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Variation in Niemann–Pick C1-like 1 gene as a determinant of apolipoprotein B-100 kinetics and response to statin therapy in centrally obese men

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Summary Objective 

Niemann–Pick C1-like 1 protein (NPC1L1) plays a key role in lipoprotein metabolism. We examined the association of common genetic polymorphisms in NPC1L1 on apolipoprotein (apo) B-100 metabolism and the response to statin treatment in 37 men with central obesity. Research methods and procedure 

Very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL)–apoB kinetics were determined using stable isotope method. NPC1L1 genotypes (1735G > C, 25432A > C and 27677T > C) were determined by allele-specific methods. These three polymorphisms are defined as haplotype, namely 1735C-25432A-27677T, and was designated as ‘haplotype 2’. Results 

Relative to non-2/2 haplotype (n = 23), subjects with the 2/2 haplotype (n = 14) had significantly increased plasma concentrations of total, LDL-cholesterol, and total apoB (P < 0·05). The fractional catabolic rate (FCR) of LDL-apoB was significantly lower in 2/2 subjects compared with non-2/2 subjects (P < 0·05), with an associated increase in LDL-apoB pool size in the former group. Sixteen subjects were then treated with 40 mg atorvastatin (6 weeks): 2/2 subjects (n = 8) had a significantly greater reduction in plasma concentrations of cholesterol and total apoB and in LDL-apoB pool size, as well as a greater increase in LDL-apoB FCR compared with non-2/2 subjects. There were no significant treatment-related between-haplotype differences in VLDL-apoB kinetics or in plasma concentrations of lathosterol and campesterol. Conclusion 

Our data demonstrate that NPC1L1 2/2 haplotype was associated with variation in LDL-apoB metabolism and its response to statin therapy in centrally obese men, by a mechanism that did not involve changes in VLDL-apoB kinetics, nor cholesterol synthesis or absorption.
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Document Type: Research Article

Affiliations: 1: Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia, 2: Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada and 3: School of Surgery and Pathology, University of Western Australia and Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Perth, Australia

Publication date: July 1, 2008

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