Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with Down syndrome

Constance Chace, Deborah Pang, Catherine Weng, Alexis Temkin, Simon Lax, Wayne P Silverman, Warren Zigman, Michel Ferin, Joseph H. Lee, Benjamin Tycko, Nicole Schupf

Research output: Contribution to journalArticle

Abstract

CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

Original languageEnglish (US)
Pages (from-to)601-612
Number of pages12
JournalJournal of Alzheimer's Disease
Volume28
Issue number3
DOIs
StatePublished - 2012

Fingerprint

Steroid 17-alpha-Hydroxylase
Aromatase
Down Syndrome
Cytochrome P-450 Enzyme System
Alzheimer Disease
Single Nucleotide Polymorphism
Genes
Sex Hormone-Binding Globulin
Estrogens
Alleles
Aptitude
Age of Onset
Biological Availability
Health Status
Psychiatry
Cohort Studies
Genotype
Hormones
Incidence

Keywords

  • Alzheimer's disease
  • aromatase
  • CYP17
  • CYP19
  • Down syndrome
  • estrogen
  • genetics

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with Down syndrome. / Chace, Constance; Pang, Deborah; Weng, Catherine; Temkin, Alexis; Lax, Simon; Silverman, Wayne P; Zigman, Warren; Ferin, Michel; Lee, Joseph H.; Tycko, Benjamin; Schupf, Nicole.

In: Journal of Alzheimer's Disease, Vol. 28, No. 3, 2012, p. 601-612.

Research output: Contribution to journalArticle

Chace, C, Pang, D, Weng, C, Temkin, A, Lax, S, Silverman, WP, Zigman, W, Ferin, M, Lee, JH, Tycko, B & Schupf, N 2012, 'Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with Down syndrome', Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 601-612. https://doi.org/10.3233/JAD-2011-110860
Chace, Constance ; Pang, Deborah ; Weng, Catherine ; Temkin, Alexis ; Lax, Simon ; Silverman, Wayne P ; Zigman, Warren ; Ferin, Michel ; Lee, Joseph H. ; Tycko, Benjamin ; Schupf, Nicole. / Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with Down syndrome. In: Journal of Alzheimer's Disease. 2012 ; Vol. 28, No. 3. pp. 601-612.
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AU - Chace, Constance

AU - Pang, Deborah

AU - Weng, Catherine

AU - Temkin, Alexis

AU - Lax, Simon

AU - Silverman, Wayne P

AU - Zigman, Warren

AU - Ferin, Michel

AU - Lee, Joseph H.

AU - Tycko, Benjamin

AU - Schupf, Nicole

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N2 - CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

AB - CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, and health status at 14-20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6-9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS.

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