A Genetic Basis of Susceptibility to Acute Pyelonephritis 英文参考文献.docVIP

AGeneticBasisofSusceptibilitytoAcutePyelonephritis Ann-CharlotteLundstedt1,ShaneMcCarthy2,MattiasC.U.Gustafsson1,GabrielaGodaly1,UlfJodal3,DianaKarpman4,IreneLeijonhufvud1, CarinLinde′n5,JeanetteMartinell3,BryndisRagnarsdottir1,MartinSamuelsson1,LennartTruedsson1,Bjo¨rnAndersson2,CatharinaSvanborg1* 1DepartmentofMicrobiology,ImmunologyandGlycobiology,InstituteofLaboratoryMedicine,LundUniversity,Lund,Sweden,2DepartmentofCell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden, 3Department of Pediatrics, the Queen Silvia Children’s Hospital, Gothenburg University, Gothenburg, Sweden, 4Department of Pediatrics, Lund University, Lund, Sweden, 5Department of Infectious Diseases, Gothenburg University,Gothenburg,Sweden Background.Forunknownreasons,urinarytractinfections(UTIs)areclusteredincertainindividuals.Hereweproposeanovel, geneticallydeterminedcauseofsusceptibilitytoacutepyelonephritis,whichisthemostsevereformofUTI.TheIL-8receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage. Methods and Findings. We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of23% and 25% comparedto7%incontrols(p,0.001andp,0.0001,respectively).Whenrefluxwasexcluded,54%ofthepatientshadCXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p,0.0001) and two sequencevariantswereshowntoimpairtranscription.Conclusions.Theresultsidentifyageneticinnateimmunedeficiency, withastronglinktoAPNandrenalscarring. Citation: LundstedtA-C,McCarthyS,GustafssonMCU,GodalyG,JodalU,etal(2007)AGeneticBasisofSusceptibilitytoAcutePyelonephritis.PLoS ONE2(9):e825.doi:10.1371/journal.pone.0000825 INTRODUCTION [14,15].ThemIL-8Rhchemokinereceptormutantmicedevelop acute, septic pyelonephritis with about 50% mortality [4,12,16]. They lack the single chemo