Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers
Substitution of asparagine for aspartic acid at residue 9 (D9N) of lipoprotein lipase markedly augments risk of ischaemic heart disease in male smokers
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DOI：
10.1016/s0021-9150(99)00309-3
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发表时间：
2000-03-01
期刊：
影响因子：
5.3
通讯作者：
Humphries, SE
中科院分区：
文献类型：
--
作者：
Talmud, PJ;Bujac, S;Humphries, SE
脂蛋白脂酶(LPL)的遗传变异可能导致缺血性心脏病(IHD)的风险，LPL是富含甘油三酯(TG)颗粒的关键酶。我们对2708名中年健康欧洲男性进行了6年以上的随访，研究了两种常见LPL变异的携带者IHD的风险，其中天冬氨酸替代天冬氨酸第9位(D9N)，丝氨酸替代第291位(N291S)。携带频率N9为2.6%，S291为3.9%。在基线水平分别为9%和14%时，这两种变异分别与较高的血浆甘油三酯相关。在基线水平，28%的男性现在吸烟，吸烟与基因无关。根据吸烟状况，通过Cox的比例风险分析，评估LPL变异与疾病结局之间的关系。与非携带者相比，S291携带者患IHD的风险没有增加，而D9N基因和吸烟状况在确定IHD风险方面存在交互作用(P=0.0003)。在2248名非N9携带者中，吸烟使II-ID事件的风险增加1.6倍(95%可信区间：1.1-2.4%)。在58名N9携带者中，42名非吸烟者没有发生IHD事件，而16名吸烟者报告了5起IHD事件。与D9非吸烟者相比，吸烟和N9等位基因的联合作用使IHD事件的风险增加10.4倍(95%可信区间：4.7-22.8%)。这些发现不能用基线甘油三酯的混淆效应来解释。N9基因携带者似乎特别容易受到吸烟对IHD风险的不利影响，但这种易感性与该变异对血浆甘油三酯水平的影响无关。(C)2000爱思唯尔爱尔兰科学有限公司保留所有权利。
Genetic variants of lipoprotein lipase (LPL), a key enzyme in the hydrolysis of triglyceride (TG)-rich particles, may contribute to ischaemic heart disease (IHD) risk. We have examined the risk of IHD in carriers of two common LPL variants, asparagine substitution for aspartic acid at residue 9 (D9N) and serine for asparagine at residue 291 (N291S) in 2708 middle-aged healthy European men, followed for over 6 years. The carrier frequencies were 2.6% for N9, and 3.9% for S291. Both variants were associated with higher plasma TG at baseline of 9% and 14%, respectively. At baseline, 28% of men were current smokers and smoking was unrelated to genotype. Associations between LPL variants and disease outcome, according to smoking status, were assessed by Cox's proportional hazards analysis. S291 carriers showed no increased risk of IHD compared to non-carriers, while there was strong evidence of interaction between D9N genotype and smoking status (P = 0.0003) in determining the risk of IHD. In 2248 non-carriers of N9, smoking increased the risk of an II-ID event by 1.6 (95% CI: 1.1-2.4%) times. Among 58 N9 carriers, no IHD events occurred in 42 who were non-smokers, whereas five events were reported in 16 who smoked. The combined effect of smoking and N9 allele was to increase the risk of an IHD event by 10.4 (95% CI: 4.7-22.8%) times compared with D9 non-smokers. These findings could not be explained by confounding effects of baseline TG. Carriers of N9 appear to be especially vulnerable to the adverse effects of cigarette smoking on IHD risk, but this susceptibility is unrelated to the influence of this variant on plasma TG levels. (C) 2000 Elsevier Science Ireland Ltd. Ail rights reserved.