Association of Multiple Sclerosis Phenotypes with Single Nucleotide Polymorphisms of IL7R, LAG3, and CD40 Genes in a Jordanian Population: A Genotype-Phenotype Study

Abstract

It is thought that genetic variations play a vital role in the Multiple Sclerosis (MS) etiology. However, the role of genetic factors that influence the clinical features of MS remains unclear. We investigated the correlation between 21 single nucleotide polymorphisms within three genes (IL7R, LAG3, and CD40) and MS clinical characteristics in the Jordanian population. Blood samples and clinical phenotypic data were collected from 218 Arab Jordanian MS patients, vitamin D was measured, genomic DNA was extracted, and genotyping of the candidate genes’ polymorphisms were analyzed using the Sequenom MassARRAY® system. The association of these single nucleotide polymorphisms (SNPs) with MS was performed using a Chi-square, Fisher exact test, and one-way ANOVA. We found a significant association between vitamin D deficiency and three SNPs of the IL7R gene, namely rs987107 (P-value = 0.047), rs3194051 (P-value = 0.03), and rs1494571 (P-value = 0.036), in addition to two SNPs of CD40, namely rs1883832 and rs6074022 (P-value = 0.049 for both). rs3194051 of the IL7R gene (P-value = 0.003) and rs1922452 of the LAG3 gene (P-value = 0.028) were strongly associated with comorbidity. The number of relapses before drug onset was found to be correlated with IL7R SNPs rs969128 (P-value = 0.04) and rs1494555 (P-value = 0.027), whereas the expanded disability status scale (EDSS) was associated with rs1494555 polymorphism of IL7R gene (P-value = 0.026). Current findings indicate important correlations between certain SNPs and the risk of various phenotypes of multiple sclerosis in the Jordanian community. Therefore, this will not only contribute to the understanding of MS, but will also assist with the development of personalized treatment procedures.

IL-7/IL7R axis dysfunction in adults with severe community-acquired pneumonia (CAP): a cross-sectional study

“…Thus, the plasmatic level was higher in rs3194051GG, rs987106AA and rs6897932CC genotypes, while the lowest was in the carriers of rs6897932TT. It is striking that the highest levels are detected in the genotype associated with severe and fatal cases, while the lowest levels are identified in the genotype TT, described previously as a protector for multiple sclerosis 11 , through of reduced exon splicing and production of soluble IL7R 23 , 24 .…”

“…These patients also predominated among the cases admitted to UCI, as well as rs987106TT genotype carriers. GG genotype has been associated with autoimmune pathologies like type I diabetes 21 and multiple sclerosis 11 , diseases that were not reported in the cases studied. Both SNPs are located in a potential regulatory zone whose effects have not been defined 14 and which it is different to those related to mutations observed in the combined severe immunodeficiency, disease that is not present in the adults studied.…”

“…Genetic variation in and the expression of the IL7R gene, as well as increased expression of receptor/ligand genes, contribute to the pathogenesis of autoimmune and chronic inflammatory diseases such as type 1 diabetes and multiple sclerosis 7 . Single-nucleotide polymorphism (SNP) of IL7R gene, such as rs6897932, rs3194051 and rs987106, has been associated with clinical severity in multiple sclerosis, hepatitis C and human immunodeficiency virus infection 11 – 14 . Four common haplotypes of the IL7R gene have been described in exonic and intronic zones and found to be associated with differential levels of sIL7R.…”

Association between LAG3/CD4 Genes Variants and Risk for Multiple Sclerosis

“…Despite LAG3/CD4 genes, SNVs have not been found to be associated with the risk for MS in GWAS, and taking into account the previously commented possible relationship between LAG3 protein and MS, it seems reasonable to investigate the possible association between LAG3/CD4 SNVs in the risk for MS. This issue has been of the topic of several studies, although the results have been controversial [ 20 , 21 , 22 , 23 ]. The current replication study aimed to establish whether the most common SNVs in these genes showed an association with the risk of MS in the Spanish Caucasian population.…”

Expression and clinical significance of IL7R, NFATc2, and RNF213 in familial and sporadic multiple sclerosis

“…Many of the cells in the innate and adaptive immune system respond to inflammation created within the central nervous system 4 . Mounting criteria have suggested that the major cause of MS is a combination of both environmental and genetic factors 5 – 7 . Genetic susceptibility plays an important role in the development of the disease, as more than 200 genetic variants associated with MS risk is identified through genome-wide association studies (GWAS) in the last few years 8 .…”