2016
Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail
Longbrake EE, Hafler DA. Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurology 2016, 73: 777-8. PMID: 27244583, PMCID: PMC5198230, DOI: 10.1001/jamaneurol.2016.1227.Peer-Reviewed Original Research
2013
Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus
Ottoboni L, Frohlich IY, Lee M, Healy BC, Keenan BT, Xia Z, Chitnis T, Guttmann CR, Khoury SJ, Weiner HL, Hafler DA, De Jager PL. Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. Neurology 2013, 81: 1891-1899. PMID: 24174586, PMCID: PMC3843384, DOI: 10.1212/01.wnl.0000436612.66328.8a.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArginineChemokine CXCL10FemaleGene Expression RegulationGenetic Predisposition to DiseaseGenotypeGlutamineHEK293 CellsHumansImmunologic FactorsLongitudinal StudiesMaleMonocytesMultiple SclerosisMutationPhorbol EstersReceptors, Tumor Necrosis Factor, Type IRNA IsoformsSignal TransductionTumor Necrosis Factor-alphaConceptsTNFRSF1A locusSusceptibility allelesFunctional consequencesRobust transcriptional responseTranscriptional responseCytoplasmic domainRNA isoformsTNF-α stimulationRho GTPaseMS susceptibility genesMS geneG proteinsSusceptibility genesMolecular levelTNF pathwayGenesAltered expressionLociTNF-α pathwayAllelesRisk allelesPathwayGTPaseImmune functionTransmembrane
2011
Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci
Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, Sandbrink R, Pohl C, Edan G, Kappos L, Miller D, Montalbán J, Polman C, Freedman M, Hartung H, Arnason B, Comi G, Cook S, Filippi M, Goodin D, Jeffery D, O'Connor P, Ebers G, Langdon D, Reder A, Traboulsee A, Zipp F, Schimrigk S, Hillert J, Bahlo M, Booth D, Broadley S, Brown M, Browning B, Browning S, Butzkueven H, Carroll W, Chapman C, Foote S, Griffiths L, Kermode A, Kilpatrick T, Lechner-Scott J, Marriott M, Mason D, Moscato P, Heard R, Pender M, Perreau V, Perera D, Rubio J, Scott R, Slee M, Stankovich J, Stewart G, Taylor B, Tubridy N, Willoughby E, Wiley J, Matthews P, Boneschi F, Compston A, Haines J, Hauser S, McCauley J, Ivinson A, Oksenberg J, Pericak-Vance M, Sawcer S, De Jager P, Hafler D, de Bakker P. Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci. Annals Of Neurology 2011, 70: 897-912. PMID: 22190364, PMCID: PMC3247076, DOI: 10.1002/ana.22609.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesSingle nucleotide polymorphismsSusceptibility lociHapMap Phase IIUnique single nucleotide polymorphismsGene discovery effortsNew susceptibility lociStrongest cis effectsMS genome-wide association studiesQuantitative trait analysisFlanking genesGenetic architectureRNA expression dataMultiple sclerosis susceptibility lociIntergenic regionSecond intronNew lociNovel susceptibility allelesAdditional lociTrait analysisAssociation studiesExpression dataChromosome 2p21LociFunctional consequencesGenome-Wide Assessment for Genetic Variants Associated with Ventricular Dysfunction after Primary Coronary Artery Bypass Graft Surgery
Fox AA, Pretorius M, Liu KY, Collard CD, Perry TE, Shernan SK, De Jager PL, Hafler DA, Herman DS, DePalma SR, Roden DM, Muehlschlegel JD, Donahue BS, Darbar D, Seidman JG, Body SC, Seidman CE. Genome-Wide Assessment for Genetic Variants Associated with Ventricular Dysfunction after Primary Coronary Artery Bypass Graft Surgery. PLOS ONE 2011, 6: e24593. PMID: 21980348, PMCID: PMC3184087, DOI: 10.1371/journal.pone.0024593.Peer-Reviewed Original ResearchConceptsCABG surgeryPostoperative ventricular dysfunctionVentricular dysfunctionSingle nucleotide polymorphismsPrimary coronary artery bypass graft surgeryCoronary artery bypass graft surgeryArtery bypass graft surgeryPrimary CABG surgeryBypass graft surgeryClinical risk factorsMechanical ventricular supportPatient risk stratificationGenetic variantsCABG cohortGraft surgeryPostoperative morbiditySurgical patientsCardiopulmonary bypassRisk stratificationVentricular supportRisk factorsLarge cohortPrevention strategiesSurgeryMale subjectsThe CD6 Multiple Sclerosis Susceptibility Allele Is Associated with Alterations in CD4+ T Cell Proliferation
Kofler DM, Severson CA, Mousissian N, De Jager PL, Hafler DA. The CD6 Multiple Sclerosis Susceptibility Allele Is Associated with Alterations in CD4+ T Cell Proliferation. The Journal Of Immunology 2011, 187: 3286-3291. PMID: 21849685, DOI: 10.4049/jimmunol.1100626.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAntigens, CDAntigens, Differentiation, T-LymphocyteCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell ProliferationCell SeparationCells, CulturedFemaleFlow CytometryGenetic Predisposition to DiseaseGenotypeHumansMaleMultiple SclerosisPhenotypeReverse Transcriptase Polymerase Chain ReactionRisk FactorsRNA, Small InterferingConceptsGenome-wide association studiesAssociation studiesAllelic variantsNew susceptibility lociSusceptibility allelesRisk allelesProliferation defectExon 5Risk-associated allelesSingle nucleotide polymorphismsExtracellular binding sitesCD6 geneSusceptibility lociLinkage disequilibriumMS risk alleleSelective knockdownT cell activationNucleotide polymorphismsAltered proliferationCell proliferationGenetic associationAllelesLong-term activationBinding sitesMS susceptibility allelesInterrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA–CLEC16A–SOCS1 gene complex
Zuvich RL, Bush WS, McCauley JL, Beecham AH, De Jager PL, Consortium T, Ivinson A, Compston A, Hafler D, Hauser S, Sawcer S, Pericak-Vance M, Barcellos L, Mortlock D, Haines J. Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA–CLEC16A–SOCS1 gene complex. Human Molecular Genetics 2011, 20: 3517-3524. PMID: 21653641, PMCID: PMC3153306, DOI: 10.1093/hmg/ddr250.Peer-Reviewed Original ResearchMeSH KeywordsCCCTC-Binding FactorChromosomes, Human, Pair 16FemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansLectins, C-TypeLinkage DisequilibriumLogistic ModelsMaleMonosaccharide Transport ProteinsMultiple SclerosisQuantitative Trait LociRepressor ProteinsSuppressor of Cytokine Signaling 1 ProteinSuppressor of Cytokine Signaling ProteinsConceptsIndependent genetic signalsGenetic signalsLymphoblastoid cell linesChromosome 16p13Cis expression QTLsOpen chromatin configurationCell linesLinkage disequilibrium patternsExpression array dataH3K27 methylationHistone modificationsGenomic regionsKb stretchStrong genetic componentSingle nucleotide polymorphismsChromatin configurationExpression correlationGene complexDisequilibrium patternsDisease locusGenesCorrelated expressionGenetic componentFunctional mechanismsLociInterferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis
Vosslamber S, van der Voort LF, van den Elskamp IJ, Heijmans R, Aubin C, Uitdehaag BM, Crusius JB, van der PouwKraan T, Comabella M, Montalban X, Hafler DA, De Jager PL, Killestein J, Polman CH, Verweij CL. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis. Genes & Immunity 2011, 12: 466-472. PMID: 21471993, DOI: 10.1038/gene.2011.18.Peer-Reviewed Original ResearchConceptsRelapsing-remitting multiple sclerosisNon-responder statusInterferon regulatory factor 5IFNβ treatmentMultiple sclerosisT2 lesionsClinical outcomesMore magnetic resonance imagingMore T2 lesionsStart of therapyGene variantsInterferon-β TherapyIFN response genesRegulatory factor 5Poor pharmacological responseMagnetic resonance imagingIFNβ therapyClinical responseFirst relapseIndependent cohortPharmacological responseClinical relevanceG allelePatientsResonance imaging
2010
HLA B*44
Healy BC, Liguori M, Tran D, Chitnis T, Glanz B, Wolfish C, Gauthier S, Buckle G, Houtchens M, Stazzone L, Khoury S, Hartzmann R, Fernandez-Vina M, Hafler DA, Weiner HL, Guttmann CR, De Jager PL. HLA B*44. Neurology 2010, 75: 634-640. PMID: 20713950, PMCID: PMC2931768, DOI: 10.1212/wnl.0b013e3181ed9c9c.Peer-Reviewed Original ResearchMeSH KeywordsAdultChi-Square DistributionDisease ProgressionFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHLA AntigensHLA-A AntigensHLA-B AntigensHLA-B44 AntigenHLA-C AntigensHumansLogistic ModelsMagnetic Resonance ImagingMaleMiddle AgedMultiple SclerosisOutcome Assessment, Health CareRadiographySeverity of Illness IndexConceptsDisease courseT2 hyperintense lesion volumeBetter radiologic outcomesHyperintense lesion volumeT2 hyperintense lesionsBrain parenchymal fractionBone Marrow Donor RegistryMHC class IMarrow Donor RegistryMS susceptibility lociClass I MHC lociRadiologic outcomesHyperintense lesionsParenchymal fractionLesion volumeOutcome measuresClinical measuresMS susceptibilityBrain volumeHLAProtective allelesLogistic regressionPatient samplesDonor registryRisk allelesA non-synonymous SNP within membrane metalloendopeptidase-like 1 (MMEL1) is associated with multiple sclerosis
Ban M, McCauley JL, Zuvich R, Baker A, Bergamaschi L, Cox M, Kemppinen A, D'Alfonso S, Guerini FR, Lechner-Scott J, Dudbridge F, Wason J, Robertson NP, De Jager PL, Hafler DA, Barcellos LF, Ivinson AJ, Sexton D, Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines J, Compston A, Sawcer S. A non-synonymous SNP within membrane metalloendopeptidase-like 1 (MMEL1) is associated with multiple sclerosis. Genes & Immunity 2010, 11: 660-664. PMID: 20574445, PMCID: PMC2946966, DOI: 10.1038/gene.2010.36.Peer-Reviewed Original ResearchVariation Within DNA Repair Pathway Genes and Risk of Multiple Sclerosis
Briggs FB, Goldstein BA, McCauley JL, Zuvich RL, De Jager PL, Rioux JD, Ivinson AJ, Compston A, Hafler DA, Hauser SL, Oksenberg JR, Sawcer SJ, Pericak-Vance MA, Haines JL, Barcellos LF, Consortium F. Variation Within DNA Repair Pathway Genes and Risk of Multiple Sclerosis. American Journal Of Epidemiology 2010, 172: 217-224. PMID: 20522537, PMCID: PMC3658128, DOI: 10.1093/aje/kwq086.Peer-Reviewed Original ResearchConceptsDNA repair pathway genesPathway genesMultiple sclerosisExcision repairGeneral transcription factor IIHDouble-strand break repairTranscription factor IIHDNA repair pathwaysNucleotide excision repairRisk of MSBase excision repairPrimary genetic risk factorProminent genetic componentHuman leukocyte antigenComplex autoimmune diseaseSingle nucleotide polymorphism (SNP) variantsCentral nervous systemLogistic regression modelingGenetic risk factorsSingle nucleotide polymorphismsBreak repairRepair pathwaysCandidate genesAutoimmune diseasesGenesGenetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility
Zuvich RL, McCauley JL, Oksenberg JR, Sawcer SJ, De Jager PL, International Multiple Sclerosis Genetics Consortium, Aubin C, Cross AH, Piccio L, Aggarwal NT, Evans D, Hafler DA, Compston A, Hauser SL, Pericak-Vance MA, Haines JL. Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Human Genetics 2010, 127: 525-535. PMID: 20112030, PMCID: PMC2854871, DOI: 10.1007/s00439-010-0789-4.Peer-Reviewed Original ResearchConceptsSingle nucleotide polymorphismsGene regionCase-control data setsPutative functional relationshipsNovel gene regionsIndependent case-control data setDense SNP mapReceptor alpha-chain geneIllumina Infinium BeadChipExperiment-wise significanceNovel associationsAlpha chain geneGenetic architectureComplex traitsStrong genetic componentGenetic variationSNP mapInfinium BeadChipAffordable genotypingBiological pathwaysGenesGenetic componentChain geneTYK2 geneNumerous family studies
2009
Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci
, , McCauley J, Zuvich R, Beecham A, De Jager P, Konidari I, Whitehead P, Aubin C, Ban M, Pobywajlo S, Briskin R, Romano S, Aggarwal N, Piccio L, McArdle W, Strachan D, Evans D, Cross A, Cree B, Rioux J, Barcellos L, Ivinson A, Compston A, Hafler D, Hauser S, Oksenberg J, Sawcer S, Pericak-Vance M, Haines J. Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Human Molecular Genetics 2009, 19: 953-962. PMID: 20007504, PMCID: PMC2816610, DOI: 10.1093/hmg/ddp542.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesSingle nucleotide polymorphismsAssociation studiesFirst genome-wide association studyGenome-wide association screenNumerous complex diseasesSusceptibility lociInitial genome-wide association studyGenome-wide significanceNovel susceptibility lociComplex genetic diseasesHundreds of associationsSNP hitsGWAS studiesGenetic diseasesLociComplex diseasesOriginal screenTMEM39AInitial associationIndependent data setsReplicationKIF21BInitial replicationScreenIntegration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score
De Jager PL, Chibnik LB, Cui J, Reischl J, Lehr S, Simon KC, Aubin C, Bauer D, Heubach JF, Sandbrink R, Tyblova M, Lelkova P, the steering committees of the BENEFIT B, Havrdova E, Pohl C, Horakova D, Ascherio A, Hafler D, Karlson E. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. The Lancet Neurology 2009, 8: 1111-1119. PMID: 19879194, PMCID: PMC3099419, DOI: 10.1016/s1474-4422(09)70275-3.Peer-Reviewed Original ResearchConceptsWeighted genetic risk scoreEpstein-Barr virusHealth Study IMultiple sclerosisC-statisticRisk factorsGenetic risk scoreImmune responseRisk scoreNurses' Health Study IDiagnosis of MSNon-genetic risk factorsHigh-risk individualsMultiple sclerosis susceptibilityEnvironmental risk factorsGenetic risk factorsNHS cohortDerivation cohortTherapeutic trialsMS riskProspective studyClinical algorithmImportant clinical applicationsHigher oddsSusceptibility lociSoluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses
Maier LM, Anderson DE, Severson CA, Baecher-Allan C, Healy B, Liu DV, Wittrup KD, De Jager PL, Hafler DA. Soluble IL-2RA Levels in Multiple Sclerosis Subjects and the Effect of Soluble IL-2RA on Immune Responses. The Journal Of Immunology 2009, 182: 1541-1547. PMID: 19155502, PMCID: PMC3992946, DOI: 10.4049/jimmunol.182.3.1541.Peer-Reviewed Original ResearchConceptsMultiple sclerosisIL-2 receptorMS subjectsHealthy controlsOrgan-specific autoimmune disordersChronic systemic inflammationType 1 diabetesT cell proliferationMultiple sclerosis subjectsStrong genetic factorIL-2 signalingSIL-2RaSystemic inflammationAutoimmune disordersImmunological perturbationsAutoimmune diseasesIL-2RAControl subjectsMS casesSerum concentrationsDisease onsetSpecific allelic variantsImmune responseAggressive formDisease riskIL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production
Maier LM, Lowe CE, Cooper J, Downes K, Anderson DE, Severson C, Clark PM, Healy B, Walker N, Aubin C, Oksenberg JR, Hauser SL, Compston A, Sawcer S, , De Jager PL, Wicker LS, Todd JA, Hafler DA. IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production. PLOS Genetics 2009, 5: e1000322. PMID: 19119414, PMCID: PMC2602853, DOI: 10.1371/journal.pgen.1000322.Peer-Reviewed Original ResearchConceptsMultiple sclerosisT1D subjectsSoluble interleukin-2 receptor productionSoluble interleukin-2 receptorOrgan-specific autoimmune disordersHealthy control subjectsInterleukin-2 receptorType 1 diabetesHuman leukocyte antigen (HLA) complexMS risk genesAutoimmune disordersControl subjectsAutoimmunity riskHealthy controlsIL2RA regionType 1Autoimmune lociRisk allelesReceptor productionCandidate gene association studiesAntigen complexGene association studiesAssociation studiesT1D.Sclerosis
2008
Integrating risk factors
De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A. Integrating risk factors. Neurology 2008, 70: 1113-1118. PMID: 18272866, DOI: 10.1212/01.wnl.0000294325.63006.f8.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntibodiesBiomarkersCase-Control StudiesComorbidityEpstein-Barr Virus InfectionsEpstein-Barr Virus Nuclear AntigensFemaleGene FrequencyGenetic Predisposition to DiseaseGenotypeHerpesvirus 4, HumanHeterozygoteHLA-DR AntigensHLA-DRB1 ChainsHumansMiddle AgedMultiple SclerosisRisk FactorsConceptsMultiple sclerosisHuman leukocyte antigenAntibody titersRisk factorsDR15 alleleEpstein-Barr virus (EBV) antibody titersAge-matched healthy womenRisk of MSEpstein-Barr virus nuclear antigen 1Independent risk factorVirus antibody titersCase-control studyNuclear antigen 1Healthy womenMS riskLeukocyte antigenRelative riskGenetic susceptibilityAntigen 1TitersWomenSclerosisRiskDR15Association
2007
Allelic variant in CTLA4 alters T cell phosphorylation patterns
Maier LM, Anderson DE, De Jager PL, Wicker LS, Hafler DA. Allelic variant in CTLA4 alters T cell phosphorylation patterns. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 18607-18612. PMID: 18000051, PMCID: PMC2141824, DOI: 10.1073/pnas.0706409104.Peer-Reviewed Original ResearchConceptsT cell antigen receptorAllelic variationMemory T cellsAutoimmune diseasesCell antigen receptorT cell signalingT cellsFunctional effectsDisease susceptibility allelesCell signalingPhosphorylation patternPhosphorylation levelsSusceptibility variantsTCR stimulationAllelic variantsHuman immune cellsAntigen receptorGenesImmune cellsHealthy individualsCTLA4 geneCellsSpecific mAbsCTLA4DiseaseThe role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases
De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD. The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes & Immunity 2007, 8: 387-397. PMID: 17538633, DOI: 10.1038/sj.gene.6364398.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseCases of IBDRisk of IBDToll-like receptorsBowel diseaseIBD risk allelesUlcerative colitisCrohn's diseaseTLR4 pathwayIBD pathophysiologyIntestinal floraTLR pathwayTLR4 allelesHost defenseReceptor pathwayRisk allelesTLR genesDiseaseTLR4Modest effectHost/pathogen interactionsTIRAPAssociationReplication studyRisk
2005
Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis
De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A, Langelier D, Bitton A, Compston A, Hafler DA, Rioux JD. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. European Journal Of Human Genetics 2005, 14: 317-321. PMID: 16391555, DOI: 10.1038/sj.ejhg.5201548.Peer-Reviewed Original ResearchMeSH KeywordsAllelesCanadaCase-Control StudiesCrohn DiseaseGene FrequencyGenetic Predisposition to DiseaseGenotypeHumansInflammationModels, StatisticalMultiple SclerosisOdds RatioPolymorphism, GeneticProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine Phosphatase, Non-Receptor Type 22Protein Tyrosine PhosphatasesRiskUnited KingdomConceptsSystemic lupus erythematosusCases of CDCrohn's diseaseMultiple sclerosisPTPN22 620W alleleAutoimmune thyroiditisRheumatoid arthritisInflammatory diseasesEvidence of associationCases of MSProtein tyrosine phosphatase PTPN22Chronic inflammatory diseaseType 1 diabetesTyrosine phosphatase PTPN22PTPN22 alleleLupus erythematosusPooled analysisControl subjectsModest odds ratiosOdds ratioDiseaseRisk allelesPhosphatase PTPN22SclerosisPossible role
2004
Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping
Sawcer SJ, Maranian M, Singlehurst S, Yeo T, Compston A, Daly MJ, De Jager PL, Gabriel S, Hafler DA, Ivinson AJ, Lander ES, Rioux JD, Walsh E, Gregory SG, Schmidt S, Pericak-Vance MA, Barcellos L, Hauser SL, Oksenberg JR, Kenealy SJ, Haines JL. Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping. Human Molecular Genetics 2004, 13: 1943-1949. PMID: 15238506, DOI: 10.1093/hmg/ddh202.Peer-Reviewed Original Research