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BASICRESEARCH www.jasn.org GeneticAnalysisof400PatientsRe nesUnderstanding andImplicatesaNewGeneinAtypicalHemolytic UremicSyndrome FengxiaoBu, 1,2YuzhouZhang, 2KaiWang, 3NicoloGhiringhelliBorsa, 2MichaelB.Jones, 2AmandaO.Taylor, 2ErikaTakanami, 2NicoleC.Meyer, 2KathyFrees, 2ChristieP.Thomas, 4CarlaNester, 2,4,5andRichardJ.H.Smith 2,4,51MedicalGeneticsCenter,SouthwestHospital,Chongqing,China;and 2MolecularOtolaryngologyandRenal ResearchLaboratories, 3CollegeofPublicHealth, 4DivisionofNephrology,DepartmentofInternalMedicine,Carver CollegeofMedicine,and 5DepartmentofPediatrics,CarverCollegeofMedicine,UniversityofIowa,IowaCity,Iowa ABSTRACT Background Geneticvariationincomplementgenesisapredisposingfactorforatypicalhemolyticuremic syndrome(aHUS),alife-threateningthromboticmicroangiopathy,howeverinterpretingtheeffectsof geneticvariantsischallengingandoftenambiguous. Methods Weanalyzed93complementandcoagulationgenesin400patientswithaHUS,usingascontrols 600healthyindividualsfromIowaand63,345non-FinnishEuropeanindividualsfromtheGenomeAggre- gationDatabase.Afteradjustingforpopulationstrati cation,wethenappliedtheFisherexact,modi edPoissonexact,andoptimaluni edsequencekernelassociationteststoassessgene-basedvariantburden. Wealsoappliedasliding-windowanalysistode nethefrequencyrangeoverwhichvariantburdenwas signi cant. Results WefoundthatpatientswithaHUSareenrichedforultrararecodingvariantsinthe CFH ,C3,CD46 ,CFI ,DGKE ,and VTN genes.Themajorityofthesigni canceiscontributedbyvariantswithaminorallele frequencyof ,0.1%.Disease-relatedvariantstendtooccurinspeci ccomplementproteindomainsofFH, CD46,andC3.Weobservednoenrichmentformultiplerarecodingvariantsingene-genecombinations. Conclusions InknownaHUS-associatedgenes,variantswithaminorallelefrequency .0.1%shouldnotbe consideredpathogenicunlessv alidenrichmentand/orfuncti onalevidenceareavailable. VTN,which encodesvitronectin,aninhibitoroftheterminalcomplementpathway,isimplicatedasanovelaHUS- associatedgene.PatientswithaHUSarenotenrichedformultiplerarevariantsincomplementgenes.In aggregate,thesedatamayhelpindirectingclinicalmanagementofaHUS. JAmSocNephrol 29: cccŒccc,2018.doi:https://doi.org/10.1681/ASN.2018070759 Atypicalhemolyticuremicsyndrome(aHUS) denesaspectrumofthromboticmicroangiopa- thies(TMAs)characterizedbyhemolyticanemia, thrombocytopenia,andacuterenalinjurynot causedbyShigatoxin-producing Escherichiacoli orADAMTS13de ciency. 1,2Itisultrarare,with anincidenceofapproximately0.5permillionper yearanduntiltheintroductionofeculizumab,a humanizedmAbagainstC5thatblocksthetermi- nalpathwayofthecomplementcascade,itcarrieda verypoorprognosis. 3,4Asthequintessential complement-mediateddisease,aHUSdevelopsin peoplecarryingpredisposinggeneticabnormalities ReceivedJuly25,2018.AcceptedSeptember12,2018. Publishedonlineaheadofprint.P ublicationdateavailableat www.jasn.org. Correspondence: Dr.RichardJ.H.Smith,MolecularOtolaryn- gologyandRenalResearchLaboratories,UniversityofIowa,285 NewtonRoad,5270CBRB,IowaCity,IA52242.Email:richard- smith@uiowa.edu Copyright©2018bytheAmericanSocietyofNephrology JAmSocNephrol 29: cccŒccc,2018 ISSN:1046-6673/2912- ccc1
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