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