Through our analysis of the genes implicated as part of the IL7R
pathway, we identified two novel gene regions, IL7
, replicated these in an independent dataset, and have highly significant overall results. Finding association with the biologically relevant ligand (IL7) of IL7R indicates that the known biological activity of these genes is relevant to MS, as opposed to some perhaps as yet unknown pleiotropic effect of these genes. The IL7/IL7R complex along with IL2RG is vital for the development, maturation, and survival of T cells, which is theorized to be where the breakdown in the body's immune response occurs. This breakdown could, therefore, play a role in the adverse autoimmunity found in MS patients (Goverman 2009
Interestingly, SOCS1 is located on chromosome 16 slightly downstream from a recently confirmed MS susceptibility locus, CLEC16A. After examining the linkage disequilibrium (LD) architecture of this region, SOCS1 and CLEC16A appear to be two independent MS disease loci (the r2 values between the CLEC16A SNP (rs7184083) and the most significant SNPs in the SOCS1 region are 0.057 (rs1640923) and 0.049 (rs12922733)). The LD block containing CLEC16A is separated from the more proximal LD block that contains the SOCS1 gene region that contains our significant SNPs. Having an associated SNP in the flanking region of a gene involved in suppression of cytokine signaling (i.e. SOCS1 functions as a suppressor of cytokine signaling) suggests that this flanking region could be a regulatory element. Having multiple associated genes in close proximity may suggest that these genes could be co-regulated. These observations warrant further investigation of this region via functional studies.
We also identified three additional strong candidate genes that have biological relevance to the etiology of MS, including Protein kinase C epsilon (PRKCE
), B-cell lymphoma 2 (BCL2
), and tyrosine kinase 2 (Tyk2
is involved in neuron channel activation and apoptosis. BCL2
is involved in activation of apoptosis. Tyk2
transmits cytokine signals by phosphorylating receptor subunits (Jiang et al. 2005
; Shirai, Adachi, and Saito 2008
). Through independent efforts, we have already identified Tyk2
as a susceptibility gene in MS. Its re-emergence here thus provides a valuable positive control and further support for the importance of Tyk2
(Ban et al. 2009
The results indicate that the multiple genetic variations in the IL7/IL7RA
pathway are important in MS pathogenesis, and by implication, that this pathway plays an important biological role in the etiology of MS. Furthermore our data support the approach of using candidate pathways as an effective way of identifying additional MS susceptibility genes. Examining the extended pathways of previously identified associated genes has recently proven useful in the identification of new disease loci (Hennah et al. 2007
; McGovern et al. 2009
). Therefore, this method of screening the biologically interacting genes of confirmed disease genes may help to elucidate additional aspects of the underlying genetic architecture of numerous complex diseases.
These data have also identified several genes that have modest significance and should be examined further. Some of the genes mentioned previously (i.e. PRKCE and BCL2) should be investigated in independent datasets. They were not strongly replicated, but had several SNPs with nominally significant p-values in the discovery dataset and trending favorably in the validation dataset. Thus, additional examination of these genes is necessary. Additionally, other genes (i.e. PRKCA, Stat5a/b, IL12A/B, T-BET, BAX, and BIM) also had several SNPs with interesting trends that were not followed up in this study. All of these genes have biological plausibility and need further exploration.
The HLA-DR*1501 allele identified decades ago confers a much larger effect on MS susceptibility (odds ratio (OR) ~3) than the effects of recently identified associations. Both the IL7RA
and the IL2RA
alleles have much smaller effects (OR~1.2 and OR~1.25, respectively) (Gregory et al. 2007
; International Multiple Sclerosis Genetics Consortium 2007
). It is possible that common alleles with smaller effects could explain a significant proportion of the genetic component of MS (Baranzini et al. 2009
; Sawcer 2008
; Wang et al. 2005
). In this study of the IL7/IL7RA
pathway, the nominally significant SNPs all have estimated GRRs of 1.11-1.64, and over 75% have GRRs<1.20. Using the pathway approach in conjunction with these large datasets and dense SNP genotyping, the etiology of MS is finally starting to be dissected. By building on the knowledge of these smaller gene effects, functional studies can help us understand the underlying mechanism of these genes and their relationships to the pathogenesis of MS.