Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk

Research output: Contribution to journalJournal articleResearchpeer-review

  • Ellen L Goode
  • Brooke L Fridley
  • Robert A Vierkant
  • Julie M Cunningham
  • Catherine M Phelan
  • Stephanie Anderson
  • David N Rider
  • Kristin L White
  • V Shane Pankratz
  • Honglin Song
  • Estrid Hogdall
  • Kjær, Susanne Krüger
  • Alice S Whittemore
  • Richard DiCioccio
  • Susan J Ramus
  • Simon A Gayther
  • Joellen M Schildkraut
  • Paul P D Pharaoh
  • Thomas A Sellers
Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging single-nucleotide polymorphism (SNP) sets. To maximize information gleaned from existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2, CDK4, RB1, CDKN2D, and CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium and National Institute of Environmental Health Sciences SNPs Program. Logistic regression assuming a log-additive model was done on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239; CCND1 rs602652, rs3212879, rs649392, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls.
Original languageEnglish
JournalCancer Epidemiology, Biomarkers & Prevention
Volume18
Issue number3
Pages (from-to)935-44
Number of pages9
ISSN1055-9965
DOIs
Publication statusPublished - 2009

Bibliographical note

Keywords: Adult; Aged; Alleles; Case-Control Studies; Cell Cycle; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Female; Genotype; Humans; Logistic Models; Markov Chains; Middle Aged; Minnesota; Neoplasm Invasiveness; North Carolina; Oncogene Proteins; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Registries; Risk

ID: 19953829