Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population A Genome-Wide Evaluation of 14,618 Participants in the Womens Genome Health Study 英文参考文献.docVIP

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Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population A Genome-Wide Evaluation of 14,618 Participants in the Womens Genome Health Study 英文参考文献.doc

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Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population A Genome-Wide Evaluation of 14,618 Participants in the Womens Genome Health Study 英文参考文献

NovelAssociationofHK1withGlycatedHemoglobinina Non-DiabeticPopulation:AGenome-WideEvaluationof 14,618ParticipantsintheWomen’sGenomeHealth Study GuillaumePare′1,2.*,DanielI.Chasman1,2.,AlexanderN.Parker3,DavidM.Nathan4,JosephP.Miletich3, RobertY.Zee1,2,PaulM.Ridker1,2 1CenterforCardiovascularDiseasePrevention,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,2DonaldW. ReynoldsCenterforCardiovascularResearch,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3Amgen,Inc., Cambridge,Massachusetts,UnitedStatesofAmerica,4DiabetesCenter,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesof America Abstract Type2diabetesisaleadingcauseofmorbidityandmortality.Whilegeneticvariantshavebeenfoundtoinfluencetherisk oftype2diabetesmellitus,relativelyfewstudieshavefocusedongenesassociatedwithglycatedhemoglobin,anindexof themeanbloodglucoseconcentrationofthepreceding8–12weeks.Epidemiologicstudiesandrandomizedclinicaltrials havedocumentedtherelationshipbetweenglycatedhemoglobinlevelsandthedevelopmentoflong-termcomplications in diabetes; moreover, higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetesriskandcardiovasculardisease.Toexaminethecommongeneticdeterminantsofglycatedhemoglobinlevels,we performedagenome-wideassociationstudythatevaluated337,343SNPsin14,618apparentlyhealthyCaucasianwomen. The results show that glycated hemoglobin levels are associated with genetic variation at the GCK (rs730497; P=2.8610212), SLC30A8 (r P=9.861028), G6PC2 (rs1402837; P=6.8610210), and HK1 (rs7072268; P=6.461029) loci. While associations at the GCK, SLC30A8, and G6PC2 loci are confirmatory, the findings at HK1 are novel.Wewereabletoreplicatethisnovelassociationinanindependentvalidationsampleof455additionalnon-diabetic menandwomen.HK1encodestheenzymehexokinase,thefirststepinglycolysisandalikelycandidateforthecontrolof gluc