title: Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease.
abstract: In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer's disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the alpha1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon -17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p = 0.019) and this difference was confined to male AD patients (p = 0.002). Among male AD patients, the ACT/AA genotype was also associated with shorter disease duration before death as compared to the ACT/AT+TT genotypes (p = 0.012). These data suggest that the ACT gene may affect AAO and disease duration of AD.
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. ikamboh@hgen.pitt.edu
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Minster
authors.forename: Margaret
authors.initials: M
authors.lastname: Kenney
authors.forename: Ayla
authors.initials: A
authors.lastname: Ozturk
authors.forename: Purnima P
authors.initials: PP
authors.lastname: Desai
authors.forename: Candace M
authors.initials: CM
authors.lastname: Kammerer
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010414:Pennsylvania / Q000453:epidemiology; D011110:Polymorphism, Genetic; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D012720:Severity of Illness Index; D000514:alpha 1-Antichymotrypsin / Q000235:genetics*
chemical_list: D000514:alpha 1-Antichymotrypsin