RESUMO
BACKGROUND: Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance). The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23. METHODS: We have evaluated six candidate genes in one of these regions (11q23), namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls. RESULTS: Promotor SNPs (-607, -137) in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P < 0.05). Follow-up analyses of an extended sample supported the same, moderate effect (P < 0.05) for one of these. Haplotype analysis of IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P < 0.0001), which was independently associated in two case-control comparisons. This same haplotype has been noted in rheumatoid arthritis. CONCLUSION: Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.
Assuntos
Doença Celíaca/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 5/genética , Estudos de Associação Genética/métodos , Estudos de Casos e Controles , Mapeamento Cromossômico , Ligação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único/genética , Risco , Fatores de RiscoRESUMO
Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.
Assuntos
Biomarcadores , Doença Celíaca/genética , Marcadores Genéticos/genética , Predisposição Genética para Doença , Genoma Humano , Polimorfismo de Nucleotídeo Único , Animais , Estudos de Casos e Controles , Doença Celíaca/imunologia , Mapeamento Cromossômico , Estudos de Coortes , Diabetes Mellitus Tipo 1/genética , Feminino , Antígenos HLA-DQ/metabolismo , Humanos , Subunidade p35 da Interleucina-12/genética , Subunidade beta de Receptor de Interleucina-18/sangue , Subunidade beta de Receptor de Interleucina-18/genética , Desequilíbrio de Ligação , Masculino , Camundongos , Reação em Cadeia da Polimerase , Proteínas RGS/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR3/genética , Fatores de Risco , Distribuição TecidualRESUMO
BACKGROUND: Helicobacter pylori infection is associated with development of chronic inflammation and infiltration of immune cells into the gastric mucosa. As unconventional T-lymphocytes expressing natural killer cell receptors are considered to play central roles in the immune response against infection, a study investigating their frequencies in normal and H. pylori-infected gastric mucosa was undertaken. MATERIALS AND METHODS: Flow cytometry was used to quantify T-cells expressing the natural killer cell markers CD161, CD56, and CD94 in freshly isolated lymphocytes from the epithelial and lamina propria layers of gastric mucosa. Thirteen H. pylori-positive and 24 H. pylori-negative individuals were studied. RESULTS: CD94(+) T-cells were the most abundant (up to 40%) natural killer receptor-positive T-cell population in epithelial and lamina propria layers of H. pylori-negative gastric mucosa. CD161(+) T-cells accounted for about one-third of all T-cells in both compartments, but the lowest proportion were of CD56(+) T-cells. Compared with H. pylori-negative mucosa, in H. pylori-infected mucosa the numbers of CD161(+) T-cells were significantly greater (p = .04) in the epithelium, whereas the numbers of CD56(+) T-cells were lower (p = .01) in the lamina propria. A minor population (< 2%) of T-cells in both mucosal layers of H. pylori-negative subjects were natural killer T-cells, and whose proportions were not significantly different (p > .05) to those in H. pylori-infected individuals. CONCLUSIONS: The predominance, heterogeneity, and distribution of natural killer cell receptor-positive T-cells at different locations within the gastric mucosa reflects a potential functional role during H. pylori infection and warrants further investigation.
Assuntos
Mucosa Gástrica/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Receptores de Células Matadoras Naturais/biossíntese , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Antígeno CD56/análise , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Subfamília B de Receptores Semelhantes a Lectina de Células NK/análise , Subfamília D de Receptores Semelhantes a Lectina de Células NK/análiseRESUMO
Hypertransaminasaemia is a common abnormality found in up to 40% of untreated coeliac patients, which resolves with the institution of a gluten-free diet. A much rarer occurrence is the association of chronic liver disease with coeliac disease. Primary biliary cirrhosis, primary sclerosing cholangitis, and chronic autoimmune hepatitis have all been recognized in coeliac patients. More recently, the occurrence of coeliac disease in patients with chronic liver disease is found to be 10 times greater than that in the general population. Of particular note are the 13 patients reported to date with liver failure and coeliac disease. Among those patients commenced on a gluten-free diet an improvement in liver function was observed. The relationship between coeliac disease, a gluten-free diet, and the course of chronic liver disease needs to be clarified.
