Publicação
Identification of genetic risk factors for Behçet’s disease
| Resumo: | Background: Behçet’s disease (BD) is a complex disorder characterized by a generalized vasculitis, whose pathophysiology remains unclear. The identification of genes involved in BD can help to elucidate the disease mechanisms and, ultimately, result in diagnostic and treatment advances.Objectives: To identify genetic risk factors implicated in BD susceptibility. Methods: We performed four independent studies: 1) Analysis of the role of the mitochondrial genome by testing the association of mitochondrial haplogroups and variants with BD risk in 615 Iranian BD cases and 434 controls; 2) Follow-up of IL10 and IL23RIL12RB2 associations, previously identified as BD risk factors, in 973 Iranian BD cases and 637 controls; 3) Gene expression profiling in 15 Portuguese BD cases and 14 controls and association testing of the differentially expressed genes in 976 Iranian BD cases and 839 controls; 4) A genome-wide association study for the Iranian population in DNA pools of 292 BD cases and 294 controls and replication of the association findings in 684 BD cases and 532 controls.Results: We identified a novel association of BD with the mitochondrial 12S rRNA gene (7.00E-03<P<3.80E-02); replicated the association of IL10 (P=2.53E-02) and IL23R-IL12RB2 loci (1.93E-06<P<1.78E-05) and identified the region upstream IL23R as the most associated one; identified EREG, AREG and NRG1 (members of the Neuregulin signalling) as downregulated in BD patients, found a novel association in the EREG-AREG locus (P=2.51E-02) and replicated three associations at NRG1 (6.61E-04<Pmeta<2.10E-03); and identified five coding variants at FUT2 associated with BD (2.97E-06<P<1.34E-04).Conclusions: During the course of this project we have uncover the mitochondrial genome,the neuregulin signaling and the FUT2 gene as novel players in BD susceptibility that may contribute to the abnormal immunological response observed in BD patients. We have further contributed to establish the IL10 and IL23R loci as worldwide risk factors for Behçet’s disease. |
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| Autores principais: | Xavier, Joana M |
| Assunto: | Doença de Behçet Susceptibilidade genética Expressão génica Estudos de associação Etiopatogénese Teses de doutoramento - 2013 |
| Ano: | 2013 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Background: Behçet’s disease (BD) is a complex disorder characterized by a generalized vasculitis, whose pathophysiology remains unclear. The identification of genes involved in BD can help to elucidate the disease mechanisms and, ultimately, result in diagnostic and treatment advances.Objectives: To identify genetic risk factors implicated in BD susceptibility. Methods: We performed four independent studies: 1) Analysis of the role of the mitochondrial genome by testing the association of mitochondrial haplogroups and variants with BD risk in 615 Iranian BD cases and 434 controls; 2) Follow-up of IL10 and IL23RIL12RB2 associations, previously identified as BD risk factors, in 973 Iranian BD cases and 637 controls; 3) Gene expression profiling in 15 Portuguese BD cases and 14 controls and association testing of the differentially expressed genes in 976 Iranian BD cases and 839 controls; 4) A genome-wide association study for the Iranian population in DNA pools of 292 BD cases and 294 controls and replication of the association findings in 684 BD cases and 532 controls.Results: We identified a novel association of BD with the mitochondrial 12S rRNA gene (7.00E-03<P<3.80E-02); replicated the association of IL10 (P=2.53E-02) and IL23R-IL12RB2 loci (1.93E-06<P<1.78E-05) and identified the region upstream IL23R as the most associated one; identified EREG, AREG and NRG1 (members of the Neuregulin signalling) as downregulated in BD patients, found a novel association in the EREG-AREG locus (P=2.51E-02) and replicated three associations at NRG1 (6.61E-04<Pmeta<2.10E-03); and identified five coding variants at FUT2 associated with BD (2.97E-06<P<1.34E-04).Conclusions: During the course of this project we have uncover the mitochondrial genome,the neuregulin signaling and the FUT2 gene as novel players in BD susceptibility that may contribute to the abnormal immunological response observed in BD patients. We have further contributed to establish the IL10 and IL23R loci as worldwide risk factors for Behçet’s disease. |
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