The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
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DOI：
10.1093/hmg/ddq090
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Booth, David R.
中科院分区：
文献类型：
--
作者：
Gandhi, Kaushal S.;McKay, Fiona C.;Booth, David R.
多发性硬化症（MS）是一种自身免疫性疾病，至少部分由异常的淋巴细胞活性引起。对99名未经治疗的MS患者的全血mRNA转录组进行了测量：43名原发性进展型MS，20名继发性进展型MS，36名复发缓解型MS和45名年龄匹配的健康对照。ANZgene多发性硬化遗传学联盟对其中115个样本进行了超过30万个SNP的基因分型。在所有形式的MS中，翻译调节、氧化磷酸化、免疫突触和抗原呈递途径的基因转录显著增加。标记T细胞的基因表达也上调（P < 10（-12））。T细胞基因特征预测疾病状态的一致性指数为0.79，年龄和性别作为协变量，但该签名与临床病程或残疾无关。ANZ基因全基因组关联筛选确定了两个具有全基因组意义的新区域：一个编码T细胞共刺激分子CD 40;另一个是染色体12 q13 -14上的区域。与MS易感性增加相关的CD 40单倍型在MS中的基因表达降低（P < 0.0007）。第二个MS易感区包括位于12 q13 -14上的17个紧密连锁不平衡基因。其中，只有13个在白细胞中表达，并且其中一个FAM 119 B在易感性单倍型中的表达低得多（P < 10（-14））。总的来说，这些数据表明在未经治疗的MS患者的全血中可以检测到T细胞的失调，并且支持在所有形式的MS的治疗中靶向活化的T细胞。
Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.