Deficiency of CARD8 Is Associated with Increased Alzheimer’s Disease Risk in Women

Abstract

NF-ĸB, a major transcription factor controlling inflammation, is activated in Alzheimer’s disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-ĸB activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-ĸB and an amplification of the inflammatory process. Apolipoprotein E (ApoE) Ε4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-ĸB 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 Ε4 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 Ε4 allele.

The Association between Polymorphism of CARD8 rs2043211 and Susceptibility to Arteriosclerosis Obliterans in Chinese Han Male Population

“…The SNP rs2043211 of CARD8 changes cysteine at codon10 to a premature termination codon, thus yielding a premature, truncated protein, which influences the protein function in inflammasome-mediated processes and NF-κB suppression [18,19]. Lots of studies show that the polymorphisms of CARD8 contribute to the development of some inflammatory diseases, such as inflammatory bowel disease [20][21][22], gout [23],abdominal aortic aneurysm [24], rheumatoid arthritis [17,25,26]and Alzheimer's disease [27,28]. As a part of innate immunity, CARD8 is involved in the modulation of inflammatory activities.…”

CARD8 rs2043211 Polymorphism is Associated with Gout in a Chinese Male Population

“…NALP3 inflammasome contains NALP3, apoptosis-associated speck (ASC)-like protein and caspase activation and recruitment domain 8 (CARD8) [11,12]. Recent studies suggest that CARD8 functional mutations contribute to the development of autoinflammatory diseases including inflammatory bowel disease, rheumatoid arthritis, and Alzheimer's disease [13,14,15,16,17]. CARD8 is a component of innate immunity involved in the suppression of NF-κB (nuclear factor κB) activation [13,16].…”

“…CARD8 can lead to the suppression of the immune response and suppression of inflammatory activities [13,16]. Several previous investigations have studied the association of a nonsense T30A polymorphism (rs2043211) in exon 5 with different inflammatory diseases including inflammatory bowel disease, rheumatoid arthritis, and Alzheimer's disease [13,15,16,17]. Considering the important role of CARD8 in the inflammatory response, we hypothesized that CARD8 rs2043211 polymorphism may influence the risk of gout development.…”

Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma

“…More recently, a single nucleotide polymorphism (SNP) in NLRP3 (rs35929419), in combination with CARD-8 polymorphism (rs2043211), has been associated with chronic inflammatory conditions (Kastbom et al, 2008;Roberts et al, 2010Roberts et al, , 2011Schoultz et al, 2009;Verma et al, 2008). The CARD-8 protein is additionally suggested to be a negative regulator of caspase-1-mediated IL-1b regulation and NF-jB activation (Fontalba et al, 2008;Razmara et al, 2002). Another SNP in NLRP3 (rs10733113), located downstream of the NLRP3 gene, has been shown to regulate NLRP3 expression and IL1b levels and has recently been implicated in Crohn's disease (Villani et al, 2009).…”