Gender-stratified analysis of DLG5 R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian cohorts

Abstract

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.Inflammatory bowel disease (IBD; OMIM 266600) comprises Crohn disease (CD; OMIM 266600) and ulcerative colitis (UC; OMIM 191390). Epidemiological and genetic studies have demonstrated that genes play an important role in the pathogenesis of IBD.1-6 Genetic variants associated with CD have been identified and replicated in the CARD15/NOD2 gene (OMIM 605956) 7-9 and in the chromosome 5q31 region (OMIM 606348), 10-13 and recently, the first generation of whole-genome association studies have identified multiple new susceptibility variants. [14][15][16][17][18][19] In 2004, Stoll et al described an association between IBD and DLG5 variants (DLG5: Drosophila Discs Large Homolog 5 (OMIM 604090). In particular, p.R30Q (c.89GRA, rs1248696, previously reported as c.113GRA) was found to be associated with IBD in a German family cohort. Stoll et al 20 replicated the R30Q association with CD in a European case-control cohort and found a non-significant overtransmission of the 30Q allele in patients with CD in a German/UK family cohort. Subsequently, Daly et al 21 replicated the association of 30Q with CD in one of two case-control cohorts and in a family cohort. However, subsequent studies have failed to replicate the association of DLG5 30Q with CD. 22-34Recently, Friedrichs et al 35 examined genderstratified data from the case-control cohorts showing association in the initial two DLG5 studies, 20 21 and found that the DLG5 30Q allele ...

Update on genetics in inflammatory disease

“…Similar results could not be replicated in a broad spectrum of subsequent studies [70][71][72][73]. Interestingly, presence of DLG5 R30Q was found to decrease the risk of developing CD specifically in women [74], whereas it increases the risk of developing CD in men [75]. This difference could be explained by the difference in male and female allele frequencies as demonstrated in several studies and it may account for the dilemma of reproducing the association of R30Q and CD.…”

“…This difference could be explained by the difference in male and female allele frequencies as demonstrated in several studies and it may account for the dilemma of reproducing the association of R30Q and CD. Contrasting are the findings from a study by Browning et al, in which in a population of 4707 CD patients no difference in male and female allele frequencies could be demonstrated [74]. In a Hungarian study the 113A allele was shown to be associated with steroid resistance [76].…”

Genetic Association of DLG5 R30Q with Familial and Sporadic Inflammatory Bowel Disease in Men

“…Recently, Biank et al, reported that R30Q is a female-specific protective factor in pediatric CD [37]. A larger gender-stratified meta-analysis with 4707 CD patients and 4973 controls showed an association of 30Q with decreased risk of CD in females [35]. These observations raise very interesting questions including what is the "gender factor" and how does it affect IBD development?…”

“…Friedrichs et al, found a male-specific association of the R30Q variant with CD, with no association of the R30Q variant with women, nor with the entire sample of men and women [27]. However, the association of the R30Q variant with IBD failed to be replicated by several other groups with samples from several different countries, including Germany, Scotland, Belgium, and Hungary [28][29][30][31][32][33][34][35][36]. A US based population of IBD patients has been also studied [17,37].…”

New serological biomarkers of inflammatory bowel disease

“…For example, 29.6% of DEFEB1 20A carriers were antiglycan positive compared to 46% positivity in non-carriers (P < 0.038). However, no association of antiglycan positivity was found with either DEFEB1 G52A variant or DLG5 (R30Q), although both were shown to be associated with increased risk for CD [53,54] . Furthermore, in contrast to other reports [32,51] , no gene dosage effect was observed on any of the antiglycan antibodies.…”