Genetic Variation in the Proximal Promoter of ABC and SLC Superfamilies Liver and Kidney Specific Expression and Promoter Activity Predict Variation 英文参考文献.docVIP

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Genetic Variation in the Proximal Promoter of ABC and SLC Superfamilies Liver and Kidney Specific Expression and Promoter Activity Predict Variation 英文参考文献.doc

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Genetic Variation in the Proximal Promoter of ABC and SLC Superfamilies Liver and Kidney Specific Expression and Promoter Activity Predict Variation 英文参考文献

GeneticVariationintheProximalPromoterofABCand SLCSuperfamilies:LiverandKidneySpecificExpression andPromoterActivityPredictVariation StephanieE.Hesselson1.,Pa¨rMatsson2.,JamesE.Shima2.,HisayoFukushima2.,SookWahYee2 ,Yuya Kobayashi4,JasonM.Gow2,ConnieHa1,BenjaminMa1,AnniePoon1,SusanJ.Johns3,DougStryke3, RichardA.Castro2,HarunobuTahara2,JiHaChoi2,LigongChen2,NicolasPicard2,ElinSjo¨din2, MaarkeJ.E.Roelofs2,ThomasE.Ferrin3,RichardMyers4,DeannaL.Kroetz2,Pui-YanKwok1,KathleenM. Giacomini2* 1Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America, 2Department of Bioengineering and TherapeuticSciences,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica,3PharmaceuticalChemistry,UniversityofCaliforniaSan Francisco, SanFrancisco, California, United States ofAmerica,4DepartmentofGenetics, Stanford University School ofMedicine, Stanford, California, United States of America Abstract Membranetransportersplaycrucialrolesinthecellularuptakeandeffluxofanarrayofsmallmoleculesincludingnutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoterregionsoftransporter genescontributetoobservedvariationindrugresponse.Atotalof579polymorphisms were identified in the proximal promoters (2250 to +50bp) and flanking 59 sequence of 107 transporters in the ATP BindingCassette(ABC)andSoluteCarrier(SLC)superfamiliesin272DNAsamplesfromethnicallydiversepopulations.Many transporterpromoterscontainedmultiplecommonpolymorphisms.Usingaslidingwindowanalysis,weobservedthat,on average,nucleotidediversity(p)waslowestatapproximately300bpupstreamofthetranscriptionstartsite,suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressedintheliverhadgreaternucleotidediversitythanthosethatwerehighlyexpressedinthekidneyconsistentwith greater negative selective pressure