Interaction of functional NPC1gene Polymorphism with smoking on coronary heart disease

Weiwei Ma,Qianqian Wang,Hu Wang,Kai Sun,Xiaohong Huang,Jing Xu,Xinxin Zheng,Lin Zhang,Ying Xin,Rutai Hui

doi:10.1186/1471-2350-11-149

Abstract

BackgroundThe protein of Niemann-pick type C1 gene (NPC1) is known to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments. This study aims to investigate whether the genetic variation in NPC1 is associated with risk of coronary heart disease (CHD) and to detect whether NPC1 might interact with smoking on the risk of CHD.MethodsWe performed a case-control study, including 873 patients with coronary heart disease (CHD) and 864 subjects without CHD as control. Polymorphisms of NPC1 gene were genotyped by polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP).ResultsA tag-SNP rs1805081 (+644A > G) in NPC1 was identified. The G allele of the +644 locus showed reduced risk of CHD than wild-type genotype in Chinese population (recessive model GG vs. AG+AA: odds ratio [OR] 0.647, 95% CI 0.428 to 0.980, P = 0.039; additive model GG vs. AG vs. AA: OR 0.847, 95% CI 0.718 to 0.998, P = 0.0471). Moreover in smokers, the G-allele carriers had reduced risk of CHD compared with A-allele carries (OR 0.552, 95% CI 0.311 to 0.979, P = 0.0421).ConclusionsThe results of the present study suggest that NPC1 variants seem to be contributors to coronary heart disease occurrence in Chinese population. Moreover, in smokers, NPC1 variants seem to confer protection to coronary heart disease.

Highlights

The protein of Niemann-pick type C1 gene (NPC1) is known to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments
It is well established that the formation of foam cell or atherosclerotic plaque is the hallmark event leading to coronary heart disease, Foam cells in atherosclerotic lesions derive from macrophages and vascular smooth muscle cells (VSMCs)[1]
Loss of NPC1 function leads to defective suppression of sterol regulatory element binding protein (SREBP)-dependent gene expression and failure to appropriately activate liver X receptor-mediated pathways, resulting in intracellular cholesterol accumulation in macrophages and fibroblasts[7,8]

Summary

Introduction

The protein of Niemann-pick type C1 gene (NPC1) is known to facilitate the egress of cholesterol and other lipids from late endosomes and lysosomes to other cellular compartments. Coronary heart disease is one of the leading causes of morbidity and mortality in China. It is still a big challenge for medical society to elucidate the pathogenesis and to identify the subjects at risk. Niemann-Pick type C disease is an autosomal, recessive disorder characterized by intracellular accumulations of cholesterol and other lipids throughout the body. The underlying gene, NPC1 responsible for 95% of Niemann-Pick type C disease, encodes a multispanning membrane protein containing a sterol-sensing domain that is required for the egress of cholesterol from late endosomes [9]

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