Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis

Abstract

Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.

Genome‐wide association studies of multiple sclerosis

“…Several other loci showed some evidence of association, but fell short of strict genome‐wide significance thresholds; these have been subsequently validated in larger studies. The three significant findings were simultaneously replicated in independent studies from the United Kingdom, the United States and the Nordic countries 31, 32. This opened the floodgates, with several successive studies GWAS and meta‐analysis followed in rapid succession, so that by 2011, common variants in 26 genomic loci had been associated with MS risk and independently replicated, but clearly only explained a fraction of MS risk attributable to genetic factors 33, 34, 35, 36, 37, 38, 39, 40, 41, 42.…”

“…The development of genetic maps covering much of the genome led to linkage analyses in extended MS affected families from a number of countries, primarily of European ancestry 23, 24, 25, 26, 27, 28, 29, 30, 31, 32. These validated the HLA association but showed no significant linkage to loci outside the MHC.…”

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

“…[1][2][3] Recently, also a detailed genetical analysis found associations with MS risk at different levels in the entire IL-7Ra pathway, for example, in the IL-7 gene itself and in the downstream signaling molecules TYK2 and SOCS1 involved in cytokine signaling and secretion. 4 The IL-7Ra/IL-7 axis is an interesting candidate in autoimmunity, because it is an important survival factor for CD4 and CD8 T cells, and is involved in early B-cell development.…”

“…A single study showed higher IL-7 mRNA levels in the mononuclear cells in CSF of MS patients compared with other neurological diseases without oligoclonal bands. 2 On the other hand only one study with MS patients in remission and during active disease exists for the protein level. 10 However, this study did not investigate IL-7 in the context of sIL-7Ra.…”

RGMA and IL21R show association with experimental inflammation and multiple sclerosis

“…5,6 Only recently, with analysis of very large cohorts, non-human leukocyte antigen MS genes are starting to be unambiguously identified. [7][8][9][10][11][12][13][14] Another important concept is the sharing of risk genes between inflammatory diseases, 15 as now demonstrated for type 1 diabetes and MS genes. 12 Therefore, cross-disciplinary genetics may be rewarding.…”