[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.

Lack of linkage and association between autoimmune thyroid diseases and the CTLA-4 gene in a large Tunisian family.

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 theta=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.

A full genome screening in a large Tunisian family affected with thyroid autoimmune disorders.

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.

Analysis of heat shock protein polymorphisms in a large family with autoimmune thyroid diseases.

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.

Analysis of immunoglobulin VH and TCR cbeta polymorphisms in a large family with thyroid autoimmune disorder.

In order to investigate the association of TCR Cbeta and immunoglobulin (Ig) VH polymorphisms with thyroid autoimmune diseases (TAD), we analyzed restriction-endonuclease-generated polymorphisms using T-cell receptor (TCR) Cbeta 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 Cbeta probe revealed two alleles of 9.2 and 10 kb. These Cbeta 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.

[Predisposition to thyroid autoimmune diseases]. / Prédisposition aux maladies autoimmunes thyroïdiennes.

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.

Expression of the autoreactive Ig repertoire in a large family, with high prevalence of thyroid autoimmune diseases.

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.