骨桥蛋白（OPN/SPP1）单倍型在克罗恩病易感性中的作用。
The role of osteopontin (OPN/SPP1) haplotypes in the susceptibility to Crohn's disease.
机构信息
Department of Medicine II - Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
出版信息
PLoS One. 2011;6(12):e29309. doi: 10.1371/journal.pone.0029309. Epub 2011 Dec 29.
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.
背景
骨桥蛋白（Osteopontin，OPN/SPP1）是一种多功能分子，在慢性炎症和自身免疫性疾病中起着关键作用。其表达在炎症性肠病（IBD）中增加。我们的研究旨在分析大样本 IBD 患者中骨桥蛋白（OPN）基因变异的相关性。
方法/主要发现：对来自 2819 名高加索个体（n=841 例克罗恩病（CD）患者、n=473 例溃疡性结肠炎（UC）患者和 n=1505 名健康无关对照）的基因组 DNA 进行了 9 个 OPN SNP（rs2728127、rs2853744、rs11730582、rs11739060、rs28357094、rs4754= p.Asp80Asp、rs1126616= p.Ala236Ala、rs1126772 和 rs9138）的分析。鉴于骨桥蛋白在 Th17 介导的疾病中的重要作用，我们对与 IBD 相关的 IL23R 变异进行了上位性分析，并分析了 Th17 细胞因子 IL-22 的血清水平。对于四个 OPN SNP（rs4754、rs1126616、rs1126772 和 rs9138），我们观察到男性和女性 CD 患者之间的分布存在显著差异。rs4754 在男性 CD 患者中具有保护作用（p=0.0004，OR=0.69）。没有其他研究的 OPN SNP 与 CD 或 UC 易感性相关。然而，几个 OPN 单倍型与 CD 易感性显著相关。最强的相关性是由包含 8 个 OPN SNP rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 的单倍型发现的（总 p 值=2.07×10⁻⁸）。总体而言，CD 合并 OPN 小等位基因携带者的平均 IL-22 分泌水平明显低于 CD 患者的 OPN 野生型等位基因（p=3.66×10⁻⁵）。OPN SNP rs28357094 与 IL23R SNP rs10489629（p=4.18×10⁻²）和 OPN SNP rs1126616 与 IL23R SNP rs2201841（p=4.18×10⁻²）之间存在弱上位性证据，但这些关联在经过 Bonferroni 校正后均不再显著。
结论/意义：我们的研究确定了 OPN 单倍型是 CD 易感性的修饰因子，而某些 OPN 变体的联合作用可能调节 IL-22 的分泌。
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