RESUMO
BACKGROUND: The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis. METHODS: To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic. RESULTS: In T1D, aside from the HLA locus, we found four regions showing a lod-score > or =1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score > or =1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5). CONCLUSION: This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.
Assuntos
Diabetes Mellitus Tipo 1/genética , Ligação Genética , Predisposição Genética para Doença , Repetições de Microssatélites/genética , Esclerose Múltipla/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico , Diabetes Mellitus Tipo 1/complicações , Feminino , Marcadores Genéticos/genética , Haplótipos , Humanos , Masculino , Ilhas do Mediterrâneo , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Locos de Características Quantitativas , Estatísticas não ParamétricasRESUMO
Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and X-linked syndrome). FOXP3 is necessary for the differentiation of a key immune suppressive subset of T-cells, the CD4+CD25+ regulatory T-cells. Previously, we reported a significant male-female bias in the common, multifactorial form of type 1 diabetes in Sardinia and evidence of linkage of chromosome Xp11 to the disease. These findings indicate that FOXP3 is a prime functional and positional candidate locus for the common form of type 1 diabetes. In the present study, we initially scanned 82 kb of the FOXP3 region for common polymorphisms, including sequencing all of the coding and functionally relevant portions of the gene in 64 Sardinian individuals. Then the most informative polymorphisms in 418 type 1 diabetic families and in 268 male case and 326 male control subjects were sequentially genotyped and tested for disease association. There is no evidence that variants in the FOXP3 regions analyzed are associated with type 1 diabetes and account for the male-female bias observed in Sardinia. Our data indicate that allelic variation in or near the coding regions of the FOXP3 gene does not have a major role in the inherited susceptibility to the common form of type 1 diabetes.
