-length human LPL promoter were carried out in COS-1 and human vascular smooth muscle cells. The mutant allele was associated with significantly decreased luciferase expression level compared to the wild type allele in both the muscle (3.394 ± 0.022 vs. 4.184 ± 0.028; P = 4.7 × 10⁻⁶) and COS-1 (11.603 ± 0.409 vs. 14.373 ± 1.096; P < 0.0001) cells. In conclusion, this study demonstrates for the first time that the polymorphic HindIII site in the LPL gene is functional because it affects the binding of a transcription factor and it also has an impact on LPL expression.
Polymorphisms of the lipoprotein lipase gene are associated with atherosclerotic cerebral infarction in the Chinese
2008, Neuroscience
Citation Excerpt :
Genomic DNA was extracted from peripheral blood leukocytes by SBS UltraPure™ Genome DNA Kit (SBS Genetech, Beijing, China). The primer sets (SBS Genetech) were based on previously published information (Gotoda et al., 1992; Peacock et al., 1992; Zhao et al., 2003): HindIII, forward primer (H1), 5′-TGA AGC TCA AAT GGA AGA GT-3′, reverse primer (H2): 5′-TAC AAG CAA ATG ACT AAA-3′; PvuII, forward primer (P1): 5′-ATG GCA CCC ATG TGT AAG GTG-3′, reverse primer (P2): 5′-GTG AAC TTC TGA TAA CAA TCT C-3′; Ser447Ter, forward primer (S1): 5′-TAC ACT AGC AAT GTC TAG GTG A-3′, reverse primer (S2): 5′-TCA GCT TTA GCC CAG AAT GC-3′. Genomic DNA 3 μl (150 ng) was used for a 30 μl PCR reaction containing 3 μl 10× buffer solution, 0.5 μl 2.5U TaqDNA polymerase (Shenergy Biocolor Bioscience & Technology Company, Shanghai, China); 1 μl (20pmol) of each primer, and 3 μl 200μmol/l) of each deoxynucleotide triphosphate.
Lipoprotein lipase (LPL), which plays an essential role in plasma lipoprotein metabolism and transportation, appears to be a risk factor for ischemic vascular diseases. Several studies have recently reported the presence of relationship between HindIII, PvuII, Ser447Ter (C→G) polymorphisms of LPL and ischemic vascular diseases.
We first studied the relationship between LPL polymorphisms and the risk of atherosclerotic cerebral infarction (CI) by detecting the frequencies of LPL HindIII, PvuII and Ser447Ter genotypes and combined genotypes in the Chinese.
We recruited 185 CI patients, confirmed by cranial computed tomography or magnetic resonance imaging/angiography, or both, and 186 control subjects. Polymerase chain reaction–restriction fragment length polymorphisms technique was used to detect HindIII, PvuII and Ser447Ter polymorphisms of the LPL gene.
The frequencies of the H+H+ genotype and H+ allele did not differ between CI and control groups. The frequencies of the P+P+ genotype and P+ allele gene were significantly higher in the CI group (P=0.040, P=0.015). The frequencies of CG+GG genotype and G allele were lower in the CI group (P<0.001, P<0.001). In the CI group, the individuals with P+P+ genotype had a significantly higher level of plasma triglyceride (TG) and a lower level of plasma high density lipoprotein cholesterol (HDL-c). CG+GG genotypes were correlated with significantly higher levels of plasma total cholesterol (TC), HDL-c and low density lipoprotein cholesterol (LDL-c) in the CI group. The frequencies of H+/C and P+/C combined genotypes were higher in the CI group than in controls (P<0.001, P<0.001). The frequency of H+/P+/C combined genotype was significantly higher in the CI group than in controls (P<0.001).
Our study suggests that PvuII and Ser447Ter polymorphisms are associated with lipid profile and CI.

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Research paperAssociations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden

Abstract

Biochem. Biophys. Res. Commun.

Genomics.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Atherosclerosis

Atherosclerosis

Lancet

Atherosclerosis

Circulation

Artery

J. Lipid Res.

Atheroscler. Thromb.

Biochem. Biophys. Res. Commun.

Human lipoprotein lipase complementary DNA sequence

Science

Postprandial lipaemia; a key for the conversion of high density lipoprotein2 into high density lipoprotein3 by hepatic lipase

J. Clin. Invest.

Structure of the human lipoprotein lipase gene

Biochemistry

Organization of the lipoprotein lipase gene and evolution of the lipase gene family

Lipoprotein lipaseBeihesda: a single amino acid substitution (Ala-176 to Thr) leads to abnormal heparin binding and loss of enzyme activity

Research paper
Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden

Postprandial lipaemia; a key for the conversion of high density lipoprotein₂ into high density lipoprotein₃ by hepatic lipase

Lipoprotein lipase_Beihesda: a single amino acid substitution (Ala-176 to Thr) leads to abnormal heparin binding and loss of enzyme activity