The polymorphism rs3024505 proximal to IL-10 is associated with risk of ulcerative colitis and Crohns disease in a Danish case-control study

Abstract

BackgroundCrohns disease (CD) and ulcerative colitis (UC) are characterized by a dysregulated inflammatory response to normal constituents of the intestinal flora in the genetically predisposed host. Heme oxygenase-1 (HO-1/HMOX1) is a powerful anti-inflammatory and anti-oxidant enzyme, whereas the pro-inflammatory interleukin 1β (IL-1β/IL1B) and anti-inflammatory interleukin 10 (IL-10/IL10) are key modulators for the initiation and maintenance of inflammation. We investigated whether single nucleotide polymorphisms (SNPs) in the IL-1β, IL-10, and HO-1 genes, together with smoking, were associated with risk of CD and UC.MethodsAllele frequencies of the IL-1β T-31C (rs1143627), and IL-10 rs3024505, G-1082A (rs1800896), C-819T (rs1800871), and C-592A (rs1800872) and HO-1 A-413T (rs2071746) SNPs were assessed using a case-control design in a Danish cohort of 336 CD and 498 UC patients and 779 healthy controls. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by logistic regression models.ResultsCarriers of rs3024505, a marker polymorphism flanking the IL-10 gene, were at increased risk of CD (OR = 1.40, 95% CI: 1.06-1.85, P = 0.02) and UC (OR = 1.43, 95% CI: 1.12-1.82, P = 0.004) and, furthermore, with risk of a diagnosis of CD and UC at young age (OR = 1.47, 95% CI: 1.10-1.96) and OR = 1.35, 95% CI: 1.04-1.76), respectively). No association was found between the IL-1β, IL-10 G-1082A, C-819T, C-592A, and HO-1 gene polymorphisms and CD or UC. No consistent interactions between smoking status and CD or UC genotypes were demonstrated.ConclusionsThe rs3024505 marker polymorphism flanking the IL-10 gene was significantly associated with risk of UC and CD, whereas no association was found between IL-1β or HO-1 gene polymorphisms and risk of CD and UC in this Danish study, suggesting that IL-10, but not IL-1β or HO-1, has a role in IBD etiology in this population.

The Polymorphism rs3024505 (C/T) Downstream of the <i>IL10 </i>Gene Is Associated with Crohn’s Disease in Serbian Patients with Inflammatory Bowel Disease

“…Therefore, in view of the abovementioned potential functional relevance of rs3024505, it is plausible to assume that C allele might increase IL10 expression causing a sustained production of IL-10 that may eventually lead to anemia in chronic inflammation present in CD patients. On the other hand, the association between C allele of rs3024505 SNP in the IL10 gene and an aggressive CD phenotype may be surprising, taking into account that this variant did not correlate with disease susceptibility in this study, as well as in other studies (Andersen et al 2010;Wang et al 2011). Our results are in contrast with the findings from New Zealand study, where individuals carrying the T allele of rs3024505 had a significantly increased risk of stricturing CD behavior (Wang et al 2011).…”

“…The subsequent GWA studies clearly associated rs3024505 with both forms of IBD, including earlyonset UC and CD (Imielinski et al 2009;Franke et al 2010;Anderson et al 2011). The replication case-control studies that followed, found the association of T allele and TT (or CT) genotype of rs3024505 SNP with UC and/or CD in Danish, Dutch, New Zealand, Australian and North Indian IBD patients (Andersen et al 2010;Festen et al 2010;Juyal et al 2011;Doecke et al 2013;Bank et al 2014), with the exception for two studies that found no association with CD in Danish and Canadian pediatric cohorts (Amre et al 2009;Bank et al 2014). The only meta-analysis done so far, that included data from just 2 publications with 6 populations of UC patients, also associated rs3024505 with UC (Doecke et al 2013).…”

“…The polymorphism C-592A was also associated with CD in Canadian pediatric patients (Amre et al 2009). However, most studies failed to find any association between IL10 promoter SNPs and susceptibility to develop IBD (Klein et al 2000;Koss et al 2000;Kim et al 2003;Balding et al 2004;Cantor et al 2005;Klausz et al 2005;Celik et al 2006;Sanchez et al 2009;Andersen et al 2010;Ahirwar et al 2012;Doecke et al 2013;Bank et al 2014;LopezHernandez et al 2015). Moreover, three meta-analysis, performed so far, were not consistent either, with each one showing associations of some of the three SNPs with one form of IBD that were not replicated by others (Zhu et al 2013;Lv et al 2014;Zou et al 2014).…”

“…1) and it was suggested that it might lie within the 3' untranslated region (3'UTR) of the IL10 gene in the vicinity of the putative regulatory sequences and affect IL-10 expression (Doecke et al 2013). Subsequent studies that assessed rs3024505 SNP in IBD patients found associations between this SNP and CD (Wang et al 2011), UC (Doecke et al 2013) or both forms of IBD (Andersen et al 2010), further validating rs3024505 as a potential biomarker of susceptibility to IBD, but more studies in different ethnic populations are needed to confirm this.…”

Relationship between IL-10 gene -819C/T polymorphism and the risk of inflammatory bowel disease: A meta-analysis

“…Finally, a total of 7 case-control studies met the preset inclusion criteria, in which 1890 cases and 2929 controls were included for the pooled analysis [15][16][17][18][19][20][21] . The characteristics of the studies are summarized in Table 1.…”