Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy

• Published in: PloS one Vol. 10; no. 6; p. e0127791
• Main Authors: Van Driest, Sara L, McGregor, Tracy L, Velez Edwards, Digna R, Saville, Ben R, Kitchner, Terrie E, Hebbring, Scott J, Brilliant, Murray, Jouni, Hayan, Kullo, Iftikhar J, Creech, C Buddy, Kannankeril, Prince J, Vear, Susan I, Brothers, Kyle B, Bowton, Erica A, Shaffer, Christian M, Patel, Neelam, Delaney, Jessica T, Bradford, Yuki, Wilson, Sarah, Olson, Lana M, Crawford, Dana C, Potts, Amy L, Ho, Richard H, Roden, Dan M, Denny, Josh C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2015; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Aged; Antibiotics; Chromosome 6; Chromosomes, Human - genetics; Chromosomes, Human, Pair 6 - genetics; Connexin 43; Connexin 43 - genetics; Creatinine; Creatinine - blood; Female; Gap junctions; Gene loci; Genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; GTPase-Activating Proteins - genetics; Health risks; Hospitals; Humans; Informatics; Kidney diseases; Male; Medical records; Medicine; Meta-analysis; Middle Aged; Pediatrics; Polymorphism, Single Nucleotide - genetics; Review boards; Risk analysis; Risk factors; Single-nucleotide polymorphism; Staphylococcus infections; Studies; Therapy; Vancomycin; Vancomycin - therapeutic use; United States > US; Tennessee; Minnesota; Ohio; Wisconsin; Nashville Tennessee; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0127791

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.