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

Abstract

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.

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

“…The Alfred patients carrying the T-allele at this locus had significantly higher sIL-7Ra levels compared with patients carrying the A-allele. In prior case-control studies involving Nordic patients, carriers of the T-allele at this locus had an increased risk of multiple sclerosis, 60,61 although replicate studies of multiple sclerosis patients from the United States did not find a similar association. 32 We did not find a relationship between the rs987106 SNP and sIL-7Ra levels in the UARTO patients.…”

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

“…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.…”

Genetics of primary progressive multiple sclerosis

“…Alleles of the IL7R contribute to MS susceptibility (Zhang et al, 2005;Gregory et al, 2007;Hafler et al, 2007;Lundmark et al, 2007). An Australian case-control study of 63 PPMS, 108 SPMS, 192 RRMS, and 182 healthy controls found that the promoter -504 T allele was overrepresented in PPMS patients (OR ¼ 2.2, p ¼ 0.013) (Booth et al, 2005).…”