Abstract
Background: Alzheimer’s disease (AD) individuals are characterized with high homocysteine (HCY) and low folate blood levels. Polymorphisms of genes encoding critical enzymes in folate metabolism have been associated with hyperhomocysteinemia and AD risk. An adenine to guanine transition at position 2756 (rs185087) of the methionine synthase (MS or MTR) gene causes hyperhomocysteinemia. However, the association between MTR A2756G polymorphism and AD remains controversial. We performed a Meta analysis pooling data from all relevant studies including cases and controls to reexamine the association between the MTR gene A2576G polymorphism and AD. Methods: We applied random-effects or fixed-effects model according to the degree of heterogeneity to combine odds ratio (OR) and 95% coincidence intervals (95% CI). And we used the Quanto 1.2.4 software to calculate genetic power. Egger’s test was carried out to evaluate the potential publication bias. Results and discussion: Eight case-control studies enrolling 2,880 cases and 2,807 controls were included in this meta analysis. The overall ORs with 95% CIs showed no statistical association between the MTR gene A2756G polymorphism and the risk of AD in the allele contrast, the recessive model or dominant model for allele A (randomeffects pooled OR 1.09, 95% CI 0.92-1.30; random-effects pooled OR 1.11, 95% CI 0.91-1.35; fixed-effects pooled OR 1.13, 95% CI 0.83-1.54, respectively). The genetic power was 11.6% in the recessive model and 43.7% in the dominant model. No association between MTR A2756G polymorphism and AD was observed, but the conclusion based on relatively small numbers of participants. Large heterogeneity was detected among combined populations in the contrast of AA vs. AG+GG (p = 0.019, I2 = 56.3%) and A vs. G (p = 0.016, I2 = 57.5%). One study was considered as the main cause of heterogeneity in both contrasts. The heterogeneity doesn’t reduce in the subgroup analyses stratified by racial descents. It can be presumed that the heterogeneity mainly results from the diagnosis of AD and genotyping methods. No publication bias was observed. Conclusions: In conclusion, the present Meta analysis suggests that MTR A2756G polymorphism is not a genetic determinant of AD. But small sample size may be one reason and it could not be ruled out that a true association exists.
Highlights
Alzheimer’s disease (AD) individuals are characterized with high homocysteine (HCY) and low folate blood levels
In conclusion, the present Meta analysis suggests that MTR A2756G polymorphism is not a genetic determinant of AD
The majority of the studies agreed that plasma HCY values increased in AD subjects [4,5,6]; there was indication that folate values reduced in the plasma of AD individuals respect to controls [4,5,6,7]
Summary
We searched MEDLINE (1966 to January 2012), EMBASE (1966 to January 2012), and Cochrane Collaboration Registry for Randomized Controlled Trials (1966 to January 2012). All studies that investigate the association of the MTR A2756G polymorphism with AD using a case-control design were considered in the meta analysis. Genotyping methods for each data set were described in the original publications. Characteristics abstracted from the studies included the name of first author, publication date, country origin, ethnicity, control characteristics, genotyping methods, total number of cases and controls, and numbers of cases and controls with MTR alleles and genotypes, respectively. Heterogeneity between studies was assessed by using the chisquare-based Q-test and was considered statistically significant if p < 0.1[27]. The pooled OR was calculated by the fixed-effects model (the Mantel-Haenszel method) when there was no or moderate heterogeneity among studies [29]. The significance of the intercept was determined by the t-test (p < 0.05 was considered representative of statistically significant publication bias) [32]
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