The Role of Osteopontin OPN-SPP1 Haplotypes in the Susceptibility to Crohns DiseaseReportar como inadecuado




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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 = 2.07×10−8. 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.

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.



Autor: Jürgen Glas , Julia Seiderer , Corinna Bayrle, Martin Wetzke, Christoph Fries, Cornelia Tillack, Torsten Olszak, Florian Beigel,

Fuente: http://plos.srce.hr/



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