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

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.

Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders.

OBJECTIVES: The signal transducer and activator of transcription 4 (STAT4) gene localised on chromosome 2q32.2-q32.3 is known to be essential for mediating responses to interleukin 12 in lymphocytes and regulating the differentiation of T helper cells. The aim of this study was to investigate the role of the STAT4 gene in susceptibility to rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) in Tunisian case control studies. METHODS: Genotyping of STAT4 rs7574865 single nucleotide polymorphism (SNP) was performed in 140 patients affected with RA, 159 patients affected with AITDs and 200 healthy controls using TaqMan® allelic discrimination assay. Data were analysed by χ2-test, genotype relative risk (GRR) and odds ratio (OR). RESULTS: Our results revealed that frequencies of the T allele and the T/T genotype were significantly higher among RA patients compared to controls (p=0.008; p=0.003, respectively). However, no significant associations with the risk of autoimmune thyroid diseases were detected. Moreover, the stratification of RA patients subgroups revealed a significant association of both T allele and T/T genotype in patients presented erosion (p=0.003; p=0.004, respectively) as well as anti-cyclic peptides-negative RA (ACPA-) (p=0.002; p=0.0003, respectively). Furthermore, genotypic association was found according to the absence of rheumatoid factor antibody (RF) (p=0.0014). But, no significant differences in allele and genotype frequencies of STAT4 rs7574865 polymorphism were detected according to the presence of another autoimmune disease, nodules and in HLA-DRB1*04 and HLA-DRB1*0404 positive subgroups. CONCLUSIONS: Our results support involvement of the STAT4 gene in the genetic susceptibility to RA but not to AITDs in the Tunisian population.

[Predisposition to autoimmune thyroid diseases within a Tunisian multiplex family]. / Prédisposition aux maladies auto-immunes thyroïdiennes au sein d'une famille tunisienne multiplexe.

The autoimmune thyroid diseases (AITDs) are multifactorial diseases which result from interplays between predisposing genes and triggering environmental factors. In order to study the genetic susceptibility factors to AITDs, we have followed up 115 control members belonging to a large Tunisian family with a high prevalence of AITDs (Akr family) during 15 years between 1990 to 2005. The follow-up of these control members have showed that 13 subjects (11.3%) developed AITDs (G2). The Hashimoto thyroiditis was the most frequently seen in 77% of the cases, whereas the Graves's disease was present in 23% of the cases. One hundred and two members remained controls (G1). High female predominance was noted in the two groups. The mean age of the G1 subjects group was slightly higher than that of G2. The prevalence of positive antithyroglobulin antibody (TgAb) and antithyroperoxydase antibody (TPOAb) was more frequent in G2 group (P=0.27 and P=0.23) respectively. The HLA haplotypes was realized in 42% of control members. The most frequent HLA haplotypes that were found were B37, DRB11 and A1. HLA B37 and DRB11 were significantly more frequent for the patients of G2 (P=0.0001 and P=0.034) respectively. Our study confirms the contribution of the genetic factors in the development of AITDs in 'Akr' family and suggested that the members of this family share the same genetic inheritance.

[Epidemiologic study of autoimmune thyroid disease in south Tunisia]. / Etude épidémiologique des maladies autoimmunes thyroïdiennes dans le sud tunisien.

In order to study incidence and prevalence of autoimmune thyroid diseases (AITDs), we studied a retrospective cohort of 1,079 patients explored in the department of Endocrinology of Sfax (south of Tunisia). The overall incidence of AITDs was 9.9%. Mean age was 39.6+15 years; sex ratio 5 F/1M. Graves' disease was the most frequent (45%). Atrophic thyroiditis was present in 32.2% of patients and Hashimoto's thyroiditis in 22.8%. The incidence of AITDs increased from 1990 to 2000 and by 2003 it had fallen to 67 cases per year. TPO antibody was present in two-thirds of patients with Hashimoto thyroiditis, and half of those with atrophic thyroiditis. TG antibodies were less frequent (one-third of patients). Association with other autoimmune diseases was noted in 6.3% of patients: type I diabetes mellitus, adrenal insufficiency and vitiligo. Statistic analysis did not disclose any association between autoantibody levels and thyroid dysfunction. There was an association between TG antibody and TSH levels among patients with Graves' disease and between TG antibody level and age in atrophic thyroiditis patients (p<0.05); a correlation was also noted between these antibodies and other autoimmune diseases (p=0.05). It is difficult to assess the frequency of ATD in the clinical setting. Characteristic features of AITDs in patients seen in south Tunisia were found to be similar to those described in the literature. Other more large-scale representative studies would be useful to establish the epidemiology of AITDs in Tunisia.