Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis

Abstract

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), chi(2)). 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.

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

“…[25][26][27][28][29][30][31] We recently demonstrated by using a multivariable model that IL-7Ra haplotype-2 was a significant predictor of more rapid CD4 T-cell recovery following suppressive cART in an Australian-based largely Caucasian HIVinfected cohort. 22 Consistent with observations in haplotype-2 carriers in HIV-uninfected cohorts, 9,11,32,33 we found that HIV-infected patients who were homozygous for haplotype-2 had significantly lower concentrations of sIL-7Ra compared with non-haplotype-2 carriers. 22 We therefore proposed that the reduced sIL-7Ra levels in haplotype-2 carriers may increase the availability of IL-7 to bind to membrane-bound IL-7Ra on T-cells, leading to faster CD4 T-cell recovery.…”

“…This association has been shown previously in Caucasian cohorts, 11,22 and rs6897932 is thought to be the functional SNP altering the splicing and production of soluble IL7Ra. 9,32 Our findings are the first description of a significant association between sIL-7Ra levels and the SNP at rs6897932 in Africans.…”

“…The IL-7Ra is also found in soluble (s) form, as sIL-7Ra in plasma, and is produced as a result of splicing exon-6 from the IL-7Ra gene mRNA. 9 Four common haplotypes of the IL-7Ra gene have been described in Caucasians 10 and found to be associated with differential levels of sIL-7Ra. 11 In HIVinfected patients, although IL-7 levels are elevated, the expression of IL-7Ra on T-cells and signalling through the receptor (measured by STAT-5 phosphorylation) is impaired and only partially corrected with cART.…”

Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression

“…Our study replicates previous reports of association between IL7R variants with PrMS, emphasizing the existence of specific genetic components implicated in the development of progressive disease. [11,21] Sequencing of IL7R in MS patients identified two missense variants (rs6897932, p.T244I and rs3194051, p.I356V) with an allelic frequency difference greater than 8% from those expected in the general population ( Table 2). The p.T244I variant, genotyped in this study, has been shown to affect alternative splicing of IL7R exon 6 and alter the amounts of soluble and membranebound protein, thus suggesting a possible mechanism for disease.…”

“…The p.T244I variant, genotyped in this study, has been shown to affect alternative splicing of IL7R exon 6 and alter the amounts of soluble and membranebound protein, thus suggesting a possible mechanism for disease. [6,21] In contrast, no functional outcome has been described for p.I356V, and association studies for this variant (rs3194051) have provided conflicting results, with some studies reporting significant association with risk of MS, [22][23][24] that others could not replicate. [6,25] In summary, our study has confirmed the association between genetic variants in IL2RA and IL7R in MS, and further defined this association to specific disease subtypes.…”