| Background:Alzheimer disease (AD) is the most common neurodegenerative disease. Pathologically, AD is characterized by neurofibrillary tangles in the neurons and extracellular deposition of amyloid within senile plaques. AD is heterogeneous and complex, and the cause of this devastating disease is largely still unknow. All mutations that are currently known to cause AD in early-onset (that is, onset before 60 to 65 years of age) autosomal- dominant families are located either in the amyloid precursor protein gene itself or in the genes that encode the proteins that lie at the catalytic centre of theγ-secretase complex: presenilin 1 and presenilin 2. By contrast, susceptibility for late-onset AD is likely to be governed by an array of common risk allele across a number of different gene and non-genetic factors that vary according to the populations. The only well-established genetic susceptibility factor for late-onset AD is theε4 allele of the apolipo- protion E (ApoE) gene. However, the presence of the ApoEε4 allele is neither necessary nor sufficient to cause AD,and only count for about 20% of all the AD cases, indicating that additional genetic factors influencing the AD risk are yet to be indentified.Objective:To describe the distribution of polymorphisms of the susceptible genes in the Chinese Han population, evaluate the association of polymorphisms of some genes with AD and to develop approaches for early diagnosis, further understanding pathogeneic mechanism of AD.Methods:A case-control study was conducted and the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the STH Q7R, IRP2 rs13180, CALHM1 rs2986017, GAB2 rs2373115 and GAB2 rs1385600 polymorphisms.Result:1. The association study between STH Q7R polymorphism and AD: The controls were all QQ genotype and in the AD group only one AD case carried the QR genotype and the rest were all QQ genotype. The frequency of the R allele was significantly lower in Chinese Han and Japanese compared to African and some Caucasian control groups (P<0.05). Studies of the Caucasian population have reported frequencies ranging from 14.5% to 25.4% for the R allele in control groups, with the highest reported in a study of the Italian population.2. The association study between IRP2 rs13180 polymorphism and AD: (1) No significant differences were demonstrated in IRP2 genotype or allele frequencies between the total sample of AD patients and controls (χ~2 =2.464, P=0.292;χ~2 =2.17, P=0.141 respectively). However, the frequency of CT and TT genotypes in the moderate to severe AD patients was 78.0%, significantly higher than that of the controls (69.8%) (χ~2=4.106, P=0.043). Logistic regression analysis demonstrated that the age-, sex- and ApoE-adjusted OR of moderate to severe AD patient with T allele was 1.62(95%CI=1.03～2.54,P=0.037). (2) The frequency of TT genotype or T allele in the moderate to severe AD patients was significantly higher than that of mild AD patients (25.8% vs 12.5%,χ~2=5.477, P=0.019; 51.9% vs 40.3%,χ~2=5.803, P=0.016 respectively). (3) MMSE scores of the AD patients with TT genotype was significantly lower than ones with CC or CT genotype (P=0.028; p=0.014 respectively). (4) No association was found between age-at-onset (AAO) of AD and IRP2 genotype (F=0.197,P=0.821).3. The association study between the CALHM1 rs2986017 polymorphism and AD: Neither the genotypic frequencies nor allelic frequencies of the rs2986017 polymorphism were statistically different in the two groups (χ~2 =0.504, P=0.777;χ~2 =0.024, P=0.878 respectively). Logistic regression analysis was used to evaluate the main and interactive effects of SNP rs2986017 and ApoE. The analysis revealed that neither the AA genotype nor the AG genotype influenced the risk of developing AD (χ~2 =0.789,P=0.374;χ~2 =0.062, P=0.804 respectively).And the one-way ANOVA analysis revealed no significant effect of the genotype on the age of onset for developing AD (F=0.950, P=0.909).4. The association study between GAB2 rs2373115 polymorphism and rs1385600 polymorphism and AD: (1) The current study does not demonstrate any significant difference in GAB2 rs2373115 genotype (χ~2=2.319, P=0.314) or allele frequencies (χ~2=0.602, P=0.438) between AD group and control group. When we stratified the subjects according to the ApoE status, we found a tendency for an increase in TT genotype and T allele frequencies in ApoEε4 carries, but did not reach significance (χ~2=3.803, P=0.149;χ~2=0.845, P=0.358 respectively). (2) No significant differences were demonstrated in GAB2 rs1385600 genotype or allele frequencies between AD patients and controls (χ~2=0.074; P=0.963;χ~2=0.05; P=0.824 respectively). When AD and control groups were stratified by ApoEε4 allele, no significant differences were observed either.Conclusion:1. STH Q7R polymorphism and AD: The Q7R polymorphism is unlikely to contribute significantly to Alzheimer's disease susceptibility of the Han population in south China.2. IRP2 rs13180 polymorphism and AD: The SNP rs13180 in the IRP2 gene is associated with moderate to severe AD, and TT genotype may be a risk factor for cognitive impairment of patients with AD in Chinese Han.3. CALHM1 rs2986017 polymorphism and AD: The SNP rs2986017 is not asso- ciated with AD, suggesting the SNP do not have a major role in AD case in Chinese Han.4. GAB2 rs2373115 and rs1385600 polymorphism and AD: The SNP rs2373115 and SNP rs1385600 are not associated with AD, suggesting these SNPs do not have a major role in AD case in Chinese Han. |
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