title: Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy.
abstract: Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10(-7)). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10(-7). Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Van Driest
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America; Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGregor
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Digna R
authors.initials: DR
authors.lastname: Velez Edwards
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Ben R
authors.initials: BR
authors.lastname: Saville
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Kitchner
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hebbring
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Murray
authors.initials: M
authors.lastname: Brilliant
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Hayan
authors.initials: H
authors.lastname: Jouni
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Prince J
authors.initials: PJ
authors.lastname: Kannankeril
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Susan I
authors.initials: SI
authors.lastname: Vear
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Brothers
authors.affiliation: Institute for Clinical and Translational Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Bowton
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Shaffer
authors.affiliation: School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Neelam
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Delaney
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Lana M
authors.initials: LM
authors.lastname: Olson
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Department of Pharmaceutical Services, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Potts
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ho
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America; Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Josh C
authors.initials: JC
authors.lastname: Denny
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002877:Chromosomes, Human / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D018031:Connexin 43 / Q000235:genetics; D003404:Creatinine / Q000097:blood*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014640:Vancomycin / Q000627:therapeutic use*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018031:Connexin 43; C500216:GJA1 protein, human; D020690:GTPase-Activating Proteins; C000590032:TBC1D32 protein, human; D014640:Vancomycin; D003404:Creatinine