全基因组关联分析对银屑病遗传学研究的启示

Enlightenment from genome-wide association study to genetics of psoriasis

银屑病是一种常见的免疫异常性增殖性皮肤病。临床特征为皮肤表面履盖大量厚实的鳞屑性斑片。虽然已有大量家族性研究资料表明银屑病的发病存在着遗传因素,但是该病的遗传模式至今尚不清楚。大量研究表明:复杂性疾病的遗传学研究除了MHC的一些位点的相关结果比较恒定外,绝大多数的研究结果变异较大。全基因组关联分析(genome-wide association study,GWAS)是一种对全基因组范围内的常见遗传变异(单核苷酸多态性和拷贝数变异)进行总体关联分析的方法,在全基因组范围内进行整体研究,能够一次性对疾病进行轮廓性概览,适用于包括银屑病在内的复杂疾病的研究。运用全基因组关联分析对银屑病进行的三个研究,刊登在今年2月的《自然-遗传学》杂志,结果发现了几个银屑病的遗传学易感位点,提示在免疫学和其它领域的几个信号通路可能参与了该病的发病机制。无论是以往的关联研究还是现在的全基因组关联分析研究,均提示银屑病与涉及人类免疫性疾病的免疫反应的MHC位点(如HLA-Cw6和其他MHC变异位点)紧密相关。还有两个与银屑病高度相关的与炎症反应密切关联的非MHC基因(IL-12B和IL23R),也在银屑病的发病机制中起着重要作用。最近运用抗IL-12p40的生物制剂有效治疗银屑病的临床试验,进一步证实了IL-12/23在银屑病病理生理过程中关键作用。在中国人群中进行了银屑病易感基因的GWAS研究发现:位于1q21上的晚期角质化包膜(late cornified envelope,LCE)基因簇中LCE3A和LCE3D的区域异常与银屑病显著性相关。与此同时,国际上另一个研究小组对西班牙、荷兰、意大利和美国人群中进行的银屑病易感基因的GWAS研究发现,LCE基因簇中LCE3B和LCE3C区域的缺失与银屑病显著性相关。这些相互独立的研究有力地证实LCE基因参与银屑病的发病。到目前为止,虽然已经有了一些针对某些基因的有效靶向治疗手段,但是将诸如LCE等基因用于未来的靶向性治疗,可能更有意义。对LCE基因认识的不断深化,不仅有利于对新的药物靶位的确定,而且对治疗的个体化也有着十分重要的意义。为了阐明银屑病的内在发病机制,未来我们亟需对更大样本的研究,以及其他易感基因位点的鉴定及其下游的功能研究;同时可以预见,利用全基因组关联分析发现的银屑病的易感基因以及其后续的深入研究,将对阐明银屑病发病机制、疾病预警、临床诊断及新药开发起到决定性的作用。

Psoriasis is a common autoimmune and hyper proliferative skin disease,characterized by thick,silvery scale patches. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. However, few of these studies have achieved consistent results,except for the MHC locus,a problem frequently encountered in the investigation of complex disease. Using high-throughput techniques to genotype hundreds of thousands of single nucleotide polymorphisms explore their relationship with phenotypes,genome-wide association studies （GWAS） are now proven to be a powerful approach for screening the susceptibility genes （loci） of complex disease. Recently,three GWAS on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis ,in both immune and non-immune pathways. The MHC locus （HLA-Cw6 and other MHC variance）, the major locus involved in the immune reactions of human immune disease,has consistently been shown to be associated with psoriasis,both in previous linkage and present GWAS. IL-12B and IL23R,which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far and potent cytokines with complex biological activities,should be of great importance in the pathogenesis of psoriasis. Recent clinical trials,in which anti-IL-12p40 antibodies were used for the treatment of psoriasis,have provided further evidence of the role of IL-12/23 in the pathophysiology of psoriasis,and highlighted a new road of treatment for psoriasis. In 2008, we performed the first large GWAS in the Chinese population and identified a novel susceptibility locus within the late eornified envelope （LCE） gene cluster： LCE3A and LCE3D on chromosome 1q21, with conclusive evidence （rs4085613, Pcombined： 6. 69 × 10-30; odds ratio= 0. 76）. Meanwhile,another group also identified a deletion comprising and I.CE gene cluster of LCE3B and LCE3C,which is significantly associated with a risk of psoriasis in Spain,Netherland,Italy and USA. Both of these independent studies provided substantial association evidence for the LCE genes involved in the pathogenesis of psoriasis. The LCE genes encode the stratum-corneum proteins of the cornified envelope, which plays an important role in epidermal terminal differentiation. As we know, psoriasis is a disease of interfollicular epidermis and rapid keratinocyte proliferation may cause the production of parakeratotic keratinocytes in psoriatic skin and,thus,the formation of poorly adherent stratum corneum,whieh in turn results in the characteristic scale or flakes of psoriasis lesions. Although some of the highlighted genes are already targeted by effective psoriasis therapies, others could become future targets for treatments,especially for the LCE genes,which will be very useful for unlocking new drug targets and tailored treatments for this painful, disfiguring skin disease. Meanwhile larger samples and improved strategy for identification of other susceptibility variants to psoriasis and downstream functional study to elucidate the underlying mechanisms of diseases are also needed. Taken together, unremitting efforts of the basic research on psoriasis will lead us to achieve a better treatment and diagnosis for psoriasis in the near future.