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

Hedi Chaker Hospital, Şafāqis, Şafāqis, Tunisia
Human Immunology (Impact Factor: 2.14). 12/2001; 62(11):1245-50. DOI: 10.1016/S0198-8859(01)00316-0
Source: PubMed


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.

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    • "Also, no difference was found in the distribution of the A and G alleles, nor did the AA, AG, or GG genotypes differ between patients and controls (Table 2 in the " Appendix " ). Our findings in this respect are similar to that reported on studies done on small samples of Tunisian and Japanese populations (Maalej et al. 2001; Sakai et al. 2001). In the available literature, studies on the polymorphism of CTLA4 exon1 A49G have shown conflicting results. "
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    ABSTRACT: This study aims to investigate the association of human leukocyte antigen (HLA) class II genes and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with autoimmune thyroid diseases in the Lebanese population. A total of 128 patients with autoimmune thyroid disease (55 with Graves' disease (GD) and 73 with Hashimoto's thyroiditis (HT)) were typed for HLA DQA1 (0301 and 0501) and DQB1 (0201, 0302, and 0303) and for 49A/G CTLA-4 using PCR-based sequence-specific priming methods. A total of 186 matched controls were typed for the same alleles and compared to the diseased population. Results showed no significant differences in HLA DQB1*0201 or DQB1*0301 allelic frequencies or CTLA-4 polymorphisms between patients and controls. For GD, there was a weak association with HLA DQB1*0302 [34.6% (19 of 55) vs. 21.5% (40 of 186), P = 0.048, odds ratio (OR) = 1.926, confidence interval (CI) = 0.999-3.715] and HLA DQB1*0302-DQA1*0501 haplotype [56.36% (31 of 55) vs. 40.8% (76 of 186), P = 0.042, OR = 1.870, CI = 1.018-3.433]. For HT, the frequencies of DQB1*0302-DQA1*0501 haplotype [28.8% (21of 73) vs. 14.5% (27 of 186), P = 0.008, OR = 2.378, CI = 1.241-4.558] and DQB1*0302-DQA1*0301 haplotype [60.2% (44 of 73) vs. 38.7% (72 of 186), P = 0.002, OR = 2.402, CI = 1.381-4.180] were significantly higher in patients. On the other hand, weak association was found between HT and DQA1*0301 allele [32.9% (24 of 73) vs. 20.9% (39 of 186), P = 0.044, OR = 1.846, CI = 1.011-3.373]. Findings show that DQB1*0302-DQA1*0501 and DQB1*0302-DQA1*0301 haplotypes may play a role in the pathogenesis of HT in the Lebanese population. For the 49A/G CTLA-4 polymorphism, no significant difference was found between patients and controls.
    Journal of community genetics 03/2012; 3(4):259-64. DOI:10.1007/s12687-012-0085-1
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    • "The exploration of the genetic component of Tunisian AITD has revealed a number of susceptibility regions and genes (Elleuch-Bougacha et al. 2001; Hadj Kacem et al. 2001, 2003; Maalej et al. 2001a). The linkage and the intra-familial association using CTLA-4 gene polymorphisms (Maalej et al. 2001b) have shown no particular role of this gene in the genetic transmission of familial AITD. However, with the case–control approach, CTLA-4 was found associated with GD (Hadj Kacem et al. 2001) as reported by several studies using Asian and European samples (Chistiakov and Turakulov 2003). "
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    ABSTRACT: The thyroglobulin (Tg) gene was reported to be linked and/or associated to autoimmune thyroid diseases (AITD) development in European Caucasian populations. Here, we attempt to replicate this finding and to evaluate the contribution of the Tg gene in the genetic susceptibility of AITD in the Tunisian population. We examined the genomic region (11.5cM) containing the Tg gene by genotyping seven microsatellite markers and four SNPs located respectively at exon 10 (Ser715Ala), exon 12 (Met1009Val), exon 21 (Ala1483Ala) and exon 33 (Arg1980Trp) in 15 Tunisian multiplex families affected with AITD including Graves' disease (GD) and Hashimoto's thyroiditis (HT) (members: 87; patients: 27 GD and 16 HT). A case-control study was performed by genotyping the Tgms2 intragenic microsatellite marker (intron 27) and four intragenic SNPs on 108 unrelated patients affected with GD and 169 normal controls. Analysis of family data did not show linkage of the thyroglobulin gene with AITD nor did analysis of case-control data show association of Tgms2 or SNPs with GD. In contrast to the European Caucasian population, we failed to detect any contribution of Tg gene in the genetic component of Tunisian AITD.
    Immunobiology 08/2008; 213(7):577-83. DOI:10.1016/j.imbio.2008.01.004 · 3.04 Impact Factor
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    • "Case–control studies on the association between the CTLA4 gene and AITD have been performed in Japan only, and their results are conflicting (Sale et al. 1997, Akamizu et al. 2000). No evidence was found for linkage between the CTLA4 gene and AITD (Nithiyananthan et al. 2002) in studies that included two genome-wide scans (Tomer et al. 1999, Sakai et al. 2001) and analyses of large Tunisian (Maalej et al. 2001) and Chinese pedigrees (Villanueva et al. 2002). Meanwhile, a number of investigations support a relation between the CTLA4 gene and features of autoimmune thyroid disease such as production of thyroid autoantibody (Tab). "
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    ABSTRACT: Autoimmune thyroid disease (AITD) occurs in two common forms: Graves' disease and Hashimoto thyroiditis. On the basis of functional and experimental data, it has been suggested that the gene encoding cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a candidate gene for conferring susceptibility to thyroid autoimmunity. In this review, we critically evaluate the evidence for pathogenetic involvement of CTLA-4 in the various forms of AITD and focus on the possible role of genetic variation of the CTLA4 locus. Population genetics data strongly suggest a role for the CTLA4 region in susceptibility to AITD. However, further functional studies are required to understand the significance of CTLA4 polymorphisms in the pathogenic mechanism of AITD.
    Journal of Molecular Endocrinology 09/2003; 31(1):21-36. DOI:10.1677/jme.0.0310021 · 3.08 Impact Factor
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