Gene–gene interaction between CARD8 and interleukin-6 reduces Alzheimer’s disease risk

Abstract

Sirs, A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer’s disease (AD) [9]. NF-jB, a major transcription factor controlling inflammation, is activated in AD brains [5], and genes encoding several different proinflammatory cytokines, such as interleukin-6 (IL-6), are induced by NF-jB in activated microglia surrounding senile plaques [4]. In contrast with the majority of CARD proteins described to date that activate NF-jB, CARD8 potently suppresses NF-jB activation and reduces the inflammatory process [8]. A biallelic (T/A) polymorphism located at the third nucleotide of codon 10 of CARD8 (rs2043211) generates a premature stop codon (allele A) that severely truncates CARD8 protein giving rise to a small N-terminal peptide unable to regulate the NF-jB signaling pathway; in contrast, the full-length protein (allele T) represses the activity of NF-jB and limits the induction of inflammatory mediators [3]. CARD8 (rs2043211) polymorphism has been associated with chronic inflammatory diseases, such as Crohn’s disease [6] and rheumatoid arthritis [3]. A biallelic (G/C) polymorphism in the promoter region (-174, rs1800795) of the IL-6 gene was found to be associated with susceptibility for AD [1, 7]. The postulated common pathway of CARD8 and IL-6 in the cerebral inflammatory response (CARD8 suppressing the NF-jB activity in the context of proinflammatory signals) prompted us to examine the combined contribution of both genes to the susceptibility for AD. The study included 239 AD patients (66% women; mean age at the time of study 75.6 years; SD 7.8; range 50– 97 years; mean age at onset 72.4 years; SD 7.9; range 48– 94 years) who met NINCDS/ADRDA criteria for probable AD. All AD cases were defined as sporadic because their family history did not mention any first-degree relative with dementia; this information was obtained by direct interviews with relatives. Control subjects consisted of 165 unrelated individuals (69% women; mean age 80.8 years; SD 7.1; range 63–98 years) who had complete neurological and medical examinations establishing that they were free of significant illness and all had MMSE scores of 28 or more. Control subjects were randomly selected from a nursing home, and they arose from the same base population as the cases. The AD and control samples were Caucasians originating from a homogeneous population in a limited geographical area in Northern Spain. All patients and control subjects were ascertained to have parents and grandparents born in Northern Spain to ensure ethnicity; consequently, possible confounding effects of the inclusion in the study of members of different ethnic groups have been minimized. Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. The study was approved by the ethical committee of the University Hospital ‘‘Marques de Valdecilla’’. The CARD8 (rs2043211) and IL-6 (-174, rs1800795) polymorphisms were determined as described A. Fontalba O. Gutierrez J. L. Fernandez-Luna Unidad de Genetica Molecular, ‘‘Marques de Valdecilla’’ University Hospital, Santander, Spain