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1.
Inflamm Bowel Dis ; 17(9): 1917-24, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21830270

RESUMO

BACKGROUND: The pregnane X receptor (PXR/NR1I2) is an important regulator of xenobiotic metabolism and intestinal integrity. However, there are controversial studies on the role of PXR/NR1I2 in inflammatory bowel disease (IBD). We therefore initiated the largest analysis to date on PXR/NR1I2 gene variants in IBD patients. METHODS: Genomic DNA from 2823 individuals of Caucasian origin including 859 patients with Crohn's disease (CD), 464 patients with ulcerative colitis (UC), and 1500 healthy, unrelated controls was analyzed for eight PXR/NR1I2 single nucleotide polymorphisms (SNPs) (rs12721602 (-25564), rs3814055 (-25385), rs1523128 (-24756), rs1523127 (-24381), rs45610735 = p.Gly36Arg (+106), rs6785049 (+7635), rs2276707 (+8055), and rs3814057 (+11156)). In addition, detailed haplotype and genotype-phenotype analyses were performed. RESULTS: The PXR/NR1I2 SNP rs2276707 was weakly associated with UC susceptibility (P = 0.01; odds ratio [OR] 1.27 [1.06-1.52]). None of the other PXR/NR1I2 SNPs were associated with UC or CD susceptibility. However, several rare PXR/NR1I2 haplotypes were highly associated with CD susceptibility. In CD, the strongest disease association was found for a haplotype consisting of the SNPs rs12721602-rs3814055-rs1523128-rs1523127-rs12721607-rs6785049-rs2276707-rs3814057 (omnibus P-value: 6.50 × 10(-15)) which was found in two separate cohorts (cohort I = discovery cohort: CD: n = 492, controls: n = 793; P = 4.51 × 10(-17); Bonferroni corrected: P = 1.27 × 10(-15); cohort II = replication cohort: CD: n = 367, controls: n = 707; P = 7.12 × 10(-4); P(corr) = 1.99 × 10(-2)). CONCLUSIONS: Several PXR/NR1I2 haplotypes contribute to CD susceptibility, suggesting a role for PXR in the IBD pathogenesis of a certain patient subcohort. Given the accumulating evidence for an important role of PXR in intestinal inflammation, further analyses are required to investigate the functional and pharmacogenetic implications of these PXR/NR1I2 gene variants in IBD.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Predisposição Genética para Doença , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Esteroides/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Estudos de Coortes , DNA/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase , Receptor de Pregnano X , Prognóstico , Adulto Jovem
2.
PLoS One ; 6(4): e19319, 2011 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-21559399

RESUMO

BACKGROUND: The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). METHODOLOGY: In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. CONCLUSIONS: This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.


Assuntos
Antígenos CD/genética , Moléculas de Adesão Celular/genética , Doença de Crohn/genética , Doenças Inflamatórias Intestinais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/fisiologia , Aderência Bacteriana , Estudos de Casos e Controles , Moléculas de Adesão Celular/fisiologia , Criança , Doença de Crohn/metabolismo , DNA/metabolismo , Escherichia coli/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/fisiologia , Variação Genética , Haplótipos , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
3.
Inflamm Bowel Dis ; 17(1): 91-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20564536

RESUMO

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy used in patients with inflammatory bowel disease (IBD) has been associated with induction of autoantibodies including antinuclear antibodies (ANA), double-strand (ds) DNA antibodies, and the occurrence of lupus-like syndrome (LLS). However, the clinical relevance of autoantibody formation and predictive factors are unclear. METHODS: 180 IBD patients treated with anti-TNF antibodies (infliximab or adalimumab, or infliximab and adalimumab consecutively) were analyzed regarding ANA and dsDNA antibody values and the development of LLS, including factors predicting the development of LLS. RESULTS: In all, 44.4% of anti-TNF-treated patients had ANA titers ≥1:240, while 15.6% had dsDNA serum levels ≥9 U/mL. However, only a minority of these patients experienced clinical symptoms of LLS; 8.9% presented with mild lupus-like symptoms with no need for intervention; 1.1% had severe symptoms consistent with LLS requiring immediate stop of anti-TNF therapy. Multivariate logistic regression analyses identified age as an independent risk factor for developing ANA ≥1:240 (P < 0.001) and LLS (P = 0.002), while concomitant immunosuppressive therapy was protective against autoantibody formation (ANA: P = 0.05) and LLS development (P = 0.04). There was a significant association between dsDNA antibody values ≥9 U/mL and LLS (P = 0.02) but not between ANA titers and LLS. CONCLUSIONS: dsDNA antibody levels ≥9 U/mL, but not ANA titers ≥1:240, are associated with clinical symptoms of LLS. IBD patients of higher age treated with anti-TNF-α antibodies are at increased risk for development of ANA and LLS, while concomitant immunosuppressive therapy may have a protective effect.


Assuntos
Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/efeitos adversos , Autoanticorpos/sangue , DNA/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Estudos de Coortes , Feminino , Humanos , Doenças Inflamatórias Intestinais/imunologia , Infliximab , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
5.
PLoS One ; 5(4): e10373, 2010 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-20454450

RESUMO

BACKGROUND: Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn's disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74-0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63-12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74-1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75-1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.


Assuntos
Doenças Autoimunes/genética , Doença de Crohn/genética , Fator de Transcrição STAT4/genética , Idade de Início , Estudos de Casos e Controles , Doença de Crohn/epidemiologia , Doença de Crohn/etiologia , Predisposição Genética para Doença/genética , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética
6.
J Gastroenterol ; 45(7): 721-31, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20428899

RESUMO

BACKGROUND AND AIMS: We analyzed the prevalence of concomitant intestinal stenosis in patients with fistulizing Crohn's disease (CD), including the NOD2/CARD15 and IL23R genotype status. METHODS: Medical records of n = 1,110 patients with inflammatory bowel diseases were screened for patients with fistulizing and stricturing CD. Study inclusion required diagnosis of stenosis made within 6 months of diagnosing fistulas. CD-associated NOD2 and IL23R variants were genotyped. Similarly, we prospectively investigated 42 patients presenting with fistulizing CD. RESULTS: In the retrospective study (n = 333 CD patients), fistulas were found in 145 (43.5%) patients and stenoses in 223 (67.0%) patients. Concomitant stenosis was diagnosed in 125 patients with fistulas resulting in a positive predictive value (PPV) of 86.2% for fistulas predicting intestinal stenosis (p = 5.53 x 10(-11); OR 5.74, 95% CI 3.22-10.50). In logistic regression analysis, presence of fistulas (OR 4.51; 95% CI 2.54-8.01, p = 2.68 x 10(-7)) and disease duration (OR 1.09; 95% CI 1.05-1.13; p = 3.19 x 10(-6)) were strongly associated with intestinal stenosis. NOD2 genotype information, but not IL23R status, increased the PPV for the correct diagnosis of stenosis (PPV = 89.9%). All homozygous carriers (100%) of NOD2 variants with fistulizing CD were diagnosed with stenosis; 1007fs homozygotes were found more often among patients with fistulas and stenoses than in patients without stenoses and fistulas (p = 0.00037). Similar results were found in the prospective analysis, in which 83.3% of the patients with fistulizing CD had concomitant stenosis. CONCLUSION: Fistulizing CD is strongly associated with concomitant intestinal stenosis, particularly in homozygous carriers of NOD2 mutations.


Assuntos
Doença de Crohn/fisiopatologia , Fístula Intestinal/etiologia , Proteína Adaptadora de Sinalização NOD2/genética , Receptores de Interleucina/genética , Constrição Patológica/etiologia , Constrição Patológica/genética , Doença de Crohn/genética , Genótipo , Humanos , Fístula Intestinal/genética , Obstrução Intestinal/etiologia , Obstrução Intestinal/genética , Modelos Logísticos , Mutação , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos
7.
PLoS One ; 5(2): e9453, 2010 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-20195480

RESUMO

BACKGROUND: Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Genomic DNA from 579 phenotypically well-characterized individuals was analyzed for the CNR1 1359 G/A SNP. Amongst these were 166 patients with UC, 216 patients with CD, and 197 healthy controls. RESULTS: Compared to healthy controls, subjects A/A homozygous for the CNR1 1359 G/A SNP had a reduced risk to develop UC (p = 0.01, OR 0.30, 95% CI 0.12-0.78). The polymorphism did not modulate CD susceptibility, but carriers of the minor A allele had a lower body mass index than G/G wildtype carriers (p = 0.0005). In addition, homozygous carriers of the G allele were more likely to develop CD before 40 years of age (p = 5.9x10(-7)) than carriers of the A allele. CONCLUSION: The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Polimorfismo de Nucleotídeo Único , Receptor CB1 de Canabinoide/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Índice de Massa Corporal , Criança , Pré-Escolar , Colite Ulcerativa/patologia , Doença de Crohn/epidemiologia , Doença de Crohn/patologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
8.
Am J Gastroenterol ; 105(8): 1811-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20197757

RESUMO

OBJECTIVES: We analyzed the efficacy and safety of the antitumor necrosis factor-alpha antibody infliximab (IFX) for induction therapy in patients with moderate-to-severe ulcerative colitis (UC) in a large single-center cohort. METHODS: A total of 90 UC patients treated with IFX for 14 weeks were analyzed retrospectively. Colitis activity index (CAI) and markers of inflammation were measured during IFX induction therapy. Genotyping for UC-associated variants in the IL23R gene and in the IL2/IL21 region was performed. RESULTS: At week 2 (after the first IFX infusion), 64.1% of IFX-treated patients had clinical response to IFX and 52.6% were in remission. At week 14 (after three infusions), 61.0% showed clinical response and 52.5% were in remission. The mean CAI decreased significantly from 10.4 points at week 0 to 5.1 at week 2 (P<0.001), to 4.4 at week 6 (P<0.001), and to 5.0 at week 14 (P<0.001). Similarly, IFX therapy significantly decreased C-reactive protein levels and leukocyte counts (P=0.01 and P=0.001 at week 2 and week 0, respectively). Multivariate regression analysis identified high CAI before IFX therapy (P=0.01) and negative antineutrophil cytoplasmatic autoantibody (ANCA) status (P=0.01) as independent positive predictors for response to IFX. Homozygous carriers of inflammatory bowel disease (IBD) risk-increasing IL23R variants were more likely to respond to IFX than were homozygous carriers of IBD risk-decreasing IL23R variants (74.1 vs. 34.6%; P=0.001). No serious adverse IFX-related events requiring hospitalization were recorded. CONCLUSIONS: Our findings suggest that IFX therapy is safe and effective in patients with moderate-to-severe UC. A high CAI before IFX therapy, ANCA seronegativity, and the IL23R genotype were predictors of early response to IFX.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/análise , Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Receptores de Interleucina/genética , Adulto , Biomarcadores/análise , Colectomia/estatística & dados numéricos , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Variação Genética , Genótipo , Humanos , Infliximab , Modelos Logísticos , Masculino , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
9.
PLoS One ; 5(12): e14466, 2010 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-21209938

RESUMO

BACKGROUND: The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10(-5), OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10(-6); OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values <10(-10). The SNPs rs2066843 and rs2076756 were in linkage disequilibrium with each other and with the three main CD-associated NOD2 mutations (D'>0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10(-16)) and behaviour (p = 0.02) were significantly associated with the need for surgery. CONCLUSION/SIGNIFICANCE: The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Variação Genética , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Frequência do Gene , Genótipo , Humanos , Doenças Inflamatórias Intestinais/genética , Pessoa de Meia-Idade , Fenótipo
10.
Am J Gastroenterol ; 104(7): 1737-44, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19455118

RESUMO

OBJECTIVES: Recently, a genome-wide association study showed that single-nucleotide polymorphisms (SNPs) in the chromosome 4q27 region containing IL2 and IL21 are associated with celiac disease. Given the increased prevalence of inflammatory bowel disease (IBD) among celiac disease patients, we investigated the possible involvement of these SNPs in IBD. METHODS: Five SNPs strongly associated with celiac disease within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block on chromosome 4q27 and one coding SNP within the IL21 gene were analyzed in a large German IBD cohort. The study population comprised a total of 2,948 Caucasian individuals, including 1,461 IBD patients (ulcerative colitis (UC): n=514, Crohn's disease (CD): n=947) and 1,487 healthy unrelated controls. RESULTS: Three of the five celiac disease risk markers had a protective effect on UC susceptibility, and this effect remained significant after correcting for multiple testing: rs6840978: P=0.0082, P(corr)=0.049, odds ratio (OR) 0.77, 95% confidence interval (CI) 0.63-0.93; rs6822844: P=0.0028, P(corr)=0.017, OR 0.73, 95% CI 0.59-0.90; rs13119723: P=0.0058, P(corr)=0.035, OR 0.75, 95% CI 0.61-0.92. A haplotype consisting of the six SNPs tested was markedly associated with UC susceptibility (P=0.0025, P(corr)=0.015, OR 0.72, 95% CI 0.58-0.89). Moreover, in UC, epistasis was observed between the IL23R SNP rs1004819 and three SNPs in the KIAA1109/TENR/IL2/IL21 block (rs13151961, rs13119723, and rs6822844). CONCLUSIONS: Similar to other autoimmune diseases such as celiac disease, rheumatoid arthritis, type 1 diabetes, Graves' disease, and psoriatic arthritis, genetic variation in the chromosome 4q27 region predisposes to UC, suggesting a common genetic background for these diseases.


Assuntos
Doença Celíaca/genética , Colite Ulcerativa/genética , Epistasia Genética , Marcadores Genéticos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Distribuição por Idade , Alelos , Estudos de Casos e Controles , Doença Celíaca/epidemiologia , Doença Celíaca/imunologia , Mapeamento Cromossômico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/imunologia , Intervalos de Confiança , Feminino , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Interleucina-2/genética , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Probabilidade , Receptores de Interleucina/genética , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Distribuição por Sexo
11.
Am J Gastroenterol ; 104(3): 665-72, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19262523

RESUMO

OBJECTIVES: Recently, a North American genome-wide association study identified three novel gene variants in PHOX2B, NCF4, and FAM92B as well as one single nucleotide polymorphisms (SNP; rs224136) in the intergenic region on chromosome 10q21.1 as being associated with Crohn's disease (CD). However, their influence on European CD patients as well as ulcerative colitis (UC) is unknown. Therefore we aimed to replicate these novel CD susceptibility variants in a large European cohort with inflammatory bowel disease and analyzed potential gene-gene interactions with variants in the NOD2/CARD15, IL23R, and ATG16L1 genes. METHODS: Genomic DNA from 2,833 Caucasian individuals including 854 patients with CD, 476 patients with UC, and 1,503 healthy unrelated controls was analyzed for SNPs in PHOX2B (rs16853571), NCF4 (rs4821544), and FAM92B (rs8050910), including rs224136 on chromosome 10q21.1. RESULTS: In our study population, no association of PHOX2B (P=0.563), NCF4 (P=0.506), FAM92B (P=0.401), and rs224136 (P=0.363) with CD was found. Similarly, none of these SNPs was associated with UC. In contrast, all analyzed SNPs in NOD2/CARD15, IL23R, and ATG16L1 were strongly associated with CD with P values ranging from 5.0x10(-3) to 1.6x10(-22), but there was no epistasis with polymorphisms in PHOX2B, NCF4, FAM92B, and rs224136. CONCLUSIONS: In contrast to the North American population, PHOX2B, NCF4, FAM92B, and rs224136 are not associated with CD in the European population, whereas NOD2/CARD15, IL23R, and ATG16L1 are strongly associated with CD in both the North American and European populations, confirming these three genes as major CD susceptibility genes in Caucasian populations.


Assuntos
Cromossomos Humanos Par 10/genética , Doença de Crohn/genética , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , NADPH Oxidases/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colite Ulcerativa/genética , Epistasia Genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Clin Immunol ; 127(1): 49-55, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18248772

RESUMO

To identify if genetic determinants of CXCL16 modulate the susceptibility and phenotype of inflammatory bowel diseases (IBD), we analyzed genomic DNA from 574 individuals (365 IBD patients, 209 healthy controls) for the CXCL16 p.Ala181Val polymorphism. In this study, we demonstrate that in Crohn's disease (CD), the CXCL16 p.Ala181Val polymorphism is not a disease susceptibility gene but associated with younger age at disease onset (p=0.016) and higher frequency of ileal involvement (p=0.024; OR 2.17; 95% CI 1.12-4.21) in ValVal carriers compared to a higher frequency of colonic involvement in AlaAla carriers (p=0.009; OR 2.60; CI 1.29-5.25). Carriers of at least one Val allele and one CARD15/NOD2 variant had a higher incidence of a stricturing and penetrating phenotype (p=0.030, OR 4.04, CI 1.27-12.84) and of stenoses (p=0.014; OR 3.97; CI 1.38-11.40) than patients carrying NOD2 variants only, suggesting that this polymorphism contributes to a severe disease phenotype in CD.


Assuntos
Quimiocinas CXC/genética , Predisposição Genética para Doença , Genótipo , Doenças Inflamatórias Intestinais/genética , Fenótipo , Polimorfismo Genético , Receptores Depuradores/genética , Adulto , Idade de Início , Quimiocina CXCL16 , Feminino , Frequência do Gene , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteína Adaptadora de Sinalização NOD2/genética
13.
Am J Gastroenterol ; 103(3): 682-91, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18162085

RESUMO

OBJECTIVES: We analyzed ATG16L1, a recently identified Crohn's disease (CD) susceptibility gene, in a large cohort with inflammatory bowel disease (IBD) including potential interactions with other IBD genes as well as factors regulating its gene expression. METHODS: Genomic DNA from 2,890 Caucasians including 768 patients with CD, 507 patients with ulcerative colitis (UC), and 1,615 healthy controls was analyzed for 9 different ATG16L1 single nucleotide polymorphisms (SNPs). Genotyping included CARD15/NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C) as well as 10 CD-associated IL23R variants. The transcriptional regulation of ATG16L1 was studied in intestinal epithelial cells following stimulation with Toll-like receptor (TLR) ligands and proinflammatory cytokines and in a murine ileitis model and CD biopsies. RESULTS: All nine ATG16L1 gene variants analyzed displayed highly significant associations with CD demonstrating a CD-protective effect for the minor allele. The strongest associations were found for rs2241879 and the coding SNP rs2241880 (T300A); P= 3.6 x 10(-6) and 3.7 x 10(-6), respectively (OR 0.74, 95% CI 0.65-0.84 for both variants). The genotype-phenotype analysis revealed no significant associations. In UC, only rs6431660 was weakly disease-associated. There was no evidence for epistasis between the ATG16L1 gene and other susceptibility genes (IL23R, CARD15, SLC22A4/5). ATG16L1 mRNA expression was not upregulated in CD and murine ileitis, and was less than threefold increased in cells stimulated with proinflammatory cytokines and TLR ligands. CONCLUSION: ATG16L1 is a CD susceptibility gene without epistatic interaction with other CD susceptibility genes and is not upregulated in intestinal inflammation.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Colite Ulcerativa/genética , Doença de Crohn/patologia , Epistasia Genética , Feminino , Expressão Gênica , Genótipo , Alemanha , Humanos , Ileíte/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo
14.
Inflamm Bowel Dis ; 14(4): 437-45, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18088064

RESUMO

BACKGROUND: Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p.His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p.His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. METHODS: Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p.His161Arg polymorphism, the 3 NOD2 variants, p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008, and 10 CD-associated IL23R variants. RESULTS: Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p.His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene. CONCLUSIONS: Intestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants.


Assuntos
Colite Ulcerativa/genética , Colo/metabolismo , Doença de Crohn/genética , Expressão Gênica , Interleucina-17/genética , Interleucina-17/metabolismo , Polimorfismo de Nucleotídeo Único , Regulação para Cima , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Epistasia Genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Adaptadora de Sinalização NOD2/genética , Fenótipo , RNA Mensageiro/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
15.
PLoS One ; 2(9): e819, 2007 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-17786191

RESUMO

BACKGROUND: The IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants. METHODS: Genomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C). RESULTS: All IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92x10(-11); OR 1.56; 95 % CI (1.37-1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46-12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04x10(-8); OR 0.43; CI (0.31-0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5. CONCLUSION: IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC.


Assuntos
Doença de Crohn/genética , Predisposição Genética para Doença , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Demografia , Epistasia Genética , Feminino , Frequência do Gene/genética , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Membro 5 da Família 22 de Carreadores de Soluto , Simportadores , Adulto Jovem
16.
Inflamm Bowel Dis ; 13(1): 71-82, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17206642

RESUMO

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with increased expression in inflammatory bowel disease. The aim of the study was to analyze the role of the MIF -173G/C single nucleotide polymorphism in Crohn's disease (CD). METHODS: Using restriction fragment length polymorphism analysis, genomic DNA of 198 patients with CD and 159 unrelated controls was analyzed for the -173G/C SNP in the MIF promoter region. Colonic MIF mRNA expression was measured by quantitative polymerase chain reaction (PCR), serum MIF levels by enzyme-linked immunosorbent assay (ELISA). RESULTS: Thirty-six of the 146 G/G wildtype carriers (24.7%) but only 3 of the 45 G/C heterozygotes (6.7%) and only 1 of the C/C homozygotes (14.3%) were diagnosed with upper gastrointestinal tract involvement (P = 0.009, odds ratio [OR] = 0.22, 95% confidence interval [CI], 0.06-0.75 for wildtype versus hetero- and homozygous carriers). This result was confirmed in a second prospective study, in which all patients diagnosed with upper gastrointestinal involvement (n = 13) were G/G wildtype carriers (P = 0.01 versus controls). All patients (n = 12; 100%) with a Crohn's disease activity index (CDAI) > 300 were G/G wildtype carriers compared to only 65.6% wildtype carriers in the group with a CDAI < 150 (P = 0.016). MIF is expressed in the colonic mucosa of CD patients and intestinal epithelial cells but its mRNA expression does not correlate with the degree of inflammation and is not upregulated by proinflammatory cytokines. In CD, MIF serum levels are not influenced by the MIF -173G/C polymorphism. CONCLUSIONS: The MIF -173G/C polymorphism appears to be a factor contributing to a particular CD phenotype characterized by protection against upper gastrointestinal tract involvement and severe disease activity.


Assuntos
Doença de Crohn/genética , Doença de Crohn/patologia , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Trato Gastrointestinal Superior/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/análise
17.
Scand J Gastroenterol ; 41(12): 1421-32, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17101573

RESUMO

OBJECTIVE: The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes. MATERIAL AND METHODS: A total of 445 unrelated patients with IBD (68.1% CD, 28.5% ulcerative colitis (UC), 3.4% indeterminate colitis (IC)) were included in the study. Clinical data were recorded by detailed questionnaire and analysis of the charts. CARD15 variants (R702W, G908R, 1007fs (frameshift)) were identified by DNA sequence analysis. RESULTS: CARD15 variants were found in 142 inflammatory bowel disease (IBD) patients (31.9%) including 120 CD patients (39.6%). In CD, the presence of two CARD15 variants was associated with ileal disease (p=0.008 versus wild-type (wt); OR 4.04; 95% CI 1.36-11.96) and a fibrostenotic phenotype (p=0.002 versus wt; OR 5.47; 95% CI 1.61-18.58). Subgroup analysis of 19 patients (4.3%) homozygous for the CARD15 variant 1007fs (3020ins C) revealed an association with onset of CD at an early age (p=0.014 versus wt), ileal involvement (p=0.001), and intestinal stenoses in all patients (p=0.001) frequently requiring surgery (73.7%; p=0.093). Of these patients 78.6% developed re-stenoses after surgical resection; 52.6% of the homozygotes were diagnosed as having entero-enteral fistulas. CONCLUSIONS: Patients homozygous for the 1007fs mutation had an early disease onset with long-segment ileal stenoses and entero-enteral fistulas. They frequently needed surgical intervention and had a high risk of re-stenosis. Genotyping therefore appears to be an important diagnostic tool in identifying severely affected patients requiring individualized treatment strategies at an early stage of the disease.


Assuntos
Doença de Crohn/genética , Mutação da Fase de Leitura , Doenças do Íleo/genética , Fístula Intestinal/genética , Proteína Adaptadora de Sinalização NOD2/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Colite/genética , Colite Ulcerativa/genética , Feminino , Genótipo , Homozigoto , Humanos , Doenças do Íleo/complicações , Doenças do Íleo/cirurgia , Fístula Intestinal/complicações , Masculino , Pessoa de Meia-Idade , Recidiva
18.
Inflamm Bowel Dis ; 12(12): 1114-21, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17119385

RESUMO

BACKGROUND AND AIM: The diagnostic and therapeutic relevance of CARD15 genotyping in Crohn's disease (CD) for daily clinical practice has not been investigated so far. We therefore analyzed whether CARD15 variants are independent predictive factors for small bowel stenosis in CD evaluated by magnetic resonance enteroclysis (MRE). On the basis of these findings, the potential implications for patient management were investigated. METHODS: Eighty CD patients with clinical symptoms suggestive of small bowel stenosis were included. All patients were genotyped for the CARD15 variants c.2104C > T (p.R702W), c.2722G > C (p.G908R), and c.3019_3020insC (p.Leu1007fsX1008) and examined by MRE of the small bowel. RESULTS: CARD15 variants were found in 40 (50%) patients. MRE identified 31 (38%) patients with small bowel stenoses. Twenty-five of the 40 (62%) patients with at least one CARD15 variant were diagnosed of intestinal stenosis by MRE (odds ratio [OR] = 9.44; confidence interval [CI] 3.21-27.77; P = 0.00028, Bonferroni corrected). Particularly, the presence of the 1007fs variant was associated with an increased risk of an intestinal stenosis (OR = 12.00, CI 3.47-41.54, P = 0.00042, Bonferroni corrected). Twenty-one of 31 (68%) patients with stenoses required surgical intervention, with 13 of these 21 (62%) patients carrying the 1007fs variant. CONCLUSION: In the largest prospective study analyzing the diagnostic value of CARD15 variants in CD patients performed so far, we identified the 1007fs variant as strong predictor for intestinal stenoses with need for surgery in CD patients. Genotyping could therefore be an important diagnostic tool in clinical practice for identifying high-risk patients with specific diagnostic and therapeutic needs. Moreover, MRE is an excellent technique for diagnosing small bowel stenoses.


Assuntos
Doença de Crohn/genética , Doença de Crohn/cirurgia , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/genética , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/genética , Adolescente , Adulto , Idoso , Algoritmos , Feminino , Genótipo , Humanos , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Valor Preditivo dos Testes , Estudos Prospectivos , Radiografia
19.
Immunogenetics ; 58(2-3): 99-106, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16485124

RESUMO

We performed a limited DNA sequence analysis of the CARD15 gene in 89 patients with Crohn's disease (CD), 19 patients with ulcerative colitis (UC), and three patients with indeterminate colitis (IC), who were heterozygous carriers of one of the common CARD15 mutations [c.2104C>T (p.R702W), c.2722G>C (p.G908R), or c.3019_3020insC (p.Leu1007fsX1008)], the c.2462+10A>C variant, or of a new amino acid substitution in the 3'-end of exon 4. CARD15 exons 4, 5, 6, 8, and 11 were amplified by PCR and completely sequenced, thereby theoretically covering 73.9% of the described CARD15 variants and 96.6% of the mutated alleles. Using this approach, eight novel amino acid substitutions [c.1171C>T (p.R391C), c.1387C>G (p.P463A), c.2138G>A (p.R713H), c.2278C>T (p.R760C), c.2368C>T (p.R790W), c.2371C>T (p.R791W), c.2475C>G (p.N825K), and c.2546C>T (p.A849V)] were detected in six CD and two IC patients, and one UC patient. A severe disease phenotype was observed especially in patients who are compound-heterozygous for a common and a novel CARD15 mutation.


Assuntos
Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Polimorfismo Genético , Adolescente , Adulto , Substituição de Aminoácidos/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Mutação , Proteína Adaptadora de Sinalização NOD2 , Fenótipo
20.
Am J Gastroenterol ; 101(1): 99-106, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16405540

RESUMO

BACKGROUND: The fractalkine receptor CX3CR1 has been shown to be involved in inflammation and immune response. Recently, two polymorphisms of CX3CR1 (V249I and T280M) were reported. AIMS: Our aim was to analyze fractalkine expression and the role of CX3CR1 polymorphisms in Crohn's disease (CD). METHODS: We determined fractalkine mRNA expression in the intestinal epithelial cell (IEC) line SW480 after stimulation with proinflammatory cytokines as well as in inflamed (n = 14) and noninflamed (n = 14) CD lesions by quantitative PCR. By restriction fragment length polymorphism analysis, genomic DNA from 206 patients with CD and 211 unrelated controls was analyzed for the two single nucleotide polymorphisms in the CX3CR1 gene, which result in the V249I and T280M substitutions. RESULTS: All proinflammatory stimuli (TNF-alpha, IL-1beta, LPS) significantly increased fractalkine mRNA expression in IEC. There was also a significant increase in fractalkine mRNA expression in inflamed lesions of CD patients when compared to noninflamed colonic mucosa (p = 0.02). Intestinal fractalkine mRNA levels correlated highly with IL-8 mRNA expression levels (r = 0.931). However, there was no difference in the V249I and T280M genotype frequencies between CD patients and the control group. In the CD group, 33.0% were heterozygous and 8.3% homozygous for the V249I polymorphism, while 23.3% were heterozygous and 4.4% homozygous for the T280M polymorphism. All T280M homozygotes were diagnosed of intestinal stenosis (p = 0.03 vs wildtype and heterozygous carriers) and had significantly more often ileocolonic involvement more often than patients with wildtype and heterozygous genotypes (p = 0.01). These associations were independent of the CARD15 genotype status. CONCLUSIONS: The expression of the chemokine fractalkine is upregulated by proinflammatory cytokines and enhanced in inflamed CD lesions. The CX3CR1 T280M polymorphism appears to influence CD phenotype and localization.


Assuntos
Quimiocinas CX3C/metabolismo , Doença de Crohn/genética , Predisposição Genética para Doença , Proteínas de Membrana/metabolismo , Polimorfismo Genético , Receptores de Quimiocinas/metabolismo , Receptores de Citocinas/metabolismo , Receptores de HIV/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Receptor 1 de Quimiocina CX3C , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CX3CL1 , Quimiocinas CX3C/genética , Intervalos de Confiança , Doença de Crohn/patologia , Feminino , Marcadores Genéticos , Humanos , Obstrução Intestinal/genética , Obstrução Intestinal/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Razão de Chances , Fenótipo , Probabilidade , Prognóstico , RNA Mensageiro/análise , Receptores de Quimiocinas/genética , Receptores de Citocinas/genética , Receptores de HIV/genética , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Índice de Gravidade de Doença
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