Association study of CARD8 (p.C10X) and NLRP3 (p.Q705K) variants with rheumatoid arthritis in French and Tunisian populations

Abstract

The objective of the study was to investigate the association of caspase activating and recruitment domain 8 (CARD8) and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) polymorphisms with rheumatoid arthritis (RA) in Tunisian and French populations. CARD8 (c.30T>A, rs2043211) and NLRP3 (c.2113C>A, rs35829419) single nucleotide polymorphisms (SNPs) were genotyped in 100 French RA trio families and 141 Tunisian patients with RA and 191 unrelated healthy controls, using TaqMan(®) allelic discrimination assay. The genetic analyses for the association and linkage in French families were performed using the comparison of allelic frequencies (AFBAC), the genotype relative risk (GRR) and the transmission disequilibrium test (TDT). Data for case and control samples were analysed by chi-square-test, GRR and odds ratio (OR). No significant differences between alleles and genotypes frequencies were detected in French trio and Tunisian patients with RA and controls, either with CARD8 or with NLRP3 SNPs both in French and in Tunisian populations. Moreover, stratifying patients according to the presence of rheumatoid factor (RF), anti-cyclic peptides antibodies (ACPA), erosion, nodules, other autoimmune disease or HLA-DRB1*04-positive subgroups did not show any significant association with CARD8 or NLRP3 (P ≥ 0.05). This study suggests that variations in the innate immunity genes CARD8 (p.C10X) and NLRP3 (p.Q705K) have no effect on RA susceptibility either in the Tunisian or in the French population.

NLRP3 rs35829419 polymorphism is associated with increased susceptibility to multiple diseases in humans

“…Subsequently, 124 articles were excluded, and16 articles were examined closely for qualitative analysis. This resulted in elimination of 3 studies that had insufficient information; finally, 13 casecontrol studies were incorporated into this meta-analysis that contained a total of 7719 patients diagnosed with diverse diseases and 7094 healthy controls (Hitomi et al, 2009;Villani et al, 2009a,b;Roberts et al, 2010;Roberts et al, 2011;Ben Hamad et al, 2012;Carlstrom, 2012;Pontillo et al, 2012a,b;Ungerback, 2012;Kastbom et al, 2013;Pontillo et al, 2013;Varghese et al, 2013). The various diseases in the included studies were myocardial infarction, Alzheimer's disease, leprosy, ankylosing spondylitis, colorectal cancer (CRC), HIV-1 infection, systemic lupus erythematosus, malignant mesothelioma, rheumatoid arthritis (RA), abdominal aortic aneurysms (AAA), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), type 1 diabetes, celiac disease, and atopic dermatitis.…”

“…Within the NLRP3 gene, approximately 60 single nucleotide polymorphisms (SNPs) have been identified, and the most prevalent polymorphisms among these are rs35829419 (Q705K), rs10754558, rs4612666, rs4925648, and rs10925019 (Schoultz et al, 2009), based on the SNP genotype data available from the US National Institute of Mental Health bipolar disorder (NIMH-BP) database dbGaP. In general, NLRP3 rs35829419 polymorphisms are associated with various inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and celiac disease (Pontillo et al, 2011;Pontillo et al, 2012a;Tan et al, 2013), and the NLRP3 polymorphism Q705K in particular is tightly linked to autoimmune disorders such as atopic dermatitis and systemic lupus erythematosus (Roberts et al, 2010;Tan et al, 2013) and to neuropathies such as late-onset Alzheimer's disease (Ben Hamad et al, 2012). It is well known that inflammatory diseases are characterized by excessive production of nuclear factor-κB (NF-κB)-dependent cytokines such as interleukin (IL)-1β, and that the NLRP3 gene polymorphism Q705K is a gain-of-function variant that leads to hyperactive inflammasomes.…”

“…The heightened activity of inflammasome sowing to NLRP3 gene polymorphism Q705Klikely constitutively cleaves pro-IL-1β leading to the overproduction of bioactive IL-1β, which participates in the host response to injury and infection as a proinflammatory cytokine (Roberts et al, 2011;Pontillo et al, 2012a). The pathogenic mechanism involving NLRP3 rs35829419 SNP is dramatically similar in the diverse disease settings discussed above (Roberts et al, 2010;Ben Hamad et al, 2012), and accumulated evidence suggests that the Q705K polymorphism promotes a disease state by causing a hyper-sensitive response to pathogen-associated molecular patterns and sustained activation of inflammation (Villani et al, 2009b;Kastbom et al, 2013). However, in direct contrast, other studies have shown a protective role for the NLRP3 polymorphism Q705K; therefore, the clinical relevance of this polymorphism remains uncertain (Hitomi et al, 2009;Ben Hamad et al, 2012).…”

“…The pathogenic mechanism involving NLRP3 rs35829419 SNP is dramatically similar in the diverse disease settings discussed above (Roberts et al, 2010;Ben Hamad et al, 2012), and accumulated evidence suggests that the Q705K polymorphism promotes a disease state by causing a hyper-sensitive response to pathogen-associated molecular patterns and sustained activation of inflammation (Villani et al, 2009b;Kastbom et al, 2013). However, in direct contrast, other studies have shown a protective role for the NLRP3 polymorphism Q705K; therefore, the clinical relevance of this polymorphism remains uncertain (Hitomi et al, 2009;Ben Hamad et al, 2012). In order to address this issue, we performed a comprehensive meta-analysis to evaluate the association of the NLRP3 Q705K gene polymorphism with the progression of a variety of human diseases of high clinical value.…”

Investigation into the association between NLRP3 gene polymorphisms and susceptibility to type 2 diabetes mellitus

“…Several previous studies have evaluated the connection between NLRP3 polymorphisms and susceptibility to many immune-mediated inflammatory diseases, including rheumatoid arthritis, Crohn's disease, celiac disease, and type 1 diabetes (Villani et al, 2009;Pontillo et al, 2010;Ben Hamad et al, 2012). Ben Hamad et al (2012) reported that variations in this gene have no effect on rheumatoid arthritis susceptibility in Tunisian and French populations.…”