title: Identification of a variant in KDR associated with serum VEGFR2 and pharmacodynamics of Pazopanib.
abstract: OBJECTIVE
  VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.
  
  
  METHODS
  We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.
  
  
  RESULTS
  rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10(-37)). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01).
  
  
  CONCLUSIONS
  Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, University of Chicago, Chicago, Illinois. mmaitlan@medicine.bsd.uchicago.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.affiliation: Glaxo SmithKline Genetics, Stevenage, United Kingdom.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, Maryland.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Department of Health Studies, University of Chicago, Chicago, Illinois.
authors.forename: Emily
authors.initials: E
authors.lastname: Kistner-Griffin
authors.affiliation: Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, Maryland.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ryan
authors.affiliation: Comprehensive Cancer Center, University of Chicago, Chicago, Illinois. Department of Health Studies, University of Chicago, Chicago, Illinois.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
authors.affiliation: Comprehensive Cancer Center, University of Chicago, Chicago, Illinois. Department of Human Genetics, University of Chicago, Chicago, Illinois.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois.
authors.forename: Dara
authors.initials: D
authors.lastname: Torgerson
authors.affiliation: Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Thomeas
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Levine
authors.affiliation: Glaxo SmithKline Computation Biology, Stevenage, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wilson
authors.affiliation: Glaxo SmithKline Genetics, Research Triangle Park, North Carolina.
authors.forename: Nan
authors.initials: N
authors.lastname: Bing
authors.affiliation: Glaxo SmithKline Oncology, Philadelphia, Pennsylvania.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Glaxo SmithKline Genetics, Philadelphia, Pennsylvania.
authors.forename: Lon R
authors.initials: LR
authors.lastname: Cardon
authors.affiliation: Glaxo SmithKline Oncology, Research Triangle Park, North Carolina.
authors.forename: Lini N
authors.initials: LN
authors.lastname: Pandite
authors.affiliation: Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, Maryland.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, University of Chicago, Chicago, Illinois. Department of Human Genetics, University of Chicago, Chicago, Illinois. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.affiliation: Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, Maryland.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois. Comprehensive Cancer Center, University of Chicago, Chicago, Illinois.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes and Nutrition, School of Medicine, University of Maryland, Baltimore, Maryland. Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D000293:Adolescent; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2