Kariuki S N, Moore J G, Kirou K A, Crow M K, Utset T O, Niewold T B
Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA.
Genes Immun. 2009 Jul;10(5):487-94. doi: 10.1038/gene.2009.15. Epub 2009 Apr 2.
Osteopontin (OPN) is a multifunctional cytokine involved in long bone remodeling and immune system signaling. Additionally, OPN is critical for interferon-alpha (IFN-alpha) production in murine plasmacytoid dendritic cells. We have previously shown that IFN-alpha is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variants of OPN have been associated with SLE susceptibility, and one study suggests that this association is particular to men. In this study, the 3' UTR SLE-risk variant of OPN (rs9138C) was associated with higher serum OPN and IFN-alpha in men (P=0.0062 and P=0.0087, respectively). In women, the association between rs9138 C and higher serum OPN and IFN-alpha was restricted to younger subjects, and risk allele carriers showed a strong age-related genetic effect of rs9138 genotype on both serum OPN and IFN-alpha (P<0.0001). In African-American subjects, the 5' region single nucleotide polymorphisms, rs11730582 and rs28357094, were associated with anti-RNP antibodies (odds ratio (OR)=2.9, P=0.0038 and OR=3.9, P=0.021, respectively). Thus, we demonstrate two distinct genetic influences of OPN on serum protein traits in SLE patients, which correspond to previously reported SLE-risk variants. This study provides a biologic relevance for OPN variants at the protein level, and suggests an influence of this gene on the IFN-alpha pathway in SLE.
骨桥蛋白（OPN）是一种多功能细胞因子，参与长骨重塑和免疫系统信号传导。此外，OPN对小鼠浆细胞样树突状细胞中α干扰素（IFN-α）的产生至关重要。我们之前已经表明，IFN-α是系统性红斑狼疮（SLE）的一种遗传风险因素。OPN的基因变异与SLE易感性相关，一项研究表明这种关联在男性中尤为明显。在本研究中，OPN的3'非翻译区SLE风险变异体（rs9138C）与男性较高的血清OPN和IFN-α相关（分别为P = 0.0062和P = 0.0087）。在女性中，rs9138C与较高的血清OPN和IFN-α之间的关联仅限于较年轻的受试者，风险等位基因携带者在血清OPN和IFN-α上均表现出rs9138基因型强烈的年龄相关遗传效应（P < 0.0001）。在非裔美国受试者中，5'区域单核苷酸多态性rs11730582和rs28357094与抗RNP抗体相关（优势比（OR）分别为2.9，P = 0.0038和OR = 3.9，P = 0.021）。因此，我们证明了OPN对SLE患者血清蛋白特征有两种不同的遗传影响，这与先前报道的SLE风险变异体相对应。本研究在蛋白水平上为OPN变异体提供了生物学相关性，并表明该基因对SLE中的IFN-α途径有影响。
