Angiotensin-converting enzyme polymorphisms AND Alzheimer’s disease susceptibility: An updated meta-analysis

Abstract

Background Many studies among different ethnic populations suggested that angiotensin converting enzyme (ACE) gene polymorphisms were associated with susceptibility to Alzheimer’s disease (AD). However, the results remained inconclusive. In the present meta-analysis, we aimed to clarify the effect of ACE polymorphisms on AD risk using all available relevant data. Methods Systemic literature searches were performed using PubMed, Embase, Alzgene and China National Knowledge Infrastructure (CNKI). Relevant data were abstracted according to predefined criteria. Results Totally, 82 independent cohorts from 65 studies were included, focusing on five candidate polymorphisms. For rs1799752 polymorphism, in overall analyses, the insertion (I) allele conferred increased risk to AD compared to the deletion (D) allele (I vs. D: OR = 1.091, 95% CI = 1.007–1.181, p = 0.032); while the I carriers showed increased AD susceptibility compared with the D homozygotes (II + ID vs. DD: OR = 1.131, 95% CI = 1.008–1.270, p = 0.036). However, none of the positive results passed FDR adjustment. In subgroup analysis restricted to late-onset individuals, the associations between rs1799752 polymorphism and AD risk were identified using allelic comparison (OR = 1.154, 95% CI = 1.028–1.295, p = 0.015, FDR = 0.020), homozygotes comparison, dominant model and recessive model (II vs. ID + DD: OR = 1.272, 95% CI = 1.120–1.444, p < 0.001, FDR < 0.001). Nevertheless, no significant association could be revealed after excluding studies not in accordance with Hardy-Weinberg equilibrium (HWE). In North Europeans, but not in East Asians, the I allele demonstrated increased AD susceptibility compared to the D allele (OR = 1.096, 95% CI = 1.021–1.178, p = 0.012, FDR = 0.039). After excluding HWE-deviated cohorts, significant associations were also revealed under homozygotes comparison, additive model (ID vs. DD: OR = 1.266, 95% CI = 1.045–1.534, p = 0.016, FDR = 0.024) and dominant model (II + ID vs. DD: OR = 1.197, 95% CI = 1.062–1.350, p = 0.003, FDR = 0.018) in North Europeans. With regard to rs1800764 polymorphism, significant associations were identified particularly in subgroup of European descent under allelic comparison (T vs. C: OR = 1.063, 95% CI = 1.008–1.120, p = 0.023, FDR = 0.046), additive model and dominant model (TT + TC vs. CC: OR = 1.116, 95% CI = 1.018–1.222, p = 0.019, FDR = 0.046). But after excluding studies not satisfying HWE, all these associations disappeared. No significant associations were detected for rs4343, rs4291 and rs4309 polymorphisms in any genetic model. Conclusions Our results suggested the significant but modest associations between rs1799752 polymorphism and risk to AD in North Europeans. While rs4343, rs4291 and rs4309 polymorphisms are unlikely to be major factors in AD development in our research.

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

“…These findings are in line with preclinical studies [78][79][80] and emphasize the important role and multifactorial contribution of this gene cluster to ACD pathogenesis. Although previous literature points to an association of ACE with AD 81 but not VaD 82,83 , we herein show that this gene underlies both ACD and vascular risk factors. A recent study supports this finding by showing that overexpression of ACE on macrophages lead to reduction in vascular amyloid and GFAP+ astroglial reactivation, which indicate its role in protection of the neurovascular unit 84 .…”

Evaluating the association between genetically proxied ACE inhibition and dementias

“…ACE and its expression have been implicated in genetic studies of AD. 31,32 In the largest GWAS study, the ACE SNP rs4277405 (minor C allele) was associated with lower risk of AD (OR = 0.94) in genome-wide level of significance, and by extension the major allele (T allele) is associated with increased AD risk. 7 The rs4277405 (T allele) was in LD with the ACE inhibition rs4343 SNP (A allele) that showed the strongest effect in our analysis.…”

Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

“…204 Another recent study comparing AD patients to age and gender matched cognitively healthy controls demonstrated that the rs4646994 ACE gene polymorphism was also associated with increased AD risk. 205 Gene polymorphisms within the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes a protein necessary for homocysteine metabolism, have been found to increase circulating Hcy levels and promote memory impairment and cognitive dysfunction, decrease cortical and hippocampal volumes, increase cerebral atrophy, and increase hippocampal apoptosis in mice. 206,207 In humans, the MTHFR gene polymorphism C677T (rs1801133), as well as MTHFR A1298C, were associated with increased late-onset AD risk.…”

“…Interestingly, a recent metanalysis including 82 cohorts from 65 individual studies revealed significant associations between the rs1799752 ACE polymorphism and increased AD risk 204 . Another recent study comparing AD patients to age and gender matched cognitively healthy controls demonstrated that the rs4646994 ACE gene polymorphism was also associated with increased AD risk 205 . Gene polymorphisms within the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes a protein necessary for homocysteine metabolism, have been found to increase circulating Hcy levels and promote memory impairment and cognitive dysfunction, decrease cortical and hippocampal volumes, increase cerebral atrophy, and increase hippocampal apoptosis in mice 206,207 .…”