Michael A Williams1, Gareth J McKay2, Robyn Carson2, David Craig2, Giuliana Silvestri3, Peter Passmore2. 1. Centre for Medical Education, Queen's University of Belfast, UK. Electronic address: m.williams@qub.ac.uk. 2. Centre for Public Health, Queen's University of Belfast, UK. 3. Centre for Experimental Medicine (GS), Queen's University of Belfast, UK.
Abstract
OBJECTIVES: Given the clinical and pathological similarities between age-related macular degeneration (AMD) and Alzheimer disease (AD), to assess whether AMD-associated single nucleotide polymorphisms (SNPs), including those from complement-related genes, are associated with AD. DESIGN: A case-control association study-type design. SETTING: A UK tertiary care dementia clinic. PARTICIPANTS: 322 cognitively normal participants and 258 cases with a clinical diagnosis of AD. MEASUREMENTS: Polymorphisms in the following genes were studied: CFH, ARMS2, C2/CFB, C3, CFI/PLA2G12a, SERPING1, TLR3, TLR4, CRP, APOE, and TOMM40. Haplotypes were analysed for CFH, TOMM40, and APOE. Univariate analysis was performed for each genetic change and case-comparator status, and then correction for multiple testing performed. RESULTS: The presence of an ε4 APOE allele was significantly associated with AD. No association was evident between CFH SNPs or haplotypes, or other AMD-associated SNPs tested, and AD. The exceptions were TOMM40 SNPs, which were associated with AD even after correction for multiple comparisons. The associations disappeared, however, when entered into a regression model including APOE genotypes. CONCLUSIONS: The results for most SNPs tested, as well as CFH haplotypes, are novel. The functional effects of abnormal complement activity in AD's pathogenesis may be contradictory, but methodological reasons may underlie the lack of association-for example, genetic changes other than SNPs being involved.
OBJECTIVES: Given the clinical and pathological similarities between age-related macular degeneration (AMD) and Alzheimer disease (AD), to assess whether AMD-associated single nucleotide polymorphisms (SNPs), including those from complement-related genes, are associated with AD. DESIGN: A case-control association study-type design. SETTING: A UK tertiary care dementia clinic. PARTICIPANTS: 322 cognitively normal participants and 258 cases with a clinical diagnosis of AD. MEASUREMENTS: Polymorphisms in the following genes were studied: CFH, ARMS2, C2/CFB, C3, CFI/PLA2G12a, SERPING1, TLR3, TLR4, CRP, APOE, and TOMM40. Haplotypes were analysed for CFH, TOMM40, and APOE. Univariate analysis was performed for each genetic change and case-comparator status, and then correction for multiple testing performed. RESULTS: The presence of an ε4 APOE allele was significantly associated with AD. No association was evident between CFH SNPs or haplotypes, or other AMD-associated SNPs tested, and AD. The exceptions were TOMM40 SNPs, which were associated with AD even after correction for multiple comparisons. The associations disappeared, however, when entered into a regression model including APOE genotypes. CONCLUSIONS: The results for most SNPs tested, as well as CFH haplotypes, are novel. The functional effects of abnormal complement activity in AD's pathogenesis may be contradictory, but methodological reasons may underlie the lack of association-for example, genetic changes other than SNPs being involved.
Authors: Phillip H Hwang; Will T Longstreth; Stephen M Thielke; Courtney E Francis; Marco Carone; Lewis H Kuller; Annette L Fitzpatrick Journal: Alzheimers Dement Date: 2021-03-31 Impact factor: 21.566
Authors: Kathryn Mullan; Michael A Williams; Chris R Cardwell; Bernadette McGuinness; Peter Passmore; Giuliana Silvestri; Jayne V Woodside; Gareth J McKay Journal: Alzheimers Dement (N Y) Date: 2017-07-19
Authors: Gordon J Smilnak; John R Deans; P Murali Doraiswamy; Sandra Stinnett; Heather E Whitson; Eleonora M Lad Journal: PLoS One Date: 2019-09-30 Impact factor: 3.240
Authors: Khanh V Do; Marie-Audrey I Kautzmann; Bokkyoo Jun; William C Gordon; Robert Nshimiyimana; Rong Yang; Nicos A Petasis; Nicolas G Bazan Journal: Proc Natl Acad Sci U S A Date: 2019-11-11 Impact factor: 11.205