新疆维汉两民族阿尔茨海默病的分子流行病学研究
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摘要
目的:了解新疆维、汉民族中老年人群阿尔茨海默病(AD)的现患状况及分布特点,探讨AD危险因素;在此基础上研究维、汉AD患者的APOE、A2M基因多态性和AD相关基因型及等位基因频率的变化,为深入研究AD的病因及其防治策略提供基础资料。
方法:2004年7月到2007年6月,根据美国精神病学会的精神障碍诊断和统计手册第四修订版(DSM-IV)中痴呆的临床诊断标准和美国国立神经病、语言机能紊乱和卒中研究所AD和相关疾病协会标准( NINCDS-ADRDA标准),采用分层随机多级整群抽样方式、以现场问卷调查与入户调查相结合的方法,抽取新疆南疆的巴州焉耆县县城及周边7个乡镇和和田地区墨玉县、和田县县城及周边6个乡镇,东疆的吐鲁番地区鄯善县县城及周边9个乡镇,北疆的博尔塔拉自治洲博乐市市区、博乐县、温泉县共31个乡镇和昌吉州昌吉市3个社区及周边5个乡镇、乌鲁木齐市白石桥社区,年龄大于50岁的维、汉族中老年人进行AD现患状况调查;采用病例对照研究方法,按病例组年龄段以1:2比例随机选出对照进行非条件的Logistic模型单因素和多因素分析,评估社会人口学因素、生物学因素、家族史等变量对AD的影响;在此基础上随机抽取209例散发AD患者,平均年龄74.2±12.6岁,其中维吾尔族111例,汉族98例;匹配正常对照220名,平均年龄73.8±13.1岁,其中维吾尔族117例,汉族103例,应用聚合酶链反应及限制性片段长度多态性技术检测APOE、A2M基因多态性,采用病例-对照的关联分析方法对AD患者与正常对照的基因型和等位基因频率进行分析。
结果:1.流行病学共调查8284人,新疆维、汉民族总的AD粗患病率为3.66%,维吾尔族、汉族AD粗患病率分别为3.24%和4.19%。按2000年全国人口年龄构成标化,维、汉民族总的AD标化患病率为3.50%,维吾尔族、汉族分别为2.68%和4.31%;新疆维、汉民族总的血管性痴呆(VD)粗患病率为1.05%,维吾尔族、汉族VD粗患病率分别为1.11%和0.97%,维、汉两民族VD的标化患病率为0.98%,维吾尔族、汉族分别为1.00%和0.96%;抽样人群中,维吾尔族男性、女性粗患病率分别为2.54%和3.93%,标化患病率分别为1.75%和3.89%;汉族男性、女性粗患病率分别为2.51%和5.54%,标化患病率分别为2.17%和6.26%。维吾尔族、汉族男女AD患病率在各年龄组间有显著性差异,均随年龄增加而上升,AD患病率均随着文化程度的增高而明显降低,维、汉不同职业AD患病率有显著性差异,均是家庭妇女AD患病率最高。2.AD危险因素的单因素分析结果显示性别、脑外伤史、饮酒史、头围、糖代谢紊乱、血清总胆固醇、低密度脂蛋白在两组间的差异具有统计学意义(P<0.05);在此基础上以是否诊断为很可能是AD为因变量,性别、脑外伤史、饮酒史、头围、糖代谢紊乱、血清总胆固醇和低密度脂蛋白为自变量,再进行多因素非条件Logistic回归分析,结果显示性别(女性)、脑外伤、糖代谢异常及血清T-ch(升高)增加AD的发病风险(OR值分别为3.159,3.085,1.779,1.626)(P均<0.05),头围(大)则减少AD的发病风险(OR=0.900)(P<0.05)。3.基因多态性分析表明在AD组和对照组中ApoE3/4基因型分布不同,AD组为28.23%,对照组为13.18%,差异具有统计学意义(P<0.05),而ApoE3/3基因型对照组明显高于AD组,差异亦有统计学意义(P<0.05);ApoEε4等位基因在AD组中出现的频率明显高于对照组,分别为14.83%和7.95%,两组间的差异也有统计学意义(P<0.05);在维、汉不同民族间ApoE3/4基因型分布和ApoEε4等位基因频率AD和对照组中的差异均有统计学差异(P<0.05);在维、汉不同民族不同性别间比较,维族男性ApoE3/4基因型分布在AD组和对照组存在差异,而ApoEε4等位基因频率分别在维族女性和汉族女性的AD组和对照组中均存在差异(P<0.05)。4.维、汉不同民族A2M基因多态型分布不同,汉族人群I/I基因型多于维族,并且等位基因I的频率也是汉族高于维族,而维族人群中I/V基因型及等位基因V的频率高于汉族,表现出明显的族别差异性(P<0.05);维、汉不同民族不同性别间A2M等位基因I及V的频率分布均有统计学意义(P<0.05)。AD组中维族女性A2M等位基因V的频率最高为9.42%,汉族男性最低为1.39%;而汉族男性A2M等位基因I的频率最高为98.61%,维族女性最低为90.58%。伴有ApoEε4的AD组与对照组间,A2M各种基因型及等位频率分布差异均无统计学意义,而不伴有ApoEε4的AD组与对照组间,A2M基因中I/V基因型分布差异有统计学意义(P<0.05),AD组I/V基因型分布高于对照组,说明A2M基因可能独立于APOEε4,而影响AD的发病。
结论:1.新疆维、汉民族AD的总粗患病率为3.66%(标化患病率为3.50%),维吾尔族AD粗患病率为3.24%(标化患病率为2.68%),汉族AD粗患病率为4.19%(标化患病率为4.31%);汉族高于维吾尔族(P<0.05),AD的患病率存在着族别、性别、年龄、职业、文化程度的差异性。2.危险因素中女性、脑外伤、糖代谢异常及血清T-ch升高是AD的危险因素,头围尺寸大是AD的保护因素。3.基因多态性分析表明与散发AD密切相关的ApoE基因在AD组和对照组中分布不同,携带ApoE3/4基因型和ApoEε4等位基因频率是AD发生的危险因素,而维、汉不同民族间ApoE各基因型及等位基因频率差异无统计学意义。4.维、汉两民族AD患者与A2MI1000V多态性有关,且A2M基因型及等位基因频率分布表现出明显的族别、性别的差异性,A2M可能独立于ApoEε4而对AD的发生起一定作用。
Objective: To find out the situlation and distribution characteristics of Alzheimer's disease among the middle-aged and elderly population in Xinjiang Uygur and Han nationalities,and furthermore,to explore the polymorphism change with APOE、A2M genes and the changes of AD genotype and allele frequency in different ethnic groups, investigate the related AD factors,and additionally,to provide the initial value for intensive study on the pathogeny,prophylaxis and treatment of AD.
Method: Adopt the combined methods of spot field and house-to-house investigation with stratified multi-stage cluster sampling according to the DSM-IV diagnostic criteria for dementia in USA and the United States language function disorders and Stroke Institute of AD and related diseases standards Association (NINCDS- ADRDA criteria). From July of 2004 to July of 2007,we randomly drew samples from the Xinjiang Uygur and Han nationalities above 50 from the 6 areas such as Bazhou Yanqi County and the surrounding seven counties and townships,Hotan Prefecture Moyu and Hotan county town and the surrounding six townships in southern Xinjiang;Turpan region southwest of the county town and surrounding nine rural towns in Eastern Xinjiang, the northern suburbs Bole area,the suburbs of the city, a total of 31 urban and township Changji Hui Autonomous Prefecture of Changji City and the surrounding village teams,Urumqi City Community. We carried a 1:2 case-control study according to the case group age and assess the socio-demographic factors,biological factors, family history etc to impact of the AD by univariate and multivariate non- conditional Logistic regression analysis. Based on epidemiological survey, we selected randomly 209 cases of sporadic AD patients whose average age is 74.2±12.6, 111 cases of Uygur and Han 98 cases were selected; we also selected 220 normal cases whoes the average age 73.8±13.1 years, with 117 cases of Uygur, 103 cases of Han. We analyzed the polymorphism change with APOE、A2M genes by polymerase chain reaction,and studied on the changes of AD genotype and allele frequency by the restriction fragment length polymorphism methods.
Results: 1.A total of 8284 survey,Xinjiang AD the average AD crude prevalence rate is 3.66% among the 8284 samples,while the rate in Uygur and Han are 3.24% and 4.19% respectively. According to population composition by age in the 2000 nationwide census,the average AD standardized illness rate is 3.50%, the rates of Uygur and Han are 2.68% and 4.31% respectively; The crude prevalence rate in vascular dementia (VD)is 1.05%,the rates of Uygu and Han are 1.11% and 0.97%,Xinjiang VD standardized illness rate is 0.98%,the rates of Uygur and Han are 1.00% and 0.96% respectively; among AD samples, the crude prevalence rate of Uighur male and female are 2.54% and 3.93% respectively,while the age-adjusted standardized illness rate are 1.75% and 3.89%; The crude prevalence rate of Han male and female are 2.51% and 5.54%,the age-adjusted standardized illness rate are 2.17% and 6.26%. The prevalence rate of male and female has significance differences among every age group,and increase with age increasing. The AD prevalence rates among Uygur and Han obviously reduce with the increasing educational level. The survey found that AD prevalence rate in Uygur and Han nationalities has significance differences in different occupations,the housewife among Uighur and Han is suffering from the highest rate of AD,workers is the lowest one.2. In the related factors of AD study: Univariate analysis showed the relationship between AD and gender,brain trauma,alcohol history,head circumference,the sugar metabolization disorder,total cholesterol,low density lipoprotein (LDL) were statistically significant (P<0.05). Multivariate analysis showed that gender,brain trauma,the sugar metabolization disorder,higher total cholesterol have effect on the risk of AD,Longer head circumference,while lower the risk of AD.3. The gene polymorphism analysis indicated that the ApoE3/4 genotype distribution is different in the AD group and the control group,the AD group is 28.23%,the control group is 13.18%,the difference has statistics significance (P<0.05); But the ApoE3/3 genotype of control group is higher than the AD group obviously,the difference also has statistics significance (P<0.05); In Uygur,Hans different nationality,the ApoE3/4 genotype distribution and allele frequencies of ApoEε4 between the AD group and the control group have also significant (P<0.05); In Uygur,Hans different nationality,during different sex the comparison,the Uygur males ApoE3/4 genotype distributes in the AD group and the control group existence difference,but ApoEε4 the allele frequency separately has the difference in the Uygur and Han women female between AD group and the control group (P<0.05). 4. A2M gene polymorphism distribution is different in Uygur and Hans different nationality,The A2M genotype distribution displays the obvious nationality difference(P<0.05),and the Han crowd I/I genotype and the allele I frequency is higher than the Uygur national minority,but in the Uygur national minority crowd the I/V genotype and the allele V frequency is higher than the Han Nationality; during different sex A2M allele I and V frequency distribution has statistics significance (P<0.05),in the AD group of the Uygur,the highest females A2M allele V frequency is female, high, above.42%, the Han male is lowest 1.39%; while the Han men A2M I allele frequencies is up to98.61 %,the lowest for women Uygurs is 90.58%. Accompanied by ApoEε4 between the AD and the control group,A2M genotype and the allele frequency distribution have not statistics significance,but is not accompanied by ApoEε4 between the AD group and the control group,the I/V genotype of A2M gene distributes in the AD group to be higher than the control group,showed significance(P<0.05).
Conclusion: 1. Xinjiang AD crude prevalence rate is 3.66%(standardized incidence is 3.50%), Uygur, Han AD Rough prevalence rates are 3.24% and 4.19% respectively(standardized incidence are 2.68%and 4.31%), the AD prevalence rates of Hans is higher than the Uygurs(P<0.05), there are significant differences among the nationality,gender,age,occupation and cultural.2.In risks analyses,the study demonstrated that gender, brain trauma,the sugar metabolization disorder,higher total cholesterol are risk factors for AD, longer head circumference may be one of protective risk factors. 3. The gene polymorphism analysis indicated the AD is closely related to the ApoE gene, and ApoE gene distributes differently in the AD group and the control group; carries the ApoE3/4 genotype and ApoEε4 the allele frequency is the risk factor AD,but between Uygur and Han different nationality, ApoE various genotypes and allele frequency difference were not statistically significant.4. The AD of Uygur and Han nationalities has relation with A2MI100V polymorphism, and A2M genotype and allele frequency distribution shows the nationality, gender differences,A2M might be independent from the ApoEε4 and have effect on occurrence of AD.
方法:2004年7月到2007年6月,根据美国精神病学会的精神障碍诊断和统计手册第四修订版(DSM-IV)中痴呆的临床诊断标准和美国国立神经病、语言机能紊乱和卒中研究所AD和相关疾病协会标准( NINCDS-ADRDA标准),采用分层随机多级整群抽样方式、以现场问卷调查与入户调查相结合的方法,抽取新疆南疆的巴州焉耆县县城及周边7个乡镇和和田地区墨玉县、和田县县城及周边6个乡镇,东疆的吐鲁番地区鄯善县县城及周边9个乡镇,北疆的博尔塔拉自治洲博乐市市区、博乐县、温泉县共31个乡镇和昌吉州昌吉市3个社区及周边5个乡镇、乌鲁木齐市白石桥社区,年龄大于50岁的维、汉族中老年人进行AD现患状况调查;采用病例对照研究方法,按病例组年龄段以1:2比例随机选出对照进行非条件的Logistic模型单因素和多因素分析,评估社会人口学因素、生物学因素、家族史等变量对AD的影响;在此基础上随机抽取209例散发AD患者,平均年龄74.2±12.6岁,其中维吾尔族111例,汉族98例;匹配正常对照220名,平均年龄73.8±13.1岁,其中维吾尔族117例,汉族103例,应用聚合酶链反应及限制性片段长度多态性技术检测APOE、A2M基因多态性,采用病例-对照的关联分析方法对AD患者与正常对照的基因型和等位基因频率进行分析。
结果:1.流行病学共调查8284人,新疆维、汉民族总的AD粗患病率为3.66%,维吾尔族、汉族AD粗患病率分别为3.24%和4.19%。按2000年全国人口年龄构成标化,维、汉民族总的AD标化患病率为3.50%,维吾尔族、汉族分别为2.68%和4.31%;新疆维、汉民族总的血管性痴呆(VD)粗患病率为1.05%,维吾尔族、汉族VD粗患病率分别为1.11%和0.97%,维、汉两民族VD的标化患病率为0.98%,维吾尔族、汉族分别为1.00%和0.96%;抽样人群中,维吾尔族男性、女性粗患病率分别为2.54%和3.93%,标化患病率分别为1.75%和3.89%;汉族男性、女性粗患病率分别为2.51%和5.54%,标化患病率分别为2.17%和6.26%。维吾尔族、汉族男女AD患病率在各年龄组间有显著性差异,均随年龄增加而上升,AD患病率均随着文化程度的增高而明显降低,维、汉不同职业AD患病率有显著性差异,均是家庭妇女AD患病率最高。2.AD危险因素的单因素分析结果显示性别、脑外伤史、饮酒史、头围、糖代谢紊乱、血清总胆固醇、低密度脂蛋白在两组间的差异具有统计学意义(P<0.05);在此基础上以是否诊断为很可能是AD为因变量,性别、脑外伤史、饮酒史、头围、糖代谢紊乱、血清总胆固醇和低密度脂蛋白为自变量,再进行多因素非条件Logistic回归分析,结果显示性别(女性)、脑外伤、糖代谢异常及血清T-ch(升高)增加AD的发病风险(OR值分别为3.159,3.085,1.779,1.626)(P均<0.05),头围(大)则减少AD的发病风险(OR=0.900)(P<0.05)。3.基因多态性分析表明在AD组和对照组中ApoE3/4基因型分布不同,AD组为28.23%,对照组为13.18%,差异具有统计学意义(P<0.05),而ApoE3/3基因型对照组明显高于AD组,差异亦有统计学意义(P<0.05);ApoEε4等位基因在AD组中出现的频率明显高于对照组,分别为14.83%和7.95%,两组间的差异也有统计学意义(P<0.05);在维、汉不同民族间ApoE3/4基因型分布和ApoEε4等位基因频率AD和对照组中的差异均有统计学差异(P<0.05);在维、汉不同民族不同性别间比较,维族男性ApoE3/4基因型分布在AD组和对照组存在差异,而ApoEε4等位基因频率分别在维族女性和汉族女性的AD组和对照组中均存在差异(P<0.05)。4.维、汉不同民族A2M基因多态型分布不同,汉族人群I/I基因型多于维族,并且等位基因I的频率也是汉族高于维族,而维族人群中I/V基因型及等位基因V的频率高于汉族,表现出明显的族别差异性(P<0.05);维、汉不同民族不同性别间A2M等位基因I及V的频率分布均有统计学意义(P<0.05)。AD组中维族女性A2M等位基因V的频率最高为9.42%,汉族男性最低为1.39%;而汉族男性A2M等位基因I的频率最高为98.61%,维族女性最低为90.58%。伴有ApoEε4的AD组与对照组间,A2M各种基因型及等位频率分布差异均无统计学意义,而不伴有ApoEε4的AD组与对照组间,A2M基因中I/V基因型分布差异有统计学意义(P<0.05),AD组I/V基因型分布高于对照组,说明A2M基因可能独立于APOEε4,而影响AD的发病。
结论:1.新疆维、汉民族AD的总粗患病率为3.66%(标化患病率为3.50%),维吾尔族AD粗患病率为3.24%(标化患病率为2.68%),汉族AD粗患病率为4.19%(标化患病率为4.31%);汉族高于维吾尔族(P<0.05),AD的患病率存在着族别、性别、年龄、职业、文化程度的差异性。2.危险因素中女性、脑外伤、糖代谢异常及血清T-ch升高是AD的危险因素,头围尺寸大是AD的保护因素。3.基因多态性分析表明与散发AD密切相关的ApoE基因在AD组和对照组中分布不同,携带ApoE3/4基因型和ApoEε4等位基因频率是AD发生的危险因素,而维、汉不同民族间ApoE各基因型及等位基因频率差异无统计学意义。4.维、汉两民族AD患者与A2MI1000V多态性有关,且A2M基因型及等位基因频率分布表现出明显的族别、性别的差异性,A2M可能独立于ApoEε4而对AD的发生起一定作用。
Objective: To find out the situlation and distribution characteristics of Alzheimer's disease among the middle-aged and elderly population in Xinjiang Uygur and Han nationalities,and furthermore,to explore the polymorphism change with APOE、A2M genes and the changes of AD genotype and allele frequency in different ethnic groups, investigate the related AD factors,and additionally,to provide the initial value for intensive study on the pathogeny,prophylaxis and treatment of AD.
Method: Adopt the combined methods of spot field and house-to-house investigation with stratified multi-stage cluster sampling according to the DSM-IV diagnostic criteria for dementia in USA and the United States language function disorders and Stroke Institute of AD and related diseases standards Association (NINCDS- ADRDA criteria). From July of 2004 to July of 2007,we randomly drew samples from the Xinjiang Uygur and Han nationalities above 50 from the 6 areas such as Bazhou Yanqi County and the surrounding seven counties and townships,Hotan Prefecture Moyu and Hotan county town and the surrounding six townships in southern Xinjiang;Turpan region southwest of the county town and surrounding nine rural towns in Eastern Xinjiang, the northern suburbs Bole area,the suburbs of the city, a total of 31 urban and township Changji Hui Autonomous Prefecture of Changji City and the surrounding village teams,Urumqi City Community. We carried a 1:2 case-control study according to the case group age and assess the socio-demographic factors,biological factors, family history etc to impact of the AD by univariate and multivariate non- conditional Logistic regression analysis. Based on epidemiological survey, we selected randomly 209 cases of sporadic AD patients whose average age is 74.2±12.6, 111 cases of Uygur and Han 98 cases were selected; we also selected 220 normal cases whoes the average age 73.8±13.1 years, with 117 cases of Uygur, 103 cases of Han. We analyzed the polymorphism change with APOE、A2M genes by polymerase chain reaction,and studied on the changes of AD genotype and allele frequency by the restriction fragment length polymorphism methods.
Results: 1.A total of 8284 survey,Xinjiang AD the average AD crude prevalence rate is 3.66% among the 8284 samples,while the rate in Uygur and Han are 3.24% and 4.19% respectively. According to population composition by age in the 2000 nationwide census,the average AD standardized illness rate is 3.50%, the rates of Uygur and Han are 2.68% and 4.31% respectively; The crude prevalence rate in vascular dementia (VD)is 1.05%,the rates of Uygu and Han are 1.11% and 0.97%,Xinjiang VD standardized illness rate is 0.98%,the rates of Uygur and Han are 1.00% and 0.96% respectively; among AD samples, the crude prevalence rate of Uighur male and female are 2.54% and 3.93% respectively,while the age-adjusted standardized illness rate are 1.75% and 3.89%; The crude prevalence rate of Han male and female are 2.51% and 5.54%,the age-adjusted standardized illness rate are 2.17% and 6.26%. The prevalence rate of male and female has significance differences among every age group,and increase with age increasing. The AD prevalence rates among Uygur and Han obviously reduce with the increasing educational level. The survey found that AD prevalence rate in Uygur and Han nationalities has significance differences in different occupations,the housewife among Uighur and Han is suffering from the highest rate of AD,workers is the lowest one.2. In the related factors of AD study: Univariate analysis showed the relationship between AD and gender,brain trauma,alcohol history,head circumference,the sugar metabolization disorder,total cholesterol,low density lipoprotein (LDL) were statistically significant (P<0.05). Multivariate analysis showed that gender,brain trauma,the sugar metabolization disorder,higher total cholesterol have effect on the risk of AD,Longer head circumference,while lower the risk of AD.3. The gene polymorphism analysis indicated that the ApoE3/4 genotype distribution is different in the AD group and the control group,the AD group is 28.23%,the control group is 13.18%,the difference has statistics significance (P<0.05); But the ApoE3/3 genotype of control group is higher than the AD group obviously,the difference also has statistics significance (P<0.05); In Uygur,Hans different nationality,the ApoE3/4 genotype distribution and allele frequencies of ApoEε4 between the AD group and the control group have also significant (P<0.05); In Uygur,Hans different nationality,during different sex the comparison,the Uygur males ApoE3/4 genotype distributes in the AD group and the control group existence difference,but ApoEε4 the allele frequency separately has the difference in the Uygur and Han women female between AD group and the control group (P<0.05). 4. A2M gene polymorphism distribution is different in Uygur and Hans different nationality,The A2M genotype distribution displays the obvious nationality difference(P<0.05),and the Han crowd I/I genotype and the allele I frequency is higher than the Uygur national minority,but in the Uygur national minority crowd the I/V genotype and the allele V frequency is higher than the Han Nationality; during different sex A2M allele I and V frequency distribution has statistics significance (P<0.05),in the AD group of the Uygur,the highest females A2M allele V frequency is female, high, above.42%, the Han male is lowest 1.39%; while the Han men A2M I allele frequencies is up to98.61 %,the lowest for women Uygurs is 90.58%. Accompanied by ApoEε4 between the AD and the control group,A2M genotype and the allele frequency distribution have not statistics significance,but is not accompanied by ApoEε4 between the AD group and the control group,the I/V genotype of A2M gene distributes in the AD group to be higher than the control group,showed significance(P<0.05).
Conclusion: 1. Xinjiang AD crude prevalence rate is 3.66%(standardized incidence is 3.50%), Uygur, Han AD Rough prevalence rates are 3.24% and 4.19% respectively(standardized incidence are 2.68%and 4.31%), the AD prevalence rates of Hans is higher than the Uygurs(P<0.05), there are significant differences among the nationality,gender,age,occupation and cultural.2.In risks analyses,the study demonstrated that gender, brain trauma,the sugar metabolization disorder,higher total cholesterol are risk factors for AD, longer head circumference may be one of protective risk factors. 3. The gene polymorphism analysis indicated the AD is closely related to the ApoE gene, and ApoE gene distributes differently in the AD group and the control group; carries the ApoE3/4 genotype and ApoEε4 the allele frequency is the risk factor AD,but between Uygur and Han different nationality, ApoE various genotypes and allele frequency difference were not statistically significant.4. The AD of Uygur and Han nationalities has relation with A2MI100V polymorphism, and A2M genotype and allele frequency distribution shows the nationality, gender differences,A2M might be independent from the ApoEε4 and have effect on occurrence of AD.
引文
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