The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects
The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects
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DOI：
10.1210/jc.2007-2815
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发表时间：
2008-06-01
影响因子：
5.8
通讯作者：
Pedersen, Oluf
中科院分区：
文献类型：
--
作者：
Grarup, Niels;Andreasen, Camilla H.;Pedersen, Oluf
内容：肝脂酶在高密度脂蛋白（HDL）和低密度脂蛋白的代谢中起着关键作用，参与胆固醇的逆向转运和形成致动脉粥样硬化的小而密的低密度lipoprotein.Objectives：目的是探讨在LIPC的变异体对代谢性状和2型糖尿病的影响在大样本的丹麦人。由于行为因素影响肝脂酶活性，我们进一步研究了基于人群的Inter 99研究中可能的基因-环境相互作用。设计：LIPC -250G>A在Inter 99研究中对（rs 2070895）变体进行基因分型（n = 6070），英国-丹麦在初级保健中筛查发现糖尿病患者强化治疗的荷兰研究丹麦筛查队列中有未确诊型糖尿病风险因素的个体2糖尿病（n = 8662），以及其他2型糖尿病患者（n = 1，064）和葡萄糖耐受对照受试者（n = 360）。在Inter 99研究中，rs 2070895的A等位基因与空腹血清HDL-胆固醇（HDL-c）增加0.057 mmol/L [ 95%置信区间（CI）0.039-0.075]相关（P = 8 x 10（-10）），并得到英国-丹麦-荷兰初级保健筛查发现糖尿病患者强化治疗研究的相关性支持[每个等位基因0.038 mmol/L（95% CI 0.024-0.053）; P = 2 x 10（-7））。等位基因对HDL-c的影响通过与自我报告的体力活动的相互作用来调节（P相互作用= 0.002），因为活跃的体力活动纯合子A等位基因携带者有0.30 mmol/L（95% CI 0.22-0.37）与纯合子G等位基因携带者相比，HDL-c升高。我们验证了LIPC启动子变异与空腹血清HDL-c的相关性，并提供了支持与体力活动相互作用的数据，这意味着在携带-250个A等位基因。这种相互作用可能对公共卫生和疾病预防产生潜在影响。
Context: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein.Objectives: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study.Design: The LIPC -250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360).Results: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [ 95% confidence interval (CI) 0.039-0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10(-10)) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [ 0.038 mmol/liter per allele (95% CI 0.024-0.053); P = 2 x 10(-7)). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (Pinteraction = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22-0.37) increase in HDL-c compared with homozygous G-allele carriers.Conclusions: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele. This interaction may have potential implications for public health and disease prevention.