Subject(s)
Graves Disease/genetics , Thyroiditis, Autoimmune/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Consanguinity , Data Interpretation, Statistical , Female , Gene Frequency , Graves Disease/epidemiology , Heredity , Humans , Incidence , Male , Middle Aged , Pedigree , Prevalence , Thyroiditis, Autoimmune/epidemiology , Tunisia/epidemiology , Young AdultABSTRACT
FKBP1B belongs to immunophilins superfamily and functions as a cytosolic receptor protein of FK506. The role of FKBP1B in the immunosuppressive pathway of FK506 is well established. Previously, we reported a strong evidence of linkage between D2S171 microsatellite marker (located in vicinity of FKBP1B gene) and susceptibility to autoimmune thyroid diseases (AITDs). In this study, we report linkage disequilibrium between the dimorphism (C/T) in the 3' untranslated region (3' UTR) of FKBP1B gene and susceptibility to AITDs. DNAs were extracted from a large Tunisian family affected with Graves' disease (GD) and Hashimoto's thyroiditis (HT) and analysed by PCR-RFLP using DraIII restriction enzyme. Our results showed an excess of transmission of the allele C from heterozygous parents to affected offspring (transmission disequilibrium test (TDT) = 4.76; p = 0.012). This suggests a linkage disequilibrium of 3' UTR (C/T) SNP with AITDs. Moreover, The FBAT analysis gives a significant association with the C allele under the recessive model (chi2 = 5.50; p = 0.018). These results support the involvement of FKBP1B gene in the genetic susceptibility to the AITDs development in the studied family.
Subject(s)
Immunophilins/genetics , Linkage Disequilibrium/genetics , Microsatellite Repeats/genetics , Tacrolimus/metabolism , Thyroiditis, Autoimmune/genetics , Humans , Tacrolimus/immunology , TunisiaABSTRACT
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 alpha (TLalpha) 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)).
Subject(s)
Major Histocompatibility Complex , Polymorphism, Genetic , Thyroiditis, Autoimmune/immunology , Tumor Necrosis Factor-alpha/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Chromosome Mapping , Female , Graves Disease/genetics , Graves Disease/immunology , Humans , Male , Middle Aged , Sequence Analysis, DNA , Thyroiditis, Autoimmune/genetics , Tumor Necrosis Factor-alpha/genetics , TunisiaABSTRACT
Genotypes of 103 short tandem repeat (STR) markers distributed at an average of 40 cM intervals throughout the genome were determined for 40 individuals from the village of BirEl Hfai (BEH). This village of approximately 31,000 individuals is localized in the south-west of Tunisia. The allele frequency distributions in BEH were compared with those obtained for individuals in the CEPH (Centre d'Etude du Polymorphisme Humain) data using a Kolmogorov-Smirnov two-sample test. Fourteen out of the 103 markers (13.2%) showed significant differences (P<0.05) in distribution between the two populations. Population heterogeneity in BEH was indicated by an excess of observed homozygosity deviations from Hardy-Weinberg equilibrium at three loci (P<0.0005). No evidence for genotypic disequilibrium was found for any of the marker pairs. This demonstrated that in spite of a high inbreeding level in the population, few markers showed evidence for a different pattern of allelic distribution compared to CEPH.
