A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer

Sarah L. Kerns, Richard Stock, Nelson Stone, Michael Buckstein, Yongzhao Shao, Christopher Campbell, Lynda Rath, Dirk De Ruysscher, Guido Lammering, Rosetta Hixson, Jamie Cesaretti, Mitchell Terk, Harry Ostrer, Barry S. Rosenstein

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Abstract

Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 × 10 -5 to 6.2 × 10-4). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value = 1.7 × 10-29). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 × 10-19). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.

Original languageEnglish (US)
Pages (from-to)e21-e28
JournalInternational Journal of Radiation Oncology Biology Physics
Volume85
Issue number1
DOIs
StatePublished - Jan 1 2013

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ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Kerns, S. L., Stock, R., Stone, N., Buckstein, M., Shao, Y., Campbell, C., Rath, L., De Ruysscher, D., Lammering, G., Hixson, R., Cesaretti, J., Terk, M., Ostrer, H., & Rosenstein, B. S. (2013). A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. International Journal of Radiation Oncology Biology Physics, 85(1), e21-e28. https://doi.org/10.1016/j.ijrobp.2012.08.003