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.

Autoimmune thyroid diseases (AITDs) including Graves disease (GD) and autoimmune hypothyroidism (AH) are associated with TNF genes polymorphisms. TNF molecules bind to TNFRI and TNFRII. No genetic association was reported between TNFR and AITDs. In this study, we have analysed two polymorphisms in TNFRI gene (TNFRI+36A/G SNP and a microsatellite (GT)(17) (GA)(n)) and one polymorphism in TNFRII gene (TNFRII +676 T/G). All these polymorphisms were studied in a large Tunisian family with high prevalence of AITDs, and on a case-control sample of 91 GD patients and 165 controls. The present study was undertaken to investigate the genetic association of these polymorphisms with AITDs development. We reported the implication of TNFRIA3 allele in AITDs pathogenesis in familial and case control studies, respectively (chi(2)=4.13, p=0.042; chi(2)=9.26, p(c)=0.005). In addition, Case-control study has revealed for the first time that TNFRII+676G allele was associated with GD (chi(2)=11.53; p=0.0007). Two TNFRI haplotypes were found to be associated with GD: TNFRI+36G-A8, TNFRI+36A-A3 (chi(2)=88.07; p=6.32x10(-21), chi(2)=16.78; p=4.2x10(-5), respectively). Our data showed that TNFRI polymorphisms have an important role in AITDs pathogenesis in both familial and case-control samples and that TNFRII was rather implicated in GD development in the Tunisian population.

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and autoimmune hypothyroidism (AH), are inherited as complex traits. Among the genes contributing to AITDs susceptibility are genes of the IL-1 family. IL-1 regulates T and B lymphocyte maturation, including the induction of several cytokines and cytokine receptors. Therefore, disturbances of this balance may not only play a role in inflammation but also in the pathogenesis of autoimmunity. In order to investigate genetic association of IL-1 gene polymorphisms with AITDs, we performed both a familial study in a large Tunisian pedigree with high prevalence of AITDs (64 patients and 176 controls), and a case-control study (131 GD unrelated patients and 225 healthy controls). PCR and PCR-RFLP methods were used to analyse respectively a VNTR in the IL-1RN gene and three SNPs in both IL-1B genes (-511 C/T and +3954 C/T) and IL-1A (-889 C/T). The family-based association study showed an association of the IL-1B+3954 C/T polymorphism (p = 0.02) and two haplotypes IL-1RN*3/C/T/T and IL-1RN*1/C/T/T (p = 0.009 and p = 0.047 respectively) with AITDs. The case-control study is the first study revealing a significant association of the IL-1A-889 C/T polymorphism (chi2 = 10.23; p = 0.0014) with susceptibility to GD. Our data suggest that the IL-1 gene cluster may harbour susceptibility genes for AITDs and GD pathogenesis in the Tunisian population.

Autoimmune thyroid diseases (AITDs), which include Hashimoto thyroiditis (HT), Graves' disease (GD) and primary idiopathic myxoedema (PIM), are recognized as multifactorial diseases. In this study, we have examined single and haplotypic genetic variation across the major histocompatibility complex (MHC) in a Tunisian isolate with a high prevalence of AITDs (62 patients: 32 with GD, 9 with HT and 21 with PIM). Genotyping was performed for HLA class I and II alleles as well as polymorphisms within tumor necrosis factor (TNF), lymphotoxin α (TLα) and heat shock protein (HSP70-02 and HSP70-hom) genes. Our results showed association of HLA-A2-B50-TNF 2 haplotype with AITDs (p=0.045). Linkage analysis using Simwalk2 program has shown significant result with TNF −308 gene polymorphism (p=0.03). The FBAT has given evidence for genetic association with TNF −308 and HLA-DR gene polymorphisms. TNF 2 allele was associated with GD (p=0.0011), whereas TNF 1, HLA-DR11 and DR12 (p=0.0039, p=0.00089 and p=0.0056, respectively) were rather implicated in HT pathogenesis. Results found by TDT–STDT have confirmed the involvement of the TNF −308 gene polymorphism in AITD pathogenesis (p<10−9).

The autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are inherited as complex traits. We initiated a whole genome linkage study of patients with AITD, in order to identify the susceptibility genes involved in their pathogenesis. We studied 39 patients affected with GD or HT and 68 related controls, who belonged to a large consanguinous family composed of more than 200 members. Linkage analysis was performed using the lod score method under two arbitrary models, one dominant and one recessive. A positive lod score was found for D2S171, assuming a recessive mode of inheritance and 50% penetrance, which suggests the presence of a major AITD susceptibility gene on chromosome 2p21. However, no linkage was found with microsatellite markers spanning the HLA system. This locus localised outside MHC will be of interest for investigation of other autoimmune disorders.

The autoimmune thyroid diseases (AITDs) including Graves’ disease and Hashimoto’s thyroiditis are inherited as complex traits. We have performed linkage and association studies to investigate the role of CTLA-4 gene in the AITDs development using the D2S311, D2S143, the intragenic CTLA-4 (AT)n microsatellite markers and the CTLA-4 (A/G) dimorphism in exon 1. Four extended pedigrees belonging to a large Tunisian family named Akr and including 154 individuals from which 20 were affected with Hashimoto’s thyroiditis and 26 with Graves’ disease, were used in this investigation. No evidence for linkage with none of the markers was found under neither dominant nor recessive models [Z=−7.14 and Z=−14.32 at θ=0.0, respectively for the CTLA-4 (AT)n marker]. A family-based association study on 51 nuclear families derived from the Akr pedigree was performed by the FBAT approach applied to the CTLA-4 (AT)n marker and the CTLA-4 (A/G) dimorphism. We found no association of individual alleles to disease for both markers. These results showed no evidence for the involvement of the CTLA-4 locus in the AITDs pathogenesis.

Graves disease and Hashimoto's thyroiditis are autoimmune thyroid diseases (AITD) in which the genetic contribution is complex. The purpose of this work was to analyze the influence of hsp70 gene polymorphisms on the susceptibility to AITD. The hsp 70-2 and hsp 70-hom polymorphism was analyzed, by PCR-RFLP using PstI and NcoI enzymes, respectively, in 40 patients affected with AITD and 38 related healthy individuals belonging to a large consanguineous family named Akr. The transmission disequilibrium test (TDT) was applied on nuclear families, deduced from the Akr pedigree, with at least one heterozygous parent for each studied polymorphism. The corresponding x2 values for hsp 70-2 and hsp 70-hom were, respectively, of 0.52, p > 0.05 and 2.77, p > 0.05. Our data indicated lack of association between these hsp polymorphisms and AITD in this large family.

In order to investigate the association of TCR Cβ and immunoglobulin (Ig) VH polymorphisms with thyroid autoimmune diseases (TAD), we analyzed restriction-endonuclease-generated polymorphisms using T-cell receptor (TCR) Cβ and VH gene-family-specific probes. We tested genomic DNAs of patients isolated from a large family affected with Graves’ disease and Hashimoto’s thyroiditis as well as the genomic DNA of unrelated Tunisian controls. Hybridization of BglII-digested DNA with a TCR Cβ probe revealed two alleles of 9.2 and 10 kb. These Cβ polymorphisms have already been found in the Caucasian population. However, there was no abnormal distribution of this polymorphism in patients with TAD, compared to related healthy individuals and to unrelated Tunisian controls. Besides, there was a low VH polymorphism in members of the family affected with TAD. Analysis of the Ig gene families revealed no restriction site polymorphism pattern specific for TAD.

OBJECTIVES:Genetic predisposition is required for the expression of thyroid autoimmune disorder addition to the immune dysfunction and the environmental factors.METHODS:In order to evaluate the role of this genetic factor, we reported the results of immunological and hormonal investigations of 62 members (TD), belonging to a large Akr family, who are related to 40 patients with Graves' disease or Hashimoto's thyroiditis.RESULTS:The hormonal analyses showed that 19 subjects exhibited an infraclinical hypothyroidism, subdivided into 7 members with pathological rates of TSH evocative of thyroid insufficiency and 12 others with compensative thyroid insufficiency. Seventeen subjects of the Akr family who had solely antithyroid autoantibodies were considered as potential candidates to develop thyroid autoimmune diseases. The clinical follow-up, during two years, confirmed the diagnosis of Hashimoto's thyroiditis in 3 members among 19 subjects with infraclinical hypothyroidism (TD05, TD28 and TD54) and in only 1 member out of the 17 potential candidates (TD03).CONCLUSION:Our results showed that a serological study of hormones and/or autoantibodies directed against thyroid antigens, could allow the detection of predisposed subjects to develop a thyroid autoimmune pathology. The Akr family seems to be suitable for the study of the localization of susceptibility genes to TAID.

We have investigated the autoreactive Ig repertoire expressed by sera Ig of patients and healthy relatives individuals, who belong to a large family with high prevalence of autoimmune thyroid diseases (AITD). We have used a panel of thyroid, muscular and nuclear self antigens. IgG autoantibodies directed against thyroid antigens were found in 17 out of 29 patients (58.62%) and in 10 out of 46 (21.7%) of relatives sera which suggested that some relatives were either predisposed to develop the AITD or already affected with AITD. IgM natural autoantibodies (NAAb) directed against muscular and nuclear antigens were found in 27 out of 46 (58.69%) of healthy individuals but not exhibited in all of the patients. In relative's sera, the presence of anti-Tg and anti-TPO seems to be associated with the increase of the NAAb activity. Our Data suggested that The emergence of anti-Tg and anti-TPO auto-antibodies is secondary to a polyclonal activation.