RESUMO
Homozygosity for a nonsense mutation in the fucosyltransferase 2 (FUT2) gene (rs601338G>A) leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. As the secretor status has been shown to be a major determinant for the gut microbial spectrum, assumed to be important in the gut immune homeostasis, we studied the association of rs601338-FUT2 with celiac disease (CelD) and inflammatory bowel disease (IBD) in the Finnish population. Rs601338 was genotyped in CelD (n = 909), dermatitis herpetiformis (DH) (n = 116), ulcerative colitis (UC) (n = 496) and Crohn's disease (CD) (n = 280) patients and healthy controls (n = 2738). CelD showed significant genotypic [P = 0.0074, odds ratio (OR): 1.28] and recessive (P = 0.015, OR: 1.28) association with the rs601338-AA genotype. This was also found in the combined CelD+DH dataset (genotype association: P = 0.0060, OR: 1.28; recessive association: P < 0.011, OR: 1.28). The A allele of rs601338 showed nominal association with dominant protection from UC (P = 0.044, OR: 0.82) and UC+CD (P = 0.035, OR: 0.84). The frequency of non-secretors (rs601338-GG) in controls, CelD, DH, UC and CD datasets was 14.7%, 18%, 18.1%, 14.3% and 16.1%, respectively. No association was evident in the DH or CD datasets alone. In conclusion, FUT2 non-secretor status is associated with CelD susceptibility and FUT2 secretor status may also play a role in IBD in the Finnish population.
Assuntos
Doença Celíaca/enzimologia , Doença Celíaca/genética , Fucosiltransferases/genética , Doenças Inflamatórias Intestinais/enzimologia , Doenças Inflamatórias Intestinais/genética , Alelos , Sequência de Bases , Estudos de Casos e Controles , Colite Ulcerativa/enzimologia , Colite Ulcerativa/genética , Doença de Crohn/enzimologia , Doença de Crohn/genética , Primers do DNA/genética , Dermatite Herpetiforme/enzimologia , Dermatite Herpetiforme/genética , Finlândia , Genes Recessivos , Estudos de Associação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
Assuntos
Doença Celíaca/genética , Doença Celíaca/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Adulto , Estudos de Casos e Controles , Criança , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Finlândia , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , SuéciaAssuntos
Poluição do Ar , Dietilaminas/toxicidade , Hidroxilaminas/toxicidade , Nitrocompostos/toxicidade , Ácidos de Enxofre/toxicidade , Animais , Reparo do DNA/efeitos dos fármacos , Drosophila/efeitos dos fármacos , Drosophila/genética , Eritrócitos/efeitos dos fármacos , Eritrócitos/ultraestrutura , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Mutagênicos , Gravidez , Ratos , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Urina/efeitos dos fármacos , Urina/microbiologiaRESUMO
The nitrosourea derivatives 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU; NSC-95441), and 1-methyl-1-nitrosourea (MNU; NSC-23909) were screened for mutagenic potential with Salmonella typhimurium strains G46 and TA1530 in vitro and in vivo. Alu were also mutagenic in the host-mediated assay. Four additional chemotherapeutic nitrosoureas were tested in vitro, three of which were mutagenic. The lack of activity of the fourth agent was probably a reflection of its stability in solution rather than a true indication of mutagenic potential. All eight agents were tested in a repair test with S. typhimurium strains TA1978 and TA1538. Results of this test were negative, reflecting the insensitivity of these strains to ethylating and methylating agents. The insensitivity of the host-mediated assay is also discussed.
