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

Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):935-44. doi: 10.1158/1055-9965.EPI-08-0860. Epub 2009 Mar 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • CCND1 protein, human
  • CCNE1 protein, human
  • CDKN2B protein, human
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Oncogene Proteins
  • Cyclin D1
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2