ABSTRACT
BACKGROUND: Human Paneth cell alpha-defensins, especially DEFA5, are involved in maintaining homeostasis of the human microbial microflora. Since breakdown of normal mucosal antibacterial defence occurs in inflammatory bowel disease (IBD), variants in the DEFA5 gene could be associated with IBD risk. SUBJECTS: A cohort of 25 patients with indeterminate colitis (IC), 405 with ulcerative colitis (UC), and 385 with Crohn's disease (CD), were compared with 201 control individuals from the Canterbury region in New Zealand. METHODS: A 15 kb haplotype block surrounding DEFA5 contained 35 HapMap markers which were polymorphic in Caucasians. Four markers (A-D) were selected to tag 27 of the 35 markers at r(2)>0.68, and were genotyped in DNA samples. RESULTS: Minor allele frequencies for all single nucleotide polymorphisms (SNPs) were somewhat elevated in patients. Subgroup analysis showed SNP A had odds ratio 1.44 in UC patients with pancolitis (95% C.I. 1.07-1.94), SNP B odds ratio 2.37 in CD patients with onset prior to 17 years age (95% C.I. 1.12-5.03), SNP C odds ratio 1.68 in UC patients with left colonic localisation (95% C.I. 1.12-2.52), and SNP D had odds ratio 1.56 in CD patients with one or more relatives with IBD (95% C.I. 1.03-2.35). Two two-marker haplotypes and one three-marker haplotype were associated with UC (p-values 0.025-0.05). CONCLUSIONS: The SNPs genotyped in our study were surrogates for common variants, and observed associations between these and IBD status are likely due to linkage disequilibrium with a functional common DEFA5 variant. Identifying such functional variants will be prioritized in subsequent work.
Subject(s)
Genetic Predisposition to Disease , Inflammatory Bowel Diseases/ethnology , Inflammatory Bowel Diseases/genetics , Polymorphism, Single Nucleotide , White People/genetics , alpha-Defensins/genetics , Adult , Case-Control Studies , Cohort Studies , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/genetics , Colitis, Ulcerative/pathology , Confidence Intervals , Crohn Disease/epidemiology , Crohn Disease/genetics , Crohn Disease/pathology , Female , Gene Frequency , Genotype , Haplotypes , Humans , Inflammatory Bowel Diseases/pathology , Linkage Disequilibrium , Male , Middle Aged , New Zealand/epidemiology , Odds Ratio , Paneth Cells/pathology , Paneth Cells/physiology , ProbabilityABSTRACT
BACKGROUND: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. METHODS: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. RESULTS: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. CONCLUSION: DLG5 30Q is associated with a small reduction in risk of CD in women.
Subject(s)
Alleles , Crohn Disease/genetics , Gene Frequency , White People/genetics , Case-Control Studies , Crohn Disease/ethnology , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Membrane Proteins/genetics , Odds Ratio , Sex Factors , Tumor Suppressor Proteins/geneticsABSTRACT
The FLOSS software package is a flexible framework for ordered subset analysis. FLOSS is specifically designed for use with the Merlin linkage analysis package, but FLOSS can be used with any linkage analysis software package that reports NPL Z-scores for each locus and family. When FLOSS is used with the Merlin linkage analysis package, one can use either non-parametric Z-scores or Kong and Cox linear allele sharing model LOD scores. Monte Carlo P-values are calculated using a permutation test with an efficient Besag-Clifford sequential stopping rule. FLOSS also has a flexible tool for assigning family covariate scores from Merlin input files. FLOSS includes user documentation and is written in Java for easy portability. The FLOSS source code is documented and designed to be extensible.
