Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis
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Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing–remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P<10−4, χ2). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), −504 C, was undertransmitted in PPMS trios (P=0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P=0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P<0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.
KeywordsGenetics Multiple sclerosis Gene expression CD127 Interleukin 7
We thank all those who contributed to the establishment of the Westmead MS DNA bank, Bruce Bennetts for useful discussions, Najwa Marmash for genotyping assistance and the patients and healthy controls who donated blood. This work was funded by a grant-in-aid from the Trish MS Research Foundation (2003), the Australian MS Society (2004) and Australian NHMRC project grant 153990. Ariel Arthur was supported by an Australian Postgraduate Award and The Nerve Foundation of the University of Sydney. Suzy Teutsch was supported by a Dora Lush NHMRC scholarship.
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