The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort

doi:10.1016/j.neulet.2003.12.052

Neuroscience Letters

Volume 357, Issue 3, 11 March 2004, Pages 167-170

https://doi.org/10.1016/j.neulet.2003.12.052 Get rights and content

Abstract

Mutations in the presenilin 1 (PSEN1) gene are known to cause nearly 50% of early-onset, familial Alzheimer's disease (AD) cases. To determine whether E318G mutation is related causally to AD in the Polish population E318G mutation frequency was assessed using PCR-RFLP method in a total of 659 subjects: 256 AD patients, 210 healthy, age-matched control subjects, 100 Parkinson's disease patients and 93 centenarians. When the mutation frequencies were compared to healthy controls, no significant differences between the groups were found. It could be concluded that E318G mutation is not related causally to AD in the Polish population, either as a risk factor or a disease causing mutation.

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Acknowledgements

This work was supported by the State Committee for Scientific Research (KBN) grant no PBZ-KBN/002/CD/P05/2000. A group of centenarians was collected as a part of a grant ‘Genetic and Environmental Longevity Factors in a Group of Polish Centenarians’ by the State Committee for Scientific Research (KBN) PBZ-KBN-022/P05/1999.

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PSEN1 gene polymorphisms in Caucasian Alzheimer's disease: A meta-analysis
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Similarly, the rs17125721 variants (A > G) localized at 9th exon of PSEN1 gene causes the change in amino acids from Glutamic acid to Glycine [13]. This transition results in non-conserved substitution, which is localized in the sixth cytoplasmic loop of presenilin-1 gene displaying the highest evolutionary variability [14]. Although several genetic predisposition studies of rs1800839 and rs17125721 polymorphisms were conducted in Alzheimer's patients, results have been inconsistent.
A meta-analysis was performed to assess PSEN1 gene polymorphisms (rs1800839 and rs17125721) in Alzheimer's disease (AD) risk.
A systematic electronic search was performed across databases to retrieve studies published before 31 January 2017. The association between the selected PSEN1 polymorphisms and AD was based on five genetic models using DerSimonian and Laird's method or Mantel-Haenszel's method.
A total of 14 case–controlled studies were included. Results showed that rs1800839 polymorphism was significantly associated with AD in allelic OR = 0.85 (95% CI [0.72–1.00]) and dominant OR = 0.82 (95% CI [0.69–0.98]) genetic models, respectively. However, an insignificant association was found for rs17125721 polymorphism in all genetic models.
Meta-analysis of PSEN1 gene suggests that the rs1800839 polymorphism has potential influence on AD among Caucasians.
Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil
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As in our cohort, independent studies in Australian, Italian and Finnish populations reached significant statistical difference in familial cases (Fig. 1). Conversely, studies in other European populations (Finnish, Polish and Spanish) have not replicated these results, finding no evidence for association between rs17125721 and AD [27–32] (Fig. 1). With the purpose of testing the multiplicative interaction between rs17125721 and APOE-ε4, our cohort was stratified according to APOE-ε4 presence (+) and ε4 absence (−).
About 30–70% of familial Alzheimer’s disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified. In silico tools were used to predict the functional impact of the variants, revealing no changes in protein functionality by exonic variants. Otherwise, all variants were predicted to alter splicing signals. Prediction results, together with previous reports, suggest a correlation between rs17125721 and AD. So, a subsequent case-control study to evaluate the role of rs1712572 on AD risk was performed in an additional sample of 120 AD sporadic cases and in 149 elderly healthy controls by TaqMan Genotyping Assay. Our data indicates a risk association for rs17125721 in familial AD cases (OR = 6.0; IC95% = 1.06–33.79; p = 0.042). In addition, we tested the multiplicative interaction between allele ε4 of the apolipoprotein E (APOE) and rs17125721 and no statistical association was found. Taken together, our findings provide new insight about the genetic relevance of low frequency PSEN1 variants for familial AD development.
Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population
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The PSEN-1 [E318G] mutation was also reported in healthy old subjects, and did not increase Aβ(1–42) generation in cellular models [11]. The possibility that the PSEN-1 [E318G] mutation was a risk factor for AD has been explored by different authors [1,2,21,33] and, apart from some conflicting data in the Finnish population [18,24], no positive correlation has come to light. However, all these studies mainly analyzed SAD cases.
Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in β-amyloid precursor protein (βAPP) processing. To date about 140 pathogenic mutations in the PSEN-1 gene have been identified and their main biochemical effect is to increase the production of the fibrillogenic peptide Aβ(1–42). An exception is the PSEN-1 [E318G] mutation that does not alter Aβ(1–42) generation and is generally considered a non-pathogenic polymorphism. Nevertheless, this mutation was reported to be a genetic risk factor for familial Alzheimer's disease (FAD) in the Australian population. To independently confirm this indication, we performed a case-control association study in the Italian population. We found a significant association (p < 0.05, Fisher's exact test) between the presence of PSEN-1 [E318G] and FAD. In addition, on measuring the Aβ(1–42) and Aβ(1–40) concentrations in fibroblast-conditioned media cultured from PSEN-1 [E318G] carriers and PSEN-1 [wild type] controls we noted a significant decrease (p < 0.05, Mann–Whitney test) in the Aβ(1–42)/Aβ(1–40) ratio in PSEN-1 [E318G] carriers, suggesting a peculiar biochemical effect of this mutation.
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The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort

Abstract

Section snippets

Acknowledgements

Am. J. Hum. Genet.

Neurosci. Lett.

Neurosci. Lett.

Neurosci. Lett.

Exp. Neurol.

Missense mutation E318G of the presenilin-1 gene appears to be a non-pathogenic polymorphism

Ann. Neurol.

A simple and efficient method for apolipoprotein E genotype determination

Neurology

Presenilin mutations in Alzheimer's disease

Hum. Mutat.

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease

Hum. Mol. Genet.

Alzheimer's Disease and Related Disorders: Glu318Gly in Presenilin-1 is a Neutral Mutation in Relation to Dementia