The role of osteopontin (OPN/SPP1) haplotypes in the susceptibility to Crohn's disease.

ABSTRACT: BACKGROUND: Osteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2819 Caucasian individuals (n?=?841 patients with Crohn's disease (CD), n?=?473 patients with ulcerative colitis (UC), and n?=?1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754?=?p.Asp80Asp, rs1126616?=?p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p?=?0.0004, OR?=?0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value?=?2.07×10??). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p?=?3.66×10??). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p?=?4.18×10?²) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p?=?4.18×10?²) but none of these associations remained significant after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion.

SUBMITTER: Glas J 

PROVIDER: S-EPMC3248444 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature