Is HCRTR2 a genetic risk factor for Alzheimer's disease?

Salvatore Gallone, Silvia Boschi, Elisa Rubino, Paola De Martino, Elio Scarpini, Daniela Galimberti, Chiara Fenoglio, Pier Luigi Acutis, Maria Grazia Maniaci, Lorenzo Pinessi, Innocenzo Rainero

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Backgrounds/Aims: Alzheimer's disease (AD) is one of the main types of dementia affecting about 50-55% of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. Methods: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. Results: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ2 = 5.77, p = 0.016; χ2 = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95% CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. Conclusion: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.

Original languageEnglish
Pages (from-to)245-253
Number of pages9
JournalDementia and Geriatric Cognitive Disorders
Volume38
Issue number3-4
DOIs
Publication statusPublished - 2014

Fingerprint

Alzheimer Disease
Sleep
Dementia
Orexin Receptors
Genes
Narcolepsy
Institutionalization
Molecular Models
Single Nucleotide Polymorphism
Neurotransmitter Agents
Alleles
Binding Sites
Orexins
Proteins

Keywords

  • Alzheimer's disease
  • Hypocretin/orexin system
  • Molecular model
  • Polymorphisms
  • Sleep disorders

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Cognitive Neuroscience
  • Medicine(all)

Cite this

Is HCRTR2 a genetic risk factor for Alzheimer's disease? / Gallone, Salvatore; Boschi, Silvia; Rubino, Elisa; De Martino, Paola; Scarpini, Elio; Galimberti, Daniela; Fenoglio, Chiara; Acutis, Pier Luigi; Maniaci, Maria Grazia; Pinessi, Lorenzo; Rainero, Innocenzo.

In: Dementia and Geriatric Cognitive Disorders, Vol. 38, No. 3-4, 2014, p. 245-253.

Research output: Contribution to journalArticle

Gallone, S, Boschi, S, Rubino, E, De Martino, P, Scarpini, E, Galimberti, D, Fenoglio, C, Acutis, PL, Maniaci, MG, Pinessi, L & Rainero, I 2014, 'Is HCRTR2 a genetic risk factor for Alzheimer's disease?', Dementia and Geriatric Cognitive Disorders, vol. 38, no. 3-4, pp. 245-253. https://doi.org/10.1159/000359964
Gallone, Salvatore ; Boschi, Silvia ; Rubino, Elisa ; De Martino, Paola ; Scarpini, Elio ; Galimberti, Daniela ; Fenoglio, Chiara ; Acutis, Pier Luigi ; Maniaci, Maria Grazia ; Pinessi, Lorenzo ; Rainero, Innocenzo. / Is HCRTR2 a genetic risk factor for Alzheimer's disease?. In: Dementia and Geriatric Cognitive Disorders. 2014 ; Vol. 38, No. 3-4. pp. 245-253.
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abstract = "Backgrounds/Aims: Alzheimer's disease (AD) is one of the main types of dementia affecting about 50-55{\%} of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. Methods: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. Results: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ2 = 5.77, p = 0.016; χ2 = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95{\%} CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. Conclusion: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.",
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AU - Boschi, Silvia

AU - Rubino, Elisa

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AU - Galimberti, Daniela

AU - Fenoglio, Chiara

AU - Acutis, Pier Luigi

AU - Maniaci, Maria Grazia

AU - Pinessi, Lorenzo

AU - Rainero, Innocenzo

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N2 - Backgrounds/Aims: Alzheimer's disease (AD) is one of the main types of dementia affecting about 50-55% of all demented patients. Sleep disturbances in AD patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble the core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. The aim of our study was to investigate whether genetic variants in the hypocretin (HCRT) and in the hypocretin receptors 1 and 2 (HCRTR1, HCRTR2) genes could modify the occurrence and the clinical features of AD and to examine if these possible variants influence the role of the protein in sleep regulation. Methods: Using a case-control strategy, we genotyped 388 AD patients and 272 controls for 10 SNPs in the HCRT, HCRTR1 and HCRTR2 genes. In order to evaluate which residues belong to the HCRTR2 binding site, we built a molecular model. Results: The genotypic and allelic frequencies of the rs2653349 polymorphism were different (χ2 = 5.77, p = 0.016; χ2 = 6.728, p = 0.035) between AD patients and controls. The carriage of the G allele was associated with an increased AD risk (OR 2.53; 95% CI 1.10-5.80). No significant differences were found in the distribution of either genotypic or allelic frequencies between cases and controls in the HCRTR1 polymorphisms rs2271933, rs10914456 and rs4949449 and in the HCRTR2 polymorphism rs3122156. Conclusion: Our data support the hypothesis that the HCRTR2 gene is likely to be a risk factor for AD. The increased risk inferred is quite small, but in the context of a multi-factorial disease, the presence of this polymorphism may significantly contribute to influencing the susceptibility for AD by interacting with other unknown genetic or environmental factors in sleep regulation.

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