ABSTRACT
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.
Subject(s)
Celiac Disease/enzymology , Celiac Disease/genetics , Fucosyltransferases/genetics , Inflammatory Bowel Diseases/enzymology , Inflammatory Bowel Diseases/genetics , Alleles , Base Sequence , Case-Control Studies , Colitis, Ulcerative/enzymology , Colitis, Ulcerative/genetics , Crohn Disease/enzymology , Crohn Disease/genetics , DNA Primers/genetics , Dermatitis Herpetiformis/enzymology , Dermatitis Herpetiformis/genetics , Finland , Genes, Recessive , Genetic Association Studies , Genotype , Humans , Polymorphism, Single Nucleotide , Risk Factors , Galactoside 2-alpha-L-fucosyltransferaseABSTRACT
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.
Subject(s)
Celiac Disease/genetics , Celiac Disease/immunology , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Adult , Case-Control Studies , Child , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Crohn Disease/genetics , Crohn Disease/immunology , Finland , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Humans , Polymorphism, Single Nucleotide , Risk Factors , SwedenSubject(s)
Air Pollution , Diethylamines/toxicity , Hydroxylamines/toxicity , Nitro Compounds/toxicity , Sulfur Acids/toxicity , Animals , DNA Repair/drug effects , Drosophila/drug effects , Drosophila/genetics , Erythrocytes/drug effects , Erythrocytes/ultrastructure , Female , Fertility/drug effects , Male , Mutagens , Pregnancy , Rats , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Urine/drug effects , Urine/microbiologyABSTRACT
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.
