Elsevier

Atherosclerosis

Volume 157, Issue 1, July 2001, Pages 123-129
Atherosclerosis

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

https://doi.org/10.1016/S0021-9150(00)00717-6Get rights and content

Abstract

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.

Introduction

Lipoprotein lipase (LPL) is predominantly found in capillaries, muscle and adipose tissue, where it is bound at the luminal surface of the vascular endothelium, and also on macrophages. It plays a key role in the hydrolysis of the triglyceride (TG) core of circulating chylomicrons and very-low-density lipoproteins (VLDL). Lipoproteins are sequestered at the endothelial surface through formation of complexes involving heparin binding domains on LPL, heparin sulphate proteoglycans and, it is thought, apolipoprotein E, which influences the stability of the LPL–lipoprotein–proteoglycan complex [1].

The human LPL gene consists of ten exons, spans about 30 kb on chromosome 8p22, and encodes a 475 amino acid polypeptide that yields a 448 amino acid mature protein after cleavage of a 27 amino acid signal peptide [2]. Full expression of enzyme activity requires the formation of a homodimeric complex. In view of its pivotal role in lipid metabolism, it is a strong candidate gene for atherogenic lipid profiles and coronary heart disease (CHD). Studies of individuals and their families exhibiting defective chylomicron and VLDL clearance have demonstrated more than 70 LPL loss of function mutations, most of which are rare and confined to a small number of founder individuals and their families [3]. Recently, a number of more common coding polymorphisms in the LPL gene have been described. Two of these, D9N (G→A nucleotide (nt) 280) and N291S (A→G nt 1127), have been variably described to have small deleterious effects on plasma high-density lipoprotein (HDL) cholesterol and TG, and another, S447X (C→G nt 1595), to have small beneficial effects, as recently reviewed [2], [4]. The evidence for an influence of these on CHD has been controversial [2], [4], although there are subsequent recent reports of a deleterious effect of the 9N allele [5], [6] and a beneficial effect of the 447X [7]. The N291S polymorphism induces an asparagine to serine change in the enzyme while D9N changes an aspartate residue to asparagine, both resulting in lower post-heparin plasma LPL activity. The D9N polymorphism leads to enzyme secretion deficiency and the N291S appears to destabilise homodimer complex formation of the enzyme with consequent loss of lipolytic activity [2]. A third and more prevalent polymorphism, S447X, creates a premature stop codon and loss of the terminal serine and glycine residues from the carboxy end of the protein. It is associated with the opposite LPL and plasma lipid effects to those of D9N and N291S [2], [4].

Most previous studies on these three polymorphisms have been conducted on European or Scandinavian populations. In this study, we examined the influence of these three polymorphisms on CHD risk by comparing two large predominantly Anglo-Celtic Australian groups: one comprised of patients, less than 50 years of age, with angiographic obstructive CHD, with or without prior myocardial infarction (MI), and the other a healthy population cohort selected randomly from the electoral roll and without historical evidence of CHD. We also examined the influence of the polymorphisms on plasma HDL cholesterol and TG in each of the two groups.

Section snippets

Study subjects

A total of 721 subjects, <50 years, with CHD and 691 community subjects, of similar age, were studied in Perth, Western Australia. The study was approved by the Ethics Committee of Royal Perth Hospital.

The CHD group consisted of subjects who were documented prospectively for inclusion in the study and for risk factors for CHD at the time of coronary angiography in the one hospital over approximately 6 years. They presented either symptomatically for elective coronary angiography or for

Results

Table 1 presents some characteristics of the two groups studied. History of hypertension and of diabetes were more frequent, and there were more smokers and ex-smokers in the CHD group (all P<0.001). Although the mean values for body mass index (BMI) were similar in males and females, the variation was greater in females and BMI was significantly higher in the CHD group only in males (P<0.001). Lipid levels differed between the sexes and are summarised separately for the sexes in Table 2. TG

Discussion

The most important finding of our study is the clearly higher frequency of the LPL 9N allele in young subjects with CHD or MI than in normal subjects, despite the very small adverse effects on HDL cholesterol and TG, and compared with the absence of an effect of the N291S mutation. We consider that our CHD and control groups were optimally recruited: the former comprised of patients presenting consecutively at <50 years age, and documented prospectively, including angiographic assessment; and

Acknowledgments

This study was supported by National Health and Medical Research Council (Australia), Medical Research Fund of Western Australia and the Royal Perth Hospital Medical Research Foundation.

References (25)

  • Kastelein JJP, Groenemeyer BE, Hallman DM, et al., The Regress Study Group. The ASN9 variant of lipoprotein lipase is...
  • H.H. Wittrup et al.

    Mutations in the lipoprotein lipase gene associated with ischemic heart disease in men. The Copenhagen City Heart Study

    Arterioscler. Thromb. Vasc. Biol.

    (1999)
  • Cited by (62)

    • Meta-analyses of four polymorphisms of lipoprotein lipase associated with the risk of Alzheimer's disease

      2016, Neuroscience Letters
      Citation Excerpt :

      No significant association was found between the PvuII(rs285) polymorphism and AD. The Asn291Ser(rs268) polymorphism occurs in exon 6 leading to an A-G transition [17]. The effect of 291Ser, which changes one amino acid, is roughly the opposite of 447Ter.

    • Reverse Cholesterol Transport in HDL Metabolism: Modulation of Structural and Functional Features of HDL Particles

      2014, The HDL Handbook: Biological Functions and Clinical Implications: Second Edition
    • Apolipoprotein B-48: A unique marker of chylomicron metabolism

      2014, Advances in Clinical Chemistry
      Citation Excerpt :

      Since the duration of transgene expression upon adenoviral infection is limited, the nonpathologic adeno-associated virus (AAV) has been used in several gene therapy studies in males [208]. As a transgene, the naturally occurring LPL variant (LPLS447X) was shown to exhibit a beneficial effect on lipid profile with a concomitant decrease in CVD risk [209–215]. Nierman et al. [216] reported the successful implementation of LPL gene therapy using an AAV1-LPLS447X vector in murine and feline models of LPL deficiency.

    • The g.-469G&gt;A polymorphism in the GPIHBP1 gene promoter is associated with hypertriglyceridemia and has an additive effect on the risk conferred by LPL defective alleles

      2013, Nutrition, Metabolism and Cardiovascular Diseases
      Citation Excerpt :

      Because of their key metabolic functions, complete deficiency in either LPL or GPIHPB1 leads to severe hyperTG associated with an accumulation of CM particles in plasma [6,20]. A partial LPL deficiency, however, is associated with a moderate hyperTG due to a reduced VLDL catabolism [7,8]. The GPIHBP1 g.-469G>A polymorphism also seems to impair VLDL catabolism as suggested by the increased levels of circulating VLDL cholesterol and TG content observed in g.-469A carriers.

    View all citing articles on Scopus
    View full text