Yau Anthony C Y, Tuncel Jonatan, Haag Sabrina, Norin Ulrika, Houtman Miranda, Padyukov Leonid, Holmdahl Rikard
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, SE-171 76, Stockholm, Sweden;
Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3716-24. doi: 10.1073/pnas.1600567113. Epub 2016 Jun 14.
Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.
全基因组关联研究已经揭示了许多与复杂自身免疫性疾病相关的基因位点。在类风湿性关节炎（RA）中，MHC基因HLA-DRB1是预测疾病发展的最强候选基因。有人提出，MHC中的其他免疫调节基因也会增加疾病风险，但由于MHC内存在很强的连锁不平衡，这一作用一直难以得到证实。我们通过分离大鼠同源片段形式的基因组区域，来测试MHC中是否存在其他易感基因座。通过近交系中的同源定位和野生大鼠中的SNP分型，我们在MHC-III区域鉴定出了一个保守的、33kb大小的单倍型Ltab-Ncr3，它可以调节关节炎的发病、严重程度和慢性病程。Ltab-Ncr3单倍型由五个多态性免疫调节基因组成：Lta（淋巴毒素-α）、Tnf、Ltb（淋巴毒素-β）、Lst1（白细胞特异性转录本1）和Ncr3（自然细胞毒性触发受体3）。Ltab-Ncr3基因表达之间的显著相关性表明，这些基因之间的相互作用可能对于将这些基因作为一个保守单倍型聚集在一起很重要。我们研究了四种不同Ltab-Ncr3单倍型与关节炎的关联以及剪接转录组，并表明较高的Ltb和Ncr3表达、较低的Lst1表达以及较短的Lst1剪接变体的表达与大鼠关节炎严重程度的降低相关。有趣的是，轻度RA患者的NCR3表达也高于重度RA患者，而LST1表达则更低。这些数据证明了保守单倍型在调节如关节炎等复杂疾病中的重要性。
