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Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases

Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessmen...

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Autores principales: Tisato, Veronica, Zuliani, Giovanni, Vigliano, Marco, Longo, Giovanna, Franchini, Eugenia, Secchiero, Paola, Zauli, Giorgio, Paraboschi, Elvezia Maria, Vikram Singh, Ajay, Serino, Maria Luisa, Ortolani, Beatrice, Zurlo, Amedeo, Bosi, Cristina, Greco, Antonio, Seripa, Davide, Asselta, Rosanna, Gemmati, Donato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843269/
https://www.ncbi.nlm.nih.gov/pubmed/29518107
http://dx.doi.org/10.1371/journal.pone.0193867
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author Tisato, Veronica
Zuliani, Giovanni
Vigliano, Marco
Longo, Giovanna
Franchini, Eugenia
Secchiero, Paola
Zauli, Giorgio
Paraboschi, Elvezia Maria
Vikram Singh, Ajay
Serino, Maria Luisa
Ortolani, Beatrice
Zurlo, Amedeo
Bosi, Cristina
Greco, Antonio
Seripa, Davide
Asselta, Rosanna
Gemmati, Donato
author_facet Tisato, Veronica
Zuliani, Giovanni
Vigliano, Marco
Longo, Giovanna
Franchini, Eugenia
Secchiero, Paola
Zauli, Giorgio
Paraboschi, Elvezia Maria
Vikram Singh, Ajay
Serino, Maria Luisa
Ortolani, Beatrice
Zurlo, Amedeo
Bosi, Cristina
Greco, Antonio
Seripa, Davide
Asselta, Rosanna
Gemmati, Donato
author_sort Tisato, Veronica
collection PubMed
description Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer’s disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.
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spelling pubmed-58432692018-03-23 Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases Tisato, Veronica Zuliani, Giovanni Vigliano, Marco Longo, Giovanna Franchini, Eugenia Secchiero, Paola Zauli, Giorgio Paraboschi, Elvezia Maria Vikram Singh, Ajay Serino, Maria Luisa Ortolani, Beatrice Zurlo, Amedeo Bosi, Cristina Greco, Antonio Seripa, Davide Asselta, Rosanna Gemmati, Donato PLoS One Research Article Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer’s disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels. Public Library of Science 2018-03-08 /pmc/articles/PMC5843269/ /pubmed/29518107 http://dx.doi.org/10.1371/journal.pone.0193867 Text en © 2018 Tisato et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tisato, Veronica
Zuliani, Giovanni
Vigliano, Marco
Longo, Giovanna
Franchini, Eugenia
Secchiero, Paola
Zauli, Giorgio
Paraboschi, Elvezia Maria
Vikram Singh, Ajay
Serino, Maria Luisa
Ortolani, Beatrice
Zurlo, Amedeo
Bosi, Cristina
Greco, Antonio
Seripa, Davide
Asselta, Rosanna
Gemmati, Donato
Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases
title Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases
title_full Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases
title_fullStr Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases
title_full_unstemmed Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases
title_short Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases
title_sort gene-gene interactions among coding genes of iron-homeostasis proteins and apoe-alleles in cognitive impairment diseases
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843269/
https://www.ncbi.nlm.nih.gov/pubmed/29518107
http://dx.doi.org/10.1371/journal.pone.0193867
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