Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis
Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis
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DOI：
10.1093/brain/awq371
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发表时间：
2011-03-01
期刊：
影响因子：
14.5
通讯作者：
Alfredsson, Lars
中科院分区：
文献类型：
--
作者：
Hedstrom, Anna Karin;Sundqvist, Emilie;Alfredsson, Lars
遗传和环境因素都显示与多发性硬化症有轻微或中度的关联。假设，基因与环境的相互作用可能会产生更强的影响。在这项研究中，我们调查了遗传风险因素和吸烟与多发性硬化症风险之间的潜在相互作用。在瑞典进行了一项基于人群的病例对照研究，涉及多发性硬化症事件病例（843例，1209例对照）。根据吸烟状况和人白细胞抗原DRB1及人白细胞抗原A基因型对病例和对照组进行分类。采用logistic回归计算95%置信区间的优势比，比较不同基因型和吸烟习惯的受试者多发性硬化症的发病率。通过计算相互作用的归因比例来评估不同基因型之间以及基因型与吸烟之间的潜在相互作用。在吸烟者中观察到携带人类白细胞抗原DRB1*15和缺乏人类白细胞抗原A*02这两个遗传危险因素之间存在显著的相互作用，而在非吸烟者中则不存在这种相互作用。不同组间的优势比有相当大的差异。与不存在这两种遗传危险因素的非吸烟者相比，同时存在这两种遗传危险因素的吸烟者的优势比为13.5（8.1-22.6）。无遗传风险的吸烟者的比值比为1.4(0.9-2.1)，同时存在遗传风险因素的非吸烟者的比值比为4.9（3.6-6.6）。在有遗传风险因素的人群中，吸烟增加了2.8倍的风险，而在没有遗传风险因素的人群中，吸烟增加了1.4倍的风险。与人类白细胞抗原基因型相关的多发性硬化症的发生风险可能受到吸烟状况的强烈影响。这些发现与我们的假设一致，即肺部免疫反应的启动可能随后导致基因易感人群的多发性硬化症。
Both genetic and environmental factors display low or modest associations with multiple sclerosis. Hypothetically, gene-environment interactions may exert much stronger effects. In this study, we investigated potential interactions between genetic risk factors and smoking in relation to risk of developing multiple sclerosis. A population-based case-control study involving incident cases of multiple sclerosis (843 cases, 1209 controls) was performed in Sweden. Cases and controls were classified according to their smoking status and human leukocyte antigen DRB1 as well as human leukocyte antigen A genotypes. Subjects with different genotypes and smoking habits were compared with regard to incidence of multiple sclerosis, by calculating odds ratios with 95% confidence intervals employing logistic regression. The potential interaction between different genotypes, as well as between genotype and smoking, was evaluated by calculating attributable proportion due to interaction. A significant interaction between two genetic risk factors, carriage of human leukocyte antigen DRB1*15 and absence of human leukocyte antigen A*02, was observed among smokers whereas such an interaction was absent among non-smokers. There were considerable differences in odds ratios between the various groups. Compared with non-smokers with neither of the genetic risk factors, the odds ratio was 13.5 (8.1-22.6) for smokers with both genetic risk factors. The odds ratio for smokers without genetic risk was 1.4 (0.9-2.1) and the odds ratio for non-smokers with both genetic risk factors was 4.9 (3.6-6.6). Among those with both genetic risk factors, smoking increased the risk by a factor of 2.8 in comparison with a factor of 1.4 among those without the genetic risk factors. The risk of developing multiple sclerosis associated with human leukocyte antigen genotypes may be strongly influenced by smoking status. The findings are consistent with our hypothesis that priming of the immune response in the lungs may subsequently lead to multiple sclerosis in genetically susceptible people.