Gene variants of adhesion molecules predispose to MS: A case-control study

Objective To examine the effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the development of MS. Methods A total of 389 Greek MS cases and 336 controls were recruited by 3 MS centers in Cyprus and Greece. In total, 147 tagging single nucleotide polymorphisms across 9 genes encoding for P-selectin (SELP), integrins (ITGA4, ITGB1, and ITGB7), adhesion molecules (ICAM1, VCAM1, and MADCAM1), fibronectin 1 (FN1), and osteopontin (SPP1) were genotyped. The clinical end point of the study was diagnosis of MS according to the 2005 revised McDonald criteria. Permutation analysis was used for adjusting for multiple comparisons. Results Overall, 21 variants across SELP, ITGA4, ITGB1, ICAM1, VCAM1, MADCAM1, FN1, and SSP1 genes were each associated with MS (pperm < 0.05). The most significant were rs3917779 and rs2076074 (SELP), rs6721763 (ITGA4), and rs1250258 (FN1), all with a permutation p value of less than 1e-004. Conclusions The current study provides preliminary evidence that variants across genes encoding adhesion molecules, responsible for lymphocyte adhesion and trafficking within the CNS, are implicated in the risk of developing MS.

[1]  Z. Nagy,et al.  The Hungarian population-based prevalence and incidence study of neuromyelitis optica spectrum disorder. , 2018 .

[2]  O. Ciccarelli,et al.  Multiple sclerosis , 2018, The Lancet.

[3]  Jorge R Oksenberg,et al.  Multiple sclerosis genetics , 2018, Multiple sclerosis.

[4]  Jorge R. Oksenberg,et al.  The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years. , 2017, Trends in genetics : TIG.

[5]  K. Tizaoui.  Multiple sclerosis genetics: Results from meta‐analyses of candidate‐gene association studies , 2017, Cytokine.

[6]  A. Antoniades,et al.  Gene variants of adhesion molecules act as modifiers of disease severity in MS , 2017, Neurology: Neuroimmunology & Neuroinflammation.

[7]  S. Thomas,et al.  P-Selectin and ICAM-1 synergy in mediating THP-1 monocyte adhesion in hemodynamic flow is length dependent. , 2017, Integrative biology : quantitative biosciences from nano to macro.

[8]  G. Comi,et al.  Survey of diagnostic and treatment practices for multiple sclerosis in Europe , 2017, European journal of neurology.

[9]  Alexander V. Favorov,et al.  A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches , 2015, Human Genetics.

[10]  S. Rittling,et al.  Osteopontin in Immune-mediated Diseases , 2015, Journal of dental research.

[11]  M. Ban,et al.  Multiple sclerosis genetics , 2014, The Lancet Neurology.

[12]  E. Dardiotis,et al.  Interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms in Greek multiple sclerosis (MS) patients with bout-onset MS , 2010, Neurological Sciences.

[13]  P. Matthews,et al.  Pathway and network-based analysis of genome-wide association studies in multiple sclerosis , 2009, Human molecular genetics.

[14]  H. Favoreel,et al.  Quantification of Fibronectin 1 (FN1) splice variants, including two novel ones, and analysis of integrins as candidate FN1 receptors in bovine preimplantation embryos , 2009, BMC Developmental Biology.

[15]  G. Ebers,et al.  The genetics of clinical outcome in multiple sclerosis , 2008, Journal of Neuroimmunology.

[16]  A. Sadovnick,et al.  Analysis of 45 candidate genes for disease modifying activity in multiple sclerosis , 2008, Journal of Neurology.

[17]  M. Cybulsky,et al.  Getting to the site of inflammation: the leukocyte adhesion cascade updated , 2007, Nature Reviews Immunology.

[18]  K. Vandenbroeck,et al.  ITGA4 polymorphisms and susceptibility to multiple sclerosis , 2007, Journal of Neuroimmunology.

[19]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[20]  A. Quattrone,et al.  The role of VLA4 polymorphisms in multiple sclerosis: An association study , 2007, Journal of Neuroimmunology.

[21]  Ludwig Kappos,et al.  A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. , 2006, The New England journal of medicine.

[22]  G. Abecasis,et al.  Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies , 2006, Nature Genetics.

[23]  S. Reingold,et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria” , 2005, Annals of neurology.

[24]  G. Abecasis,et al.  A note on exact tests of Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[25]  G. Salemi,et al.  Multiple Sclerosis Severity Score: Using disability and disease duration to rate disease severity , 2005, Neurology.

[26]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[27]  R. Rudick,et al.  Natalizumab: α4-integrin antagonist selective adhesion molecule inhibitors for MS , 2004 .

[28]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[29]  J. Kurtzke.  Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[30]  V. Durmanova,et al.  VLA4 Gene Polymorphism and Susceptibility to Multiple Sclerosis in Slovaks. , 2015, Folia biologica.

[31]  R. Rudick,et al.  Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS. , 2004, Expert review of neurotherapeutics.

[32]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.