强直性脊柱炎患者Fc受体样基因遗传易感性及与环境交互作用研究
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摘要
目的分析可能与强直性脊柱炎(ankylosing spondylitis, AS)发病有关的Fc受体样基因遗传易感性及环境影响因素,并初步探讨基因与环境暴露因素交互效用(gene-environmental interaction)在强直性脊柱炎发生中的作用,为强直性脊柱炎的病因学研究和预防干预提供科学依据。
方法选择安徽省某三甲医院风湿科门诊2007年7月-2009年3月165例AS患者作为病例组,选择184例同期健康献血者作为对照,参照Bath强直性脊柱炎功能指数(Bath AS functional index, BASFI)和总体背痛程度量表设计问卷,调查患者的一般人口学特征(性别、年龄、民族、职业等)、实验室检查结果和环境因素暴露情况(吸烟、饮酒、饮食、感染史等)。采集强直性脊柱炎患者及对照的外周静脉血(约5ml),乙二胺四乙酸(ethylene diamine tetraacetic acid, EDTA)抗凝并分离血浆,盐析法提取DNA,采用聚合酶链式反应(polymerase chain reaction, PCR)对目的基因进行扩增,并采用连接酶检测反应(ligase detection reaction, LDR)进行Fc受体样基因簇单核苷酸筛查和鉴定。通过病例对照设计研究方案进行遗传易感性分析,同时采用多项有序分类的Logisitc回归方法对可能影响患者总体背痛程度和BASFI指数的影响因素进行分析;并用单纯病例研究(case-only study)的方法,应用Logistic回归对Fc受体样3基因(Fc receptor like,FCRL3 )、FCRL5基因多态性与吸烟、饮酒、睡眠状况、感染史等多种环境危险因素之间的交互作用进行初步分析。其中吸烟患者定义为每天吸烟1支以上持续1年或1年内吸烟总量在18包以上,饮酒患者定义为每周饮酒2次及以上,睡眠状况分为较好、一般及较差3类,感染史分为有、无2类。以α=0.05为检验水准。
结果165例AS患者中男性133例(80.6%),女性32例(19.4%),男女之比为4.16:1.。患者平均年龄为28.4±9.2岁,职业构成以农民(40.2%)和工人(24.1%)为主。遗传易感性研究结果显示,FCRL3基因可能与AS遗传易感性无关(χ2=0.00,p=0.983;χ2=0.099,p=0.952),而FCRL5基因可能与AS遗传易感性有关(χ2=27.61,p=0.00;χ2=42.30,p=0.00)。多因素Logistic回归分析结果显示,性别、病程、学历、饮酒史可能是BASFI指数的影响因素(p<0.05)。交互作用分析提示饮酒与FCRL3基因存在一定的交互作用[OR=2.56(1.12-5.88), p=0.026];睡眠情况与FCRL3基因[OR=0.15(0.09-0.24), p=0.00]、FCRL5基因[OR=0.14(0.09-0.22), p=0.00]均存在明显的交互作用。
结论Fc受体样基因簇中存在与AS发生有关的易感基因,同时在从事体力劳动的青壮年男性群体中开展有关强直性脊柱炎知识的健康教育,普及饮酒对本病的危害,提倡充足睡眠的重要性,对于该病的早期预防与控制,都有非常重要的公共卫生学价值。
Objective To analyze FCRL genetic susceptibility and environmental factors of ankylosing spondylitis, and explore the gene-environmental interaction role in ankylosing spondylitis, in order to provide a scientific basis for the etiology research and prevention of ankylosing spondylitis.
Methods 165 AS outpatients were selected from the department of rheumatism and immunity of a Grade III Level A hospital in Anhui province, and 184 cases of healthy blood donors were selected as controls the same period. The questionnaire was designed according to the Bath AS functional index and the total backache index. The demographic characteristics (sex, age, nation and occupy), laboratory test results and environmental factors exposure (smoking, drinking, diet and infection history) were investigated. The peripheral blood (5ml) of outpatients and controls were anticoagulanted by EDTA and the plasma were segregated. DNA were extracted by salting-out method. The objective gene was amplified by PCR, and FCRL gene cluster single nucleotide were screened and identified by LDR. A case-control study method was used to analyze genetic susceptibility, while a multinomial Logistic regression was used to analyze the factors of total bachache degree and BASFI index of AS patients. The interaction between FCRL3, FCRL5 gene and environmental factors (smoking,drinking,sleeping condition and infection history )was studied by using Logistic regression and according to case-only study method. The smoking patients were defined as one cigarette a day lasting for one year or 18 bags per year, the drinking patients were defined as more than two times per week, the sleeping condition contains well, moderate and bad three categories, the infection history contains yes or no two categories.α=0.05.
Results The male outpatients were 133 cases(80.6%),the female outpatients were 32 cases(19.4%),and the male to female ratio was 4.16:1.The average age of patients was 28.4±9.2 years, and the main occupations were farmers(40.2%) and workers(24.1%). Genetic susceptibility results showed that there may be no association between FCRL3 gene and the gentic susceptibility of AS(χ2=0.00,p=0.983;χ2=0.099,p=0.952), but there is an association between FCRL5 gene and the genetic susceptibility of AS(χ2=27.61,p=0.00;χ2=42.30,p=0.00). Multivariate Logistic regression showed that sex, disease history, education degree and drinking history were factors of BASFI index(p<0.05). Interaction analysis pointed out that there was certain interaction between drinking and FCRL3 gene[OR=2.56(1.12-5.88), p=0.026], and there was also significant interaction between FCRL3 gene[OR=0.15(0.09-0.24), p=0.00], FCRL5 gene[OR=0.14(0.09-0.22), p=0.00]and sleeping conditions.
Conclusions Some susceptibility genes related to the pathogenesis of AS may occurred in FCRL gene cluster. The health education of ankylosing spondylitis in a crowd of young men who had a manual work, and to popularize the harm of drinking and the importance of adequate sleeping can show a lot of public health significance for the early prevention and control of ankylosing spondylitis.
方法选择安徽省某三甲医院风湿科门诊2007年7月-2009年3月165例AS患者作为病例组,选择184例同期健康献血者作为对照,参照Bath强直性脊柱炎功能指数(Bath AS functional index, BASFI)和总体背痛程度量表设计问卷,调查患者的一般人口学特征(性别、年龄、民族、职业等)、实验室检查结果和环境因素暴露情况(吸烟、饮酒、饮食、感染史等)。采集强直性脊柱炎患者及对照的外周静脉血(约5ml),乙二胺四乙酸(ethylene diamine tetraacetic acid, EDTA)抗凝并分离血浆,盐析法提取DNA,采用聚合酶链式反应(polymerase chain reaction, PCR)对目的基因进行扩增,并采用连接酶检测反应(ligase detection reaction, LDR)进行Fc受体样基因簇单核苷酸筛查和鉴定。通过病例对照设计研究方案进行遗传易感性分析,同时采用多项有序分类的Logisitc回归方法对可能影响患者总体背痛程度和BASFI指数的影响因素进行分析;并用单纯病例研究(case-only study)的方法,应用Logistic回归对Fc受体样3基因(Fc receptor like,FCRL3 )、FCRL5基因多态性与吸烟、饮酒、睡眠状况、感染史等多种环境危险因素之间的交互作用进行初步分析。其中吸烟患者定义为每天吸烟1支以上持续1年或1年内吸烟总量在18包以上,饮酒患者定义为每周饮酒2次及以上,睡眠状况分为较好、一般及较差3类,感染史分为有、无2类。以α=0.05为检验水准。
结果165例AS患者中男性133例(80.6%),女性32例(19.4%),男女之比为4.16:1.。患者平均年龄为28.4±9.2岁,职业构成以农民(40.2%)和工人(24.1%)为主。遗传易感性研究结果显示,FCRL3基因可能与AS遗传易感性无关(χ2=0.00,p=0.983;χ2=0.099,p=0.952),而FCRL5基因可能与AS遗传易感性有关(χ2=27.61,p=0.00;χ2=42.30,p=0.00)。多因素Logistic回归分析结果显示,性别、病程、学历、饮酒史可能是BASFI指数的影响因素(p<0.05)。交互作用分析提示饮酒与FCRL3基因存在一定的交互作用[OR=2.56(1.12-5.88), p=0.026];睡眠情况与FCRL3基因[OR=0.15(0.09-0.24), p=0.00]、FCRL5基因[OR=0.14(0.09-0.22), p=0.00]均存在明显的交互作用。
结论Fc受体样基因簇中存在与AS发生有关的易感基因,同时在从事体力劳动的青壮年男性群体中开展有关强直性脊柱炎知识的健康教育,普及饮酒对本病的危害,提倡充足睡眠的重要性,对于该病的早期预防与控制,都有非常重要的公共卫生学价值。
Objective To analyze FCRL genetic susceptibility and environmental factors of ankylosing spondylitis, and explore the gene-environmental interaction role in ankylosing spondylitis, in order to provide a scientific basis for the etiology research and prevention of ankylosing spondylitis.
Methods 165 AS outpatients were selected from the department of rheumatism and immunity of a Grade III Level A hospital in Anhui province, and 184 cases of healthy blood donors were selected as controls the same period. The questionnaire was designed according to the Bath AS functional index and the total backache index. The demographic characteristics (sex, age, nation and occupy), laboratory test results and environmental factors exposure (smoking, drinking, diet and infection history) were investigated. The peripheral blood (5ml) of outpatients and controls were anticoagulanted by EDTA and the plasma were segregated. DNA were extracted by salting-out method. The objective gene was amplified by PCR, and FCRL gene cluster single nucleotide were screened and identified by LDR. A case-control study method was used to analyze genetic susceptibility, while a multinomial Logistic regression was used to analyze the factors of total bachache degree and BASFI index of AS patients. The interaction between FCRL3, FCRL5 gene and environmental factors (smoking,drinking,sleeping condition and infection history )was studied by using Logistic regression and according to case-only study method. The smoking patients were defined as one cigarette a day lasting for one year or 18 bags per year, the drinking patients were defined as more than two times per week, the sleeping condition contains well, moderate and bad three categories, the infection history contains yes or no two categories.α=0.05.
Results The male outpatients were 133 cases(80.6%),the female outpatients were 32 cases(19.4%),and the male to female ratio was 4.16:1.The average age of patients was 28.4±9.2 years, and the main occupations were farmers(40.2%) and workers(24.1%). Genetic susceptibility results showed that there may be no association between FCRL3 gene and the gentic susceptibility of AS(χ2=0.00,p=0.983;χ2=0.099,p=0.952), but there is an association between FCRL5 gene and the genetic susceptibility of AS(χ2=27.61,p=0.00;χ2=42.30,p=0.00). Multivariate Logistic regression showed that sex, disease history, education degree and drinking history were factors of BASFI index(p<0.05). Interaction analysis pointed out that there was certain interaction between drinking and FCRL3 gene[OR=2.56(1.12-5.88), p=0.026], and there was also significant interaction between FCRL3 gene[OR=0.15(0.09-0.24), p=0.00], FCRL5 gene[OR=0.14(0.09-0.22), p=0.00]and sleeping conditions.
Conclusions Some susceptibility genes related to the pathogenesis of AS may occurred in FCRL gene cluster. The health education of ankylosing spondylitis in a crowd of young men who had a manual work, and to popularize the harm of drinking and the importance of adequate sleeping can show a lot of public health significance for the early prevention and control of ankylosing spondylitis.
引文
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2.蔡安季,苏卓娃,陈群.强直性脊柱炎发病机制的研究进展.放射免疫学杂志, 2007;20(1):54-57.
3.Lowe B, Psych D, Willand D, et al.Psychiatric comorbidity and work disability in patients with inflammatory rheumatic diseases.Psychosom Med,2004;66:395-402.
4.Warren A, Russell R.The importance of improving function in patients with pain.J Chin Rheumatol,2005,11:S6-S10.
5.Brown MA.Breakthroughs in genetic studies of ankylosing spondylitis.Rheuma- Tology(Oxford) ,2008,47:132-137.
6.Brown MA, Kennedy LG,MacGregor AJ,et al.Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment.Arthritis Rheum ,1997;40:1823-1828.
7.Masir N,Jones M,Pozzobon M,et al.Expression pattern of FCRL (FREB, FcRX) in normal and neoplastic human B cells. Br J Haematol,2004;127:335-343.
8.Hu X,Chang M,Saiki RK,et al.The functional -169T→C single-nucleotide polymorphism in FCRL3 is not associated with rheumatoid arthritis in white North Americans.Arthritis Rheum,2006;54:1022–1025.
9.N.Andrien,A M Goldstein.The case-combined-control design was efficient in detecting gene-environment interactions.Journal of Clinical Epidemiology,2004,57:662-671.
10.PENG XE,SHI Xishun,ZHOU Zijing,et al.Relationship between esophageal cancer and interactions of genes and environmental factors.World Chin J Digestol,2004,12:2531-2533.
11.施小明.单纯病例研究.疾病控制杂志,2001;5(3):239-242.
12 . BAI Jiangling , XUN Pengcheng , ZHAO Yang , et al . Estimation on gene-environment interaction in the partial case-control study . Chin J Epidemiol,2006,27:72-75.
13.汪媛.几种基因-环境、基因-基因交互作用研究方法的样本量比较.疾病控制杂志,2003;7(2):138-141.
14.Van der Linden S, Valkenburg HA, Cats A.Evaluation of diagnostic criteria for ankylosing spondylitis : a proposal for modification of the New York criteria.Arthritis Rheum, 1984,27(4):361-368.
15.Jin GF,Hu ZB,Ma HX,et al .Interaction between familial cancer history and smoking on the risk of lung cancer in a Chinese population.Chin J Epidemiol,2006;27:1095-1096.
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