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

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. 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 = 2.07×10⁻⁸). 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 = 3.66×10⁻⁵). 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. Our study identified OPN
haplotypes as modifiers of CD susceptibility, while the combined
effects of certain OPN variants may modulate IL-22 secretion.