Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of <i>TMEM39A, IL12B</i> and <i>CLBL</i> genes

Varadé, Jezabel; Comabella, Manuel; Ortíz, Miguel A; Arroyo, Rafael; Fernández, Óscar; Pinto-Medel, Mª Jesus; Fedetz, Marı́a; Izquierdo, Guillermo; Lucas, Miguel; Lopez‐Gómez, Carlos; Rabasa, Antonio Catalá; Alcina, Antonio; Matesanz, Fuencisla; Alloza, Iraide; Antigüedad, Alfredo Rodríguez; García-Barcina, María; Otaegui, David; Olascoaga, Javier; Sáiz, Albert; Blanco, Yolanda; Montalbán, Xavier; Vandenbroeck, Koen; Urcelay, Elena

doi:10.1177/1352458511432741

Cited by 27 publications

(21 citation statements)

References 36 publications

(40 reference statements)

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“…The identified SNP rs9657904 was reported to be associated with multiple sclerosis (MS), an auto-immune disease, in several genome wide association studies (GWAS) (34)(35)(36). In our findings, in male subgroup, the rs9657904 CC genotype of CBLB was associated with a worse OS, compared with the T genotypes, which was in consistence with studies of MS.…”

Section: Table 2 Associations Between the Genotypes Of Cblb And Progrsupporting

confidence: 72%

Single nucleotide polymorphisms of casitas B-lineage lymphoma proto-oncogene-b predict outcomes of patients with advanced non-small cell lung cancer after first-line platinum based doublet chemotherapy

et al. 2018

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Background: Casitas B-lineage lymphoma proto-oncogene-b (CBLB) influences the threshold of T cell activation and controlling peripheral T cell tolerance. In the present study, we hypothesize that potentially functional single nucleotide polymorphisms (SNPs) in CBLB are associated with clinical outcomes in patients advanced non-small cell lung cancer (NSCLC) treated with the first-line chemotherapy. Methods:We genotyped three SNPs (rs2305035, rs3772534 and rs9657904) at CBLB in 116 advanced NSCLC patients with progression free survival (PFS) data and 133 advanced NSCLC patients with overall survival (OS) data, and we assessed their associations, 95% confidence interval (CI), with clinical outcomes by using Cox proportional hazards regression analyses. In silico functional analysis was also performed for the SNPs under investigation. Results: We found that associations between the three SNPs and PFS/OS were not significant in the overall NSCLC patients. The rs2305035 AA genotype was associated with a worse PFS in female patients and those of non-smokers or light smokers (95% CI, 1.14-11.81, P=0.030; 95% CI, 1.42-10.24, P=0.008; and 95% CI, 1.39-9.93, P=0.009; respectively), compared with the GG+AA genotypes. We also found that the rs9657904 CC genotype was significantly associated with a worse OS than TT + TC genotypes in male advanced NSCLC patients. Further in silico functional analysis revealed that the rs965704 T allele was significantly associated with lower mRNA expression levels of the CBLB gene.Conclusions: Our findings identified two CBLB SNPs (rs2305035 and rs9657904) that were significantly associated with PFS and OS in several subgroups of Chinese advanced NSCLC patients after the first-line chemotherapy.

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Section: Table 2 Associations Between the Genotypes Of Cblb And Progrsupporting

confidence: 72%

Single nucleotide polymorphisms of casitas B-lineage lymphoma proto-oncogene-b predict outcomes of patients with advanced non-small cell lung cancer after first-line platinum based doublet chemotherapy

et al. 2018

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“…Genome-wide association study on two independent data set identifies TMEM39A as susceptibility loci (rs1132200, P = 3.09 × 10 −8 OR = 1.24) for MS.[27] In a recent study on replication of TMEM39A (rs1132200) in 2863 Spanish MS patients and 2930 controls identified this gene as susceptibility gene for MS ( p M-H = 0.001, OR M-H [95% CI] =0.84 [0.75–0.93]). [28] Our data showed nominal association for rs1132200 ( P = 0.023, OR = 1.41, CI = 1.05–1.91). In this study, there was also a nominal association for IL2RA gene associated variant rs2104286 ( P = 0.04, OR = 1.3, CI = 1.006–1.67).…”

Section: Discussionmentioning

confidence: 70%

CD6 gene polymorphism rs17824933 is associated with multiple sclerosis in Indian population

D'Cunha¹,

Pandit²,

Malli³

2016

Ann Indian Acad Neurol

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Background:Multiple sclerosis (MS) prevalence has increased worldwide. The known genetic association for MS in the west has not been studied in detail in nonwhite populations and particularly Indians.Objective:The objective of this study was to evaluate some known genetic variations outside the major histocompatibility complex (MHC) region associated with MS in patients of Indian origin.Materials and Methods:We investigated 10 gene-associated single nucleotide polymorphisms (SNP's) outside the MHC region in 300 patients and 720 unrelated controls. Genotyping was performed on an ABI7500 real-time polymerase chain reaction genotyping platform using predesigned TaqMan SNP genotyping assays.Results:CD6 gene associated SNP (rs17824933) showed significant association with MS (P = 4.2 × 10−5, odds ratio [OR] = 2.24, confidence interval (CI) = 1.51–3.33). A modest association was also noted for TMEM39A rs1132200 (P = 0.023, OR = 1.41, CI = 1.05–1.91) and IL2RA rs2104286 (P = 0.04, OR = 1.3, CI = 1.006–1.67). In the remaining SNPs, the allele frequencies were overexpressed in patients when compared to healthy controls.Conclusion:Our data illustrate the similarity in risk association between Indian and European populations for MS.

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“…These include MERTK , a receptor tyrosine kinase that negatively regulates lipopolysaccharide-induced NF-κB activation; 33, 34 MALT1 , which forms a trimeric complex with BCL10 and CARD11 to regulate NF-κB signaling necessary for the generation of neuroinflammatory Th17 cells; 35 IL12B , an activator of STAT4 upstream of Th1 differentiation; 36 BATF , which encodes basic leucine zipper transcription factor, which along with RORC (RORγt) is part of the molecular signature for all IL-17 producing cells in vivo, 37, 38 SOX8 , a transcription factor expressed in neural crest development, 11, 39 and ZNF746 , which transcriptionally represses the PPAR-γ coactivator. 40 …”

Section: Resultsmentioning

confidence: 99%

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Hussman¹,

Beecham

Schmidt

et al. 2016

Genes Immun

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Objective To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS). Methods The Genome-Wide Association Studies noise-reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on significance of linkage disequilibrium (LD) blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Results The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte, and leukocyte activation (p=6.1E-15, 1.2E-14, and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. Conclusions A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.

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Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CLBL genes

Abstract: Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p(M-H)=0.001; OR(M-H) (95% CI)= 0.84 (0.75-0.93)], IL12B [rs6887695: p(M-H)=0.03; OR(M-H) (95% CI)= 1.09 (1.01-1.17)] and CBLB [rs9657904: p(M-H)=0.01; OR(M-H) (95% CI)= 0.89 (0.81-0.97)].

Cited by 27 publications

References 36 publications

Single nucleotide polymorphisms of casitas B-lineage lymphoma proto-oncogene-b predict outcomes of patients with advanced non-small cell lung cancer after first-line platinum based doublet chemotherapy

Single nucleotide polymorphisms of casitas B-lineage lymphoma proto-oncogene-b predict outcomes of patients with advanced non-small cell lung cancer after first-line platinum based doublet chemotherapy

CD6 gene polymorphism rs17824933 is associated with multiple sclerosis in Indian population

GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

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