| 1. |
- Tsolaki, Anthoula C., et al.
(författare)
-
Prevalence of Apolipoprotein E Polymorphisms in Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Elderly : A Northern Greece Study
- 2018
-
Ingår i: Neurodegenerative Diseases. - : S. Karger. - 1660-2854 .- 1660-2862. ; 18:4, s. 216-224
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Apolipoprotein E epsilon 4 allele (APOE epsilon 4) is a major genetic risk factor for Alzheimer's disease (AD). APOE epsilon 4 carriers have a higher risk of cognitive impairment and AD in a gene dose-dependent manner. The above notion is investigated in the Greek population. Methods: A sample of 1,703 subjects (967 AD patients, 576 mild cognitive impairment [MCI] and 160 Healthy Elderly), was genotyped for APOE from 2008 to 2017. DNA was extracted from peripheral blood using the QIAamp Blood DNA purification kit (Qiagen Inc., USA). Descriptive statistics, one-way analysis of variance with Bonferroni post hoc tests, Pearson chi-square test, and binary logistic regression models were used for the statistical analysis. Results: The APOE genotype and allele frequencies in AD group were significantly different from those in the Control and MCI groups. The frequencies of epsilon 4/4 homozygotes were 1.9, 1.6, and 5.7%, while the epsilon 4/- carriers' distribution was 22.5, 24.1, and 37.4% in the Control, MCI, and AD groups respectively. The estimated odds of epsilon 4/4 for AD was 5.731-fold higher compared to the estimated odds of epsilon 3/3. The interaction between gender and APOE did not have a significant effect on the odds for MCI (p = 0.942) and AD (p = 0.984). Conclusion: In Greece, APOE epsilon 4 presence is related to an increased risk for AD in a dose-related manner. Contrary to long-standing views, men and women with the APOE epsilon 4 genotype have nearly the same odds of developing MCI and AD.
|
|
| 2. |
- Belloy, Michael E., et al.
(författare)
-
Challenges at the APOE locus : a robust quality control approach for accurate APOE genotyping
- 2022
-
Ingår i: Alzheimer's Research & Therapy. - : Springer Nature. - 1758-9193. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.Methods: We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches.Results: Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions: We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.
|
|
