Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-α gene and their associations with multiple sclerosis

Teutsch, Suzy; Booth, David R.; Bennetts, Bruce; Heard, Robert; Stewart, Graeme J.

doi:10.1038/sj.ejhg.5200994

Cited by 89 publications

(74 citation statements)

References 30 publications

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“…In an earlier association study of IL7R in MS, which included a scan for novel SNPs, only one of these five SNPs (rs987106) was identified as polymorphic in the investigated casecontrol data set. 17 In the present study, three of five SNPs-rs987106 and rs987107 in intron 6, and rs3194051 in exon 8-were associated with MS. The SNP in exon 8 encodes an amino-acid substitution (Val356Ile) in the Cterminal domain of the translated protein.…”

Section: Ms Susceptibility Genes: Lag3 and Il7rsupporting

confidence: 48%

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

et al. 2005

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Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this twostage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (Po0.08) between patients and controls. After additional genotyping in stage two, two genes-each containing at least three significantly (Po0.05) associated SNPs-conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis-and, by extension, derangement of immune homeostasis-influence the risk of MS.

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Section: Ms Susceptibility Genes: Lag3 and Il7rsupporting

confidence: 48%

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

et al. 2005

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“…The SNP that tagged haplotype-2 in Caucasians, as described previously 10 and shown in Figure 1, was genotyped.…”

Section: Patient Selectionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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“…5 Recently, other non-HLA genes have been shown to be associated with MS. One of these genes is the interleukin-7 receptor a-chain (IL-7Ra). [6][7][8][9] Its product forms a heterodimer with the common IL-2R g-chain to bind IL-7, or with the thymic stromal lymphopoietin receptor (TSLPR) to bind TSLP. IL-7 is an essential cytokine in the development, survival, proliferation and differentiation of T and B lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants

et al. 2010

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The receptor for the homeostatic T cell cytokine interleukin-7 (IL-7Ra) has recently shown genetic association to multiple sclerosis (MS). To investigate the functional contribution of IL-7Ra polymorphisms to the pathogenesis of MS, we correlated the IL-7Ra haplotypes with different T cell parameters in a group of MS patients and healthy controls. We show that carriers of one of the four IL-7Ra haplotypes (Hap4) show a higher expression of IL-7Ra (CD127) on their CD4þ T cells, compared with noncarriers (P ¼ 0.04). Moreover, Hap4 carriers possess higher frequencies of recent thymic emigrants (RTEs, CD31 þ ) in both the regulatory T cell (Treg; P ¼ 0.007) and conventional T cell (Tconv) population (P ¼ 0.0001). This effect is most pronounced within the MS population (Treg, P ¼ 0.0077; Tconv, P ¼ 0.0007), whereas in healthy controls significance was only reached for Tconv (P ¼ 0.043; Treg, P ¼ 0.11). Because previous studies showed a decreased RTE-Treg frequency in MS patients compared to healthy subjects, we here conclude that this decrease is localized within the MS population of non-Hap4 carriers. In conclusion, our findings suggest that IL-7Ra polymorphisms can influence T cell development and homeostasis, and thereby contribute to the altered immune regulation associated with disease development in patients with MS.

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Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-α gene and their associations with multiple sclerosis

Cited by 89 publications

References 30 publications

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

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

Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants

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