Non-Ceruloplasmin Copper Distincts Subtypes in Alzheimer’s Disease: a Genetic Study of ATP7B Frequency
| Autor: | Rosanna Squitti, Nicola Antonio Colabufo, Serena Bucossi, Chiara Congiu, Mariacarla Ventriglia, Stefania Mariani, Cristian Bonvicini, Imane Ghafir El Idrissi, Orazio Zanetti, Paolo Maria Rossini, Mauro Rongioletti, Massimo Gennarelli |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Neuroscience (miscellaneous) Disease Gastroenterology Cohort Studies 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Gene Frequency Alzheimer Disease Internal medicine Free copper Genotype ATP7B medicine Humans Allele Aged Aged 80 and over Genetics biology Genetic heterogeneity Haplotype Ceruloplasmin Non-ceruloplasmin-copper 030104 developmental biology Haplotypes Italy Neurology Alzheimer’s disease Copper Copper-Transporting ATPases Multiple comparisons problem biology.protein Biomarker (medicine) Female 030217 neurology & neurosurgery |
| Popis: | Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer’s disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 μM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76-fold higher risk of having a non-Cp-Cu higher than 1.9 μmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD. |
| Databáze: | OpenAIRE |
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