Frequencies Of ApoE Gene Polymorphism And PPC Allele Length Polymorphism At The Upstream Region Of Cav-1 Gene And Association Of These Polymorphisms With AD, MCI And VD

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 ADObjectives: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 ADObjectives: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 MCIObjectives: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 VDObjectives: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.