ApoE基因多态性和cav-1基因上游PPC长度多态性与AD、MCI和VD的相关性研究
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摘要
痴呆是严重危害老年人健康的常见疾病。随着人口老龄化的进一步发展，由痴呆造成的社会和经济负担会日益沉重。加快对痴呆病理生理机制的研究和药物开发刻不容缓。AD作为痴呆最主要的类型，目前取得的最大进展是对淀粉样蛋白级联反应在AD病理机制中作用的认识，而这来源于AD的3种致病性基因突变的发现。实际上，基因突变导致的AD仅占AD患者的一小部分，目前绝大部分的研究集中在AD的易感基因领域，由此而推及到其他类型的认知损害性疾病，如MCI和VD等。目前ApoEε4是唯一得到一致认同的AD风险基因，但是ε2与AD以及ApoE基因多态性与MCI和VD的相关性有待进一步证实，需要不同地区、不同种族的大样本分子流行病学研究。本研究在中国南方汉族人群中对ApoE基因多态性以及一种新的AD候选基因，即cav-1基因上游PPC的长度多态性与AD、MCI和VD的相关性进行了研究。
第一部分ApoE基因多态性与AD的相关性研究
目的：观察ApoE的ε2、ε4等位基因和携带ε2、ε4的基因型与AD及其不同亚型的相关性，并探讨其对AD发病年龄的影响以及在不同年龄段对于AD患病风险的影响。
方法：采用酚-氯仿法提取260例AD患者和286例正常对照者的外周血DNA，以扩增抗拒突变系统法检测ApoE基因多态性，在AD和NC组间进行病例对照研究，通过Logistic回归分析平衡混杂因素，观察ApoE基因多态性和AD的关系。
结果：在AD、LOAD和EOAD组，ε2等位基因和ε2(+)基因型的分布频率均显著低于相应的对照组(P＜0．05)；而ε4等位基因和ε4(+)基因型的频率则显著高于对照组(P＜0．05)。
在AD组，以ε3ε3基因型为参照，经Logistic回归分析平衡其他混杂因素，结果显示ε3ε4(P=0．000，OR=3．104，95％CI=2．031～4．745)和ε4ε4(P=0．000，OR=24．120，95％CI=5．567～104．512)显著增加AD的患病风险。ε4(+)基因型与AD患病呈显著正相关(P=0．000，OR=3．630，95％CI=2．425～5．424)，而携带ε2能显著降低AD的患病风险(P=0．046，OR=0．502，95％CI=0．255～0．988)。分层分析发现，ε2(+)基因型的作用仅见于女性和家族史(-)者；而ε4(+)基因型的作用可见于各个亚组。携带ε2或ε4对AD的发病年龄均无显著性影响(P＞0．05)。随着ε2拷贝数的增加，AD的患病率逐渐下降，但发病年龄无显著变化(P＞0．05)；而ε4拷贝数的增加则显著提高了AD的患病率，但对发病年龄也没有显著影响(P＞0．05)。
在LOAD组，ε2ε3基因型可以降低LOAD的患病风险(P=0．043，OR=0．358，95％CI=0．133～0．966)，而ε3ε4(P=0．000，OR=3．727，95％CI=2．101～6．610)和ε4ε4(P=0．000，OR=39．587，95％CI=5．039～311．017)增加LOAD的风险。ε2(+)基因型携带者LOAD的患病风险是ε3ε3携带者的36．4％(P=0．033，OR=0．364，95％CI=0．144～0．920)，而携带ε4患LOAD的风险是ε3ε3携带者的4．565倍(P=0．000，OR=4．565，95％CI=2．651～7．861)。分层分析发现，ε2(+)基因型的作用仅见于女性，但在家族史(-)者也存在降低LOAD风险的趋势(P=0．051)；ε4(+)基因型在各个亚组均增加LOAD的易感性。携带ε2的LOAD患者的发病年龄在女性亚组高于非携带者，而ε4携带者的发病年龄在女性和家族史(-)亚组明显低于非携带者。ε2拷贝数的增加使LOAD的患病率逐渐下降，发病年龄显著提高。而ε4拷贝数的增加则显著增加了LOAD的患病率，且明显降低了LOAD的发病年龄。
在EOAD组，ε3ε4(P=0．004，OR=2．613，95％CI=1．362～5．012)和ε4ε4(P=0．010，OR=15．866，95％CI=1．911～131．735)显著增加EOAD的易感性。ε2(+)基因型与EOAD的患病风险无显著相关性(P=0．458)，而ε4携带者患EOAD的风险是ε3ε3携带者的2．912倍(P=0．001，OR=2．912，95％CI=1．565～5．420)。分层分析发现，ε4(+)基因型的作用主要见于女性和家族史(-)者。携带ε2或ε4对EOAD的发病年龄均无显著性影响(P＞0．05)。ε4拷贝数的增加则显著提高了EOAD的患病率，但对EOAD的发病年龄没有显著影响(P＞0．05)。
按年龄进行细化分层发现，ApoEε2和ε4均在66-70岁年龄段对AD的患病风险施加最显著的影响。
结论：ApoEε4是AD(包括LOAD和EOAD)的危险因素，能以剂量依赖的方式增加患病风险，并能以剂量依赖的方式降低LOAD的发病年龄。ApoEε2是LOAD而非EOAD的保护性因素，可以提高LOAD的发病年龄。ApoEε2和ε4对AD的影响是年龄依赖性的，并受性别因素的影响。
第二部分cav-1基因上游PPC长度多态性与AD的相关性研究
目的：观察cav-1基因上游PPC长度多态性在汉族AD患者和正常对照者中的分布情况，以及和AD及其亚型的相关性。
方法：采用聚丙烯酰胺凝胶电泳法检测257例AD患者和279例正常对照者cav-1基因上游PPC长度多态性，通过Logistic回归分析观察其与AD的相关性。
结果：在AD和NC组中共检测到12种不同长度的等位片断，呈近似正态分布。S、L等位片断和携带S、L片段的基因型以及等长基因型均不影响AD的患病风险，也不影响AD的发病年龄。
以M／M基因型为参照，经Logistic回归分析发现，M／L基因型可以显著增加LOAD的患病风险(P=0．043，OR=2．196，95％CI=1．025～4．702)。分层分析发现，携带L等位片断使男性患LOAD的风险增加(P=0．007，OR=6．481，95％CI=1．685～24．935)，并可以降低非ε4携带者患LOAD的发病年龄(P=0．035)。
在EOAD组，携带S等位片断使女性的患病风险增加(P=0．013，OR=5．342，95％CI=1．426～20．004)，而等长基因型则增加了男性患EOAD的风险(P=0．038，OR=4．400，95％CI=1．082～1 7．884)。
对LOAD和EOAD组进行比较发现，L(+)基因型在男性LOAD组的分布频率明显高于EOAD组(x~2=3．979，P=0．046)；而S(+)基因型(x~2=5．358，P=0．021)在女性EOAD组的分布频率显著高于LOAD组。
按年龄进行细化分层发现，PPC基因型对AD的影响具有年龄依赖性。
结论：cav-1基因上游PPC-L等位片断是男性患LOAD的危险因素，而S等位片断是女性患EOAD的危险因素。等长基因型增加男性患EOAD的风险。L(+)基因型可以降低非ε4携带者患LOAD的发病年龄。PPC基因型对AD的影响具有年龄依赖性。LOAD和EOAD在遗传性易感因素方面可能存在差异。
第三部分ApoE基因多态性和cav-1基因上游PPC长度多态性与MCI的相关性研究
目的：观察cav-1基因上游PPC长度多态性在MCI患者中的分布，以及ApoE基因多态性和PPC长度多态性与MCI的相关性。
方法：分别应用扩增抗拒突变系统法和聚丙烯酰胺凝胶电泳法检测96例MCI患者和286例正常对照者的ApoE基因多态性和PPC长度多态性，采用病例对照和Logistic回归分析方法观察其与MCI的相关性。
结果：ε2在MCI和NC组间无明显差异(P=0．306)，而ε4在MCI组的分布显著高于NC组(x~2=22．572，P=0．000)。经Logistic回归分析发现，ε3ε4(P=0．041，OR=1．865，95％CI=1．025～3．393)和ε4ε4(P=0．007，OR=10．388，95％CI=1．870～57．705)显著增加MCI的患病风险。ε4(+)基因型与MCI的患病风险呈显著正相关(P=0．05，OR=2．241，95％CI=1．283～3．914)，而携带ε2不影响MCI的患病风险(P=0．614)。分层分析显示，ε4的作用主要体现在女性和家族史(-)者。ApoE基因多态性不影响MCI的发病年龄。
与AD组比较发现，ε2(+)基因型在MCI组的分布频率显著增高(x~2=6．040，P=0．014)；而ε4(+)基因型在两组间无显著性差异(P=0．116)。
在非ε4携带者中，MCI组L等位基因和L(+)基因型的分布频率高于NC组，经Logistic回归分析证明，携带L等位片段增加非ε4携带者患MCI的风险(P=0．032，OR=2．410，95％CI=1．080～5．379)。PPC长度多态性不影响MCI的发病年龄，在AD和MCI组间无差异。
结论：ApoEε4是MCI的危险因素，但不影响MCI的发病年龄。ε4的作用受性别影响，在女性作用显著。ε2在MCI组的分布频率显著低于AD组。cav-1基因上游PPC-L等位片断是非ε4携带者患MCI的危险因素。
第四部分ApoE基因多态性和cav-1基因上游PPC长度多态性与VD的相关性研究
目的：观察cav-1基因上游PPC长度多态性在VD患者中的分布，以及ApoE基因多态性和PPC长度多态性与VD的相关性。
方法：分别应用扩增抗拒突变系统法和聚丙烯酰胺凝胶电泳法检测54例VD患者和60例正常对照者的ApoE基因多态性和PPC长度多态性，采用病例对照和Logistic回归分析方法观察其与VD的相关性。
结果：ε2、ε4等位基因和携带ε2、ε4的基因型在VD和NC组间均无显著性差异(P＞0．05)，而与AD组相比，ε4(+)基因型在AD组的分布频率显著高于VD组(x~2=8．884，P=0．003)。
PPC长度多态性在VD与NC、VD与AD组间均没有显著性差异(P＞0．05)。
结论：ApoE基因多态性和PPC长度多态性均不影响VD的患病风险。
Dementia is one of the most common disorders among older populations.Withthe growth of old people,there are increasing demands on health services and costsfor patients with dementia at an alarming rate.Alzheimer's disease (AD) is the majorcause of dementia.The most important achievement in AD research is theamyloid-cascade hypothesis coming from the discoveries of three causative genes thatfacilitated the development of AD and dementia genetics.At present,most studiesfocus on susceptibility genes for AD and then expand to mild cognitive impairment(MCI) and vascular dementia (VD) et al.The ApoEε4 allele is the only consistentlyidentified risk factor for AD so far.The putative protective effect ofε2 allele and theassociation of ApoE gene polymorphism with MCI and VD remain in debate,especially in Han Chinese population.Moreover,it is essential to discover andidentify more new susceptibility genes to understand the pathogenesis of dementiabetter.We have described the frequencies of ApoE gene polymorphism and PPC allelelength polymorphism at the upstream region of cav-1 gene and the association ofthese polymorphisms with AD,MCI and VD in a clinic-based Han Chinesepopulation in Southern China.
Section 1 Association between ApoE gene polymorphism and AD
Objectives:To investigate the association between ApoE genotypes and AD as wellas the effect on age at onset.
Methods:260 patients with AD and 286 cognitively-normal control individuals weregenotyped for the ApoE alleles by amplification refractory mutation system (ARMS).Allele frequencies and genotypes in patients and control individuals were compared.Odds Ratio (OR) for developing AD and mean age at onset in different genotypeswere calculated using Logistic regression analysis and t test respectively.
Results:The frequencies ofε2 allele andε2(+) genotype were much lower in AD/LOAD/EOAD groups compared to NC groups.However,those ofε4 allele andε4(+) genotype were significantly higher.
OR for developing AD was significantly increased in carriers of ApoEε4 alleleand decreased in those of ApoEε2 allele compared to individuals with theε3ε3genotype.Individuals carryingε4ε4 genotype had OR of 24.120,while carriers ofε3ε4 had OR of 3.104.Individuals withε2(+) genotype andε4(+) genotype had OR of0.502 and 3.630 respectively.OR for developing AD was much higher in females.Risk increased or decreased but age at onset of AD didn't change with increasingcopies of the APOEε4 orε2 allele respectively.
The association between ApoE genotypes and LOAD was similar.Compared toε3ε3 genotype,carriers ofε3ε4 andε4ε4 genotype had OR of 3.727 and 39.587respectively,while individuals withε2ε3 had OR of 0.358.Individuals carryingε2(+)andε4(+) genotype had OR of 0.364 and 3.630 respectively.ApoE genotype hadstronger effects on LOAD in females too.Age at onset in LOAD patients wassignificantly elevated in a dose dependent manner with increasing copies ofε2 allelewhile reduced with increasing copies ofε4 allele.
ApoEε2 allele didn't correlate with the risk of developing EOAD,while carrierofε4(+) genotype had OR of 2.912.Individuals carryingε3ε4 andε4ε4 genotype hadOR of 2.613 and 15.866 respectively.The risk of EOAD was only increased in femaleindividuals withε4(+) genotype.Age at onset didn't change with increasing APOEε2orε4 allele.
Analysis in age at onset subgroups indicated that both APOEε2 andε4 allele hadmost obvious effects on AD from 66 to 70 years old.
Conclusion:ApoEε4 is a risk factor for developing AD(both LOAD and EOAD),which acts in a dose dependent manner.ApoEε2 is a protective factor for LOADrather than EOAD.The ApoE genotype specific effects on AD vary by age and sex.
Section 2 Association between PPC Allele Length Polymorphismat the Upstream Region of cav-1 Gene and AD
Objectives:To observe the frequencies of PPC allele length polymorphism in HanChinese AD patients and cognitively-normal control individuals and to investigate theassociation between PPC genotypes and AD.
Methods:257 patients with AD and 279 control individuals were genotyped for PPC by polyacrylamide gel electrophoresis(PAGE).Allele frequencies and genotypes inpatients and control individuals were compared.Odds Ratio for developing AD andmean age at onset in different genotypes were calculated using Logistic regressionanalysis and t test respectively.
Result:12 PPC allele lengths ranging from 118bp to 162bp were found in AD andcontrol individuals.Both short and long alleles didn't correlate with the risk fordeveloping AD and age at onset of AD.
Carriers of M/L genotype had OR of 2.196 compared to M/M genotype.OR was6.481 in males with long alleles for developing LOAD.Age at onset in LOADpatients was significantly reduced in absence of ApoEε4.
Females with short alleles had OR of 5.342 for EOAD and males with PPChomozygote for length had OR of 4.400 for developing EOAD.
The frequency of long alleles-positive genotype was significantly increased inmale LOAD group than in EOAD group,while that of short alleles-positive genotypewas much lower in female LOAD group than in EOAD group.
PPC alleles had different ORs for developing AD in distinct age at onsetsubgroups.
Conclusions:Long alleles of PPC have a risk effect on LOAD in males and shortalleles were risk factors of EOAD in females.Homozygote for length has a risk effecton EOAD in males.Long alleles can lower age at onset of LOAD in absence ofApoEε4 significantly.
Section 3 Association ofApoE gene polymorphismand PPC Allele Length Polymorphism with MCI
Objectives:To investigate the association of ApoE genotypes and PPC genotypeswith MCI.
Methods:96 patients with MCI and 286 control individuals were genotyped for ApoEand PPC.Allele frequencies and genotypes in patients and control individuals werecompared.Odds Ratio for developing MCI and mean age at onset in differentgenotypes were calculated using Logistic regression analysis and t test respectively.
Results:ApoEε2 allele didn't correlate with the risk of developing MCI,while carrierofε4(+) genotype had OR of 2.241.Individuals carryingε3ε4 andε4ε4 genotype hadOR of 1.865 and 10.388 respectively.The risk of MCI was only increased in female individuals withε4(+) genotype.Age at onset didn't change with increasing APOEε2orε4 allele.
Compared to AD group,the frequency ofε2(+) genotype was significantlyincreased in MCI group,but that ofε4(+) genotype was similar in MCI patients.
In absence of ApoEε4,the frequencies of long alleles and long alleles-positivegenotypes were much higher in MCI patients than in control individuals.Carriers oflong alleles had OR of 2.410 of developing MCI.
PPC genotypes didn't correlate with age at onset of MCI.
Conclusions:APOEε4 allele is a risk factor of MCI by sex but has no effect on age atonset.Long alleles of PPC have a risk effect on MCI in absence of ApoEε4.
Section 4 Association ofApoE gene polymorphismand PPC Allele Length Polymorphism with VD
Objectives:To investigate the association of ApoE genotypes and PPC genotypeswith VD.
Methods:54 patients with VD and 60 control individuals were genotyped for ApoEand PPC.Allele frequencies and genotypes in patients and control individuals werecompared.Odds Ratio for developing VD was calculated by Logistic regressionanalysis.
Results:The frequencies of ApoE alleles and genotypes in VD patients were notdifferent from those of control individuals,but the frequency ofε4(+) genotype in VDgroup was significantly lower than in AD group.
The frequencies of PPC alleles and genotypes in VD patients were not differentfrom those of control individuals.
Conclusions:ApoE and PPC genotypes have no effect on developing VD.
第一部分ApoE基因多态性与AD的相关性研究
目的：观察ApoE的ε2、ε4等位基因和携带ε2、ε4的基因型与AD及其不同亚型的相关性，并探讨其对AD发病年龄的影响以及在不同年龄段对于AD患病风险的影响。
方法：采用酚-氯仿法提取260例AD患者和286例正常对照者的外周血DNA，以扩增抗拒突变系统法检测ApoE基因多态性，在AD和NC组间进行病例对照研究，通过Logistic回归分析平衡混杂因素，观察ApoE基因多态性和AD的关系。
结果：在AD、LOAD和EOAD组，ε2等位基因和ε2(+)基因型的分布频率均显著低于相应的对照组(P＜0．05)；而ε4等位基因和ε4(+)基因型的频率则显著高于对照组(P＜0．05)。
在AD组，以ε3ε3基因型为参照，经Logistic回归分析平衡其他混杂因素，结果显示ε3ε4(P=0．000，OR=3．104，95％CI=2．031～4．745)和ε4ε4(P=0．000，OR=24．120，95％CI=5．567～104．512)显著增加AD的患病风险。ε4(+)基因型与AD患病呈显著正相关(P=0．000，OR=3．630，95％CI=2．425～5．424)，而携带ε2能显著降低AD的患病风险(P=0．046，OR=0．502，95％CI=0．255～0．988)。分层分析发现，ε2(+)基因型的作用仅见于女性和家族史(-)者；而ε4(+)基因型的作用可见于各个亚组。携带ε2或ε4对AD的发病年龄均无显著性影响(P＞0．05)。随着ε2拷贝数的增加，AD的患病率逐渐下降，但发病年龄无显著变化(P＞0．05)；而ε4拷贝数的增加则显著提高了AD的患病率，但对发病年龄也没有显著影响(P＞0．05)。
在LOAD组，ε2ε3基因型可以降低LOAD的患病风险(P=0．043，OR=0．358，95％CI=0．133～0．966)，而ε3ε4(P=0．000，OR=3．727，95％CI=2．101～6．610)和ε4ε4(P=0．000，OR=39．587，95％CI=5．039～311．017)增加LOAD的风险。ε2(+)基因型携带者LOAD的患病风险是ε3ε3携带者的36．4％(P=0．033，OR=0．364，95％CI=0．144～0．920)，而携带ε4患LOAD的风险是ε3ε3携带者的4．565倍(P=0．000，OR=4．565，95％CI=2．651～7．861)。分层分析发现，ε2(+)基因型的作用仅见于女性，但在家族史(-)者也存在降低LOAD风险的趋势(P=0．051)；ε4(+)基因型在各个亚组均增加LOAD的易感性。携带ε2的LOAD患者的发病年龄在女性亚组高于非携带者，而ε4携带者的发病年龄在女性和家族史(-)亚组明显低于非携带者。ε2拷贝数的增加使LOAD的患病率逐渐下降，发病年龄显著提高。而ε4拷贝数的增加则显著增加了LOAD的患病率，且明显降低了LOAD的发病年龄。
在EOAD组，ε3ε4(P=0．004，OR=2．613，95％CI=1．362～5．012)和ε4ε4(P=0．010，OR=15．866，95％CI=1．911～131．735)显著增加EOAD的易感性。ε2(+)基因型与EOAD的患病风险无显著相关性(P=0．458)，而ε4携带者患EOAD的风险是ε3ε3携带者的2．912倍(P=0．001，OR=2．912，95％CI=1．565～5．420)。分层分析发现，ε4(+)基因型的作用主要见于女性和家族史(-)者。携带ε2或ε4对EOAD的发病年龄均无显著性影响(P＞0．05)。ε4拷贝数的增加则显著提高了EOAD的患病率，但对EOAD的发病年龄没有显著影响(P＞0．05)。
按年龄进行细化分层发现，ApoEε2和ε4均在66-70岁年龄段对AD的患病风险施加最显著的影响。
结论：ApoEε4是AD(包括LOAD和EOAD)的危险因素，能以剂量依赖的方式增加患病风险，并能以剂量依赖的方式降低LOAD的发病年龄。ApoEε2是LOAD而非EOAD的保护性因素，可以提高LOAD的发病年龄。ApoEε2和ε4对AD的影响是年龄依赖性的，并受性别因素的影响。
第二部分cav-1基因上游PPC长度多态性与AD的相关性研究
目的：观察cav-1基因上游PPC长度多态性在汉族AD患者和正常对照者中的分布情况，以及和AD及其亚型的相关性。
方法：采用聚丙烯酰胺凝胶电泳法检测257例AD患者和279例正常对照者cav-1基因上游PPC长度多态性，通过Logistic回归分析观察其与AD的相关性。
结果：在AD和NC组中共检测到12种不同长度的等位片断，呈近似正态分布。S、L等位片断和携带S、L片段的基因型以及等长基因型均不影响AD的患病风险，也不影响AD的发病年龄。
以M／M基因型为参照，经Logistic回归分析发现，M／L基因型可以显著增加LOAD的患病风险(P=0．043，OR=2．196，95％CI=1．025～4．702)。分层分析发现，携带L等位片断使男性患LOAD的风险增加(P=0．007，OR=6．481，95％CI=1．685～24．935)，并可以降低非ε4携带者患LOAD的发病年龄(P=0．035)。
在EOAD组，携带S等位片断使女性的患病风险增加(P=0．013，OR=5．342，95％CI=1．426～20．004)，而等长基因型则增加了男性患EOAD的风险(P=0．038，OR=4．400，95％CI=1．082～1 7．884)。
对LOAD和EOAD组进行比较发现，L(+)基因型在男性LOAD组的分布频率明显高于EOAD组(x~2=3．979，P=0．046)；而S(+)基因型(x~2=5．358，P=0．021)在女性EOAD组的分布频率显著高于LOAD组。
按年龄进行细化分层发现，PPC基因型对AD的影响具有年龄依赖性。
结论：cav-1基因上游PPC-L等位片断是男性患LOAD的危险因素，而S等位片断是女性患EOAD的危险因素。等长基因型增加男性患EOAD的风险。L(+)基因型可以降低非ε4携带者患LOAD的发病年龄。PPC基因型对AD的影响具有年龄依赖性。LOAD和EOAD在遗传性易感因素方面可能存在差异。
第三部分ApoE基因多态性和cav-1基因上游PPC长度多态性与MCI的相关性研究
目的：观察cav-1基因上游PPC长度多态性在MCI患者中的分布，以及ApoE基因多态性和PPC长度多态性与MCI的相关性。
方法：分别应用扩增抗拒突变系统法和聚丙烯酰胺凝胶电泳法检测96例MCI患者和286例正常对照者的ApoE基因多态性和PPC长度多态性，采用病例对照和Logistic回归分析方法观察其与MCI的相关性。
结果：ε2在MCI和NC组间无明显差异(P=0．306)，而ε4在MCI组的分布显著高于NC组(x~2=22．572，P=0．000)。经Logistic回归分析发现，ε3ε4(P=0．041，OR=1．865，95％CI=1．025～3．393)和ε4ε4(P=0．007，OR=10．388，95％CI=1．870～57．705)显著增加MCI的患病风险。ε4(+)基因型与MCI的患病风险呈显著正相关(P=0．05，OR=2．241，95％CI=1．283～3．914)，而携带ε2不影响MCI的患病风险(P=0．614)。分层分析显示，ε4的作用主要体现在女性和家族史(-)者。ApoE基因多态性不影响MCI的发病年龄。
与AD组比较发现，ε2(+)基因型在MCI组的分布频率显著增高(x~2=6．040，P=0．014)；而ε4(+)基因型在两组间无显著性差异(P=0．116)。
在非ε4携带者中，MCI组L等位基因和L(+)基因型的分布频率高于NC组，经Logistic回归分析证明，携带L等位片段增加非ε4携带者患MCI的风险(P=0．032，OR=2．410，95％CI=1．080～5．379)。PPC长度多态性不影响MCI的发病年龄，在AD和MCI组间无差异。
结论：ApoEε4是MCI的危险因素，但不影响MCI的发病年龄。ε4的作用受性别影响，在女性作用显著。ε2在MCI组的分布频率显著低于AD组。cav-1基因上游PPC-L等位片断是非ε4携带者患MCI的危险因素。
第四部分ApoE基因多态性和cav-1基因上游PPC长度多态性与VD的相关性研究
目的：观察cav-1基因上游PPC长度多态性在VD患者中的分布，以及ApoE基因多态性和PPC长度多态性与VD的相关性。
方法：分别应用扩增抗拒突变系统法和聚丙烯酰胺凝胶电泳法检测54例VD患者和60例正常对照者的ApoE基因多态性和PPC长度多态性，采用病例对照和Logistic回归分析方法观察其与VD的相关性。
结果：ε2、ε4等位基因和携带ε2、ε4的基因型在VD和NC组间均无显著性差异(P＞0．05)，而与AD组相比，ε4(+)基因型在AD组的分布频率显著高于VD组(x~2=8．884，P=0．003)。
PPC长度多态性在VD与NC、VD与AD组间均没有显著性差异(P＞0．05)。
结论：ApoE基因多态性和PPC长度多态性均不影响VD的患病风险。
Dementia is one of the most common disorders among older populations.Withthe growth of old people,there are increasing demands on health services and costsfor patients with dementia at an alarming rate.Alzheimer's disease (AD) is the majorcause of dementia.The most important achievement in AD research is theamyloid-cascade hypothesis coming from the discoveries of three causative genes thatfacilitated the development of AD and dementia genetics.At present,most studiesfocus on susceptibility genes for AD and then expand to mild cognitive impairment(MCI) and vascular dementia (VD) et al.The ApoEε4 allele is the only consistentlyidentified risk factor for AD so far.The putative protective effect ofε2 allele and theassociation of ApoE gene polymorphism with MCI and VD remain in debate,especially in Han Chinese population.Moreover,it is essential to discover andidentify more new susceptibility genes to understand the pathogenesis of dementiabetter.We have described the frequencies of ApoE gene polymorphism and PPC allelelength polymorphism at the upstream region of cav-1 gene and the association ofthese polymorphisms with AD,MCI and VD in a clinic-based Han Chinesepopulation in Southern China.
Section 1 Association between ApoE gene polymorphism and AD
Objectives:To investigate the association between ApoE genotypes and AD as wellas the effect on age at onset.
Methods:260 patients with AD and 286 cognitively-normal control individuals weregenotyped for the ApoE alleles by amplification refractory mutation system (ARMS).Allele frequencies and genotypes in patients and control individuals were compared.Odds Ratio (OR) for developing AD and mean age at onset in different genotypeswere calculated using Logistic regression analysis and t test respectively.
Results:The frequencies ofε2 allele andε2(+) genotype were much lower in AD/LOAD/EOAD groups compared to NC groups.However,those ofε4 allele andε4(+) genotype were significantly higher.
OR for developing AD was significantly increased in carriers of ApoEε4 alleleand decreased in those of ApoEε2 allele compared to individuals with theε3ε3genotype.Individuals carryingε4ε4 genotype had OR of 24.120,while carriers ofε3ε4 had OR of 3.104.Individuals withε2(+) genotype andε4(+) genotype had OR of0.502 and 3.630 respectively.OR for developing AD was much higher in females.Risk increased or decreased but age at onset of AD didn't change with increasingcopies of the APOEε4 orε2 allele respectively.
The association between ApoE genotypes and LOAD was similar.Compared toε3ε3 genotype,carriers ofε3ε4 andε4ε4 genotype had OR of 3.727 and 39.587respectively,while individuals withε2ε3 had OR of 0.358.Individuals carryingε2(+)andε4(+) genotype had OR of 0.364 and 3.630 respectively.ApoE genotype hadstronger effects on LOAD in females too.Age at onset in LOAD patients wassignificantly elevated in a dose dependent manner with increasing copies ofε2 allelewhile reduced with increasing copies ofε4 allele.
ApoEε2 allele didn't correlate with the risk of developing EOAD,while carrierofε4(+) genotype had OR of 2.912.Individuals carryingε3ε4 andε4ε4 genotype hadOR of 2.613 and 15.866 respectively.The risk of EOAD was only increased in femaleindividuals withε4(+) genotype.Age at onset didn't change with increasing APOEε2orε4 allele.
Analysis in age at onset subgroups indicated that both APOEε2 andε4 allele hadmost obvious effects on AD from 66 to 70 years old.
Conclusion:ApoEε4 is a risk factor for developing AD(both LOAD and EOAD),which acts in a dose dependent manner.ApoEε2 is a protective factor for LOADrather than EOAD.The ApoE genotype specific effects on AD vary by age and sex.
Section 2 Association between PPC Allele Length Polymorphismat the Upstream Region of cav-1 Gene and AD
Objectives:To observe the frequencies of PPC allele length polymorphism in HanChinese AD patients and cognitively-normal control individuals and to investigate theassociation between PPC genotypes and AD.
Methods:257 patients with AD and 279 control individuals were genotyped for PPC by polyacrylamide gel electrophoresis(PAGE).Allele frequencies and genotypes inpatients and control individuals were compared.Odds Ratio for developing AD andmean age at onset in different genotypes were calculated using Logistic regressionanalysis and t test respectively.
Result:12 PPC allele lengths ranging from 118bp to 162bp were found in AD andcontrol individuals.Both short and long alleles didn't correlate with the risk fordeveloping AD and age at onset of AD.
Carriers of M/L genotype had OR of 2.196 compared to M/M genotype.OR was6.481 in males with long alleles for developing LOAD.Age at onset in LOADpatients was significantly reduced in absence of ApoEε4.
Females with short alleles had OR of 5.342 for EOAD and males with PPChomozygote for length had OR of 4.400 for developing EOAD.
The frequency of long alleles-positive genotype was significantly increased inmale LOAD group than in EOAD group,while that of short alleles-positive genotypewas much lower in female LOAD group than in EOAD group.
PPC alleles had different ORs for developing AD in distinct age at onsetsubgroups.
Conclusions:Long alleles of PPC have a risk effect on LOAD in males and shortalleles were risk factors of EOAD in females.Homozygote for length has a risk effecton EOAD in males.Long alleles can lower age at onset of LOAD in absence ofApoEε4 significantly.
Section 3 Association ofApoE gene polymorphismand PPC Allele Length Polymorphism with MCI
Objectives:To investigate the association of ApoE genotypes and PPC genotypeswith MCI.
Methods:96 patients with MCI and 286 control individuals were genotyped for ApoEand PPC.Allele frequencies and genotypes in patients and control individuals werecompared.Odds Ratio for developing MCI and mean age at onset in differentgenotypes were calculated using Logistic regression analysis and t test respectively.
Results:ApoEε2 allele didn't correlate with the risk of developing MCI,while carrierofε4(+) genotype had OR of 2.241.Individuals carryingε3ε4 andε4ε4 genotype hadOR of 1.865 and 10.388 respectively.The risk of MCI was only increased in female individuals withε4(+) genotype.Age at onset didn't change with increasing APOEε2orε4 allele.
Compared to AD group,the frequency ofε2(+) genotype was significantlyincreased in MCI group,but that ofε4(+) genotype was similar in MCI patients.
In absence of ApoEε4,the frequencies of long alleles and long alleles-positivegenotypes were much higher in MCI patients than in control individuals.Carriers oflong alleles had OR of 2.410 of developing MCI.
PPC genotypes didn't correlate with age at onset of MCI.
Conclusions:APOEε4 allele is a risk factor of MCI by sex but has no effect on age atonset.Long alleles of PPC have a risk effect on MCI in absence of ApoEε4.
Section 4 Association ofApoE gene polymorphismand PPC Allele Length Polymorphism with VD
Objectives:To investigate the association of ApoE genotypes and PPC genotypeswith VD.
Methods:54 patients with VD and 60 control individuals were genotyped for ApoEand PPC.Allele frequencies and genotypes in patients and control individuals werecompared.Odds Ratio for developing VD was calculated by Logistic regressionanalysis.
Results:The frequencies of ApoE alleles and genotypes in VD patients were notdifferent from those of control individuals,but the frequency ofε4(+) genotype in VDgroup was significantly lower than in AD group.
The frequencies of PPC alleles and genotypes in VD patients were not differentfrom those of control individuals.
Conclusions:ApoE and PPC genotypes have no effect on developing VD.
引文
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