title: Variants in CYP17 and CYP19 cytochrome P450 genes are associated with onset of Alzheimer's disease in women with down syndrome.
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.
authors: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
authors: Constance
authors: C
authors: Chace
authors: Deborah
authors: D
authors: Pang
authors: Catherine
authors: C
authors: Weng
authors: Alexis
authors: A
authors: Temkin
authors: Simon
authors: S
authors: Lax
authors: Wayne
authors: W
authors: Silverman
authors: Warren
authors: W
authors: Zigman
authors: Michel
authors: M
authors: Ferin
authors: Joseph H
authors: JH
authors: Lee
authors: Benjamin
authors: B
authors: Tycko
authors: Nicole
authors: N
authors: Schupf
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D001141:Aromatase / Q000235:genetics*; D015331:Cohort Studies; D004185:Disability Evaluation; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008593:Menopause / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D011863:Radioimmunoassay; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; D012738:Sex Hormone-Binding Globulin; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase