Deficiency of CARD8 is associated with increased Alzheimer's disease risk in women.
NF-kappaB, a major transcription factor controlling inflammation, is activated in Alzheimer's disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-kappaB activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-kappaB and an amplification of the inflammatory process. Apolipoprotein E (ApoE) epsilon4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-kappaB and enhanced brain inflammation. In a case-control study in 300 AD patients and 300 healthy controls, we examined whether the CARD8 (p.C10X) polymorphism, independently or in concert with the ApoE epsilon4 allele, might predispose to AD. Women, but not men, carrying the CARD8 AA genotype (truncated protein) had a 2.39-fold higher risk of developing AD than subjects with the CARD8 TT genotype (full-length protein). This association with susceptibility to AD was independent of the ApoE epsilon4 allele.
Unidad de Genética Molecular, Marqués de Valdecilla University Hospital, Santander, Spain.
Ana
A
Fontalba
Olga
O
Gutiérrez
Javier
J
Llorca
Ignacio
I
Mateo
José
J
Berciano
José Luis
JL
Fernández-Luna
Onofre
O
Combarros
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D017678:Sex Distribution
D053327:Apolipoprotein E4; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins