Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease.
OBJECTIVE
Inflammation has been extensively implicated in the pathogenesis of Alzheimer's disease (AD). Although there is evidence of a key role for cytokines in neuroinflammation processes, so far the proinflammatory cytokine interleukin (IL)-18 has not been associated with AD. The aim of this study was to investigate the impact of two polymorphisms of the human IL-18 gene promoter at positions -607 (C/A) and -137 (G/C) on both susceptibility to and progression of AD.


RESULTS
The results revealed that the genotype distribution of the -607 (C/A) polymorphism was different between patients with AD and control subjects (chi2 = 7.99, df = 2, p = 0.0184). In particular, carriers of the CC genotype were at increased risk of developing AD (OR 2.33; 95% CI 1.29 to 4.22; p = 0.0052). The observed genotypes were in Hardy-Weinberg equilibrium, as for the -607 polymorphism, whereas the -137 polymorphism appeared in Hardy-Weinberg disequilibrium only in the patient group (p = 0.0061). Finally, in a 2 year follow-up study, the -137 CC genotype was strongly and specifically associated with a faster cognitive decline (F = 4.024; df = 4,192; p = 0.0037 for time by IL-18 -137 G/C group interaction) with no interaction effect with the apolipoprotein E epsilon4/non-epsilon4 allele presence.


CONCLUSIONS
As IL-18 cytokine promoter gene polymorphisms have been previously described to have functional consequences on IL-18 expression, it is possible that individuals with a prevalent IL-18 gene variant have a dysregulated immune response, suggesting that IL-18 mediated immune mechanisms may play a crucial role in AD.
Bossù
Paola
P
IRCCS Santa Lucia Foundation, Rome, Italy. p.bossu@hsantalucia.it
Ciaramella
Antonio
A
Moro
Maria Luisa
ML
Bellincampi
Lorenza
L
Bernardini
Sergio
S
Federici
Giorgio
G
Trequattrini
Alberto
A
Macciardi
Fabio
F
Spoletini
Ilaria
I
Di Iulio
Fulvia
F
Caltagirone
Carlo
C
Spalletta
Gianfranco
G
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology; D008297:Male; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic
D020382:Interleukin-18