Human Molecular Genetics Advance Access published online on May 10, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn145
Published by Oxford University Press 2008
No Association between the SRD5A2 Gene A49T Missense Variant and Prostate Cancer Risk: Lessons Learned
1 University of Southern California, Department of Preventive Medicine, Los Angeles, CA 90033 U.S.A. 2 Norris Comprehensive Cancer Center, Los Angeles, CA 90033 U.S.A. 3 University of Southern California, Department of Urology, Los Angeles, CA 90033 U.S.A. 4 Tulane Cancer Center, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112 U.S.A. 5 University of Sydney, Plunkett Chair of Molecular Biology (Medicine), Camperdown, NSW 2006 Australia 6 Cancer Research Center, University of Hawaii, Honolulu, HI 96813 U.S.A.
* Corresponding author: C. Leigh Pearce, PhD, 1441 Eastlake Avenue, MS44, Room 4425, Los Angeles, California 90033, Phone: (323) 865-0437, Fax: (323) 865-0127, e-mail cpearce{at}usc.edu
Received January 30, 2008; Revised April 16, 2008; Accepted May 7, 2008
The steroid 5-alpha reductase type II gene (SRD5A2) encodes the enzyme which converts testosterone (T) to the more active androgen dihydrotestosterone (DHT). A non-synonymous single nucleotide polymorphism (SNP), A49T (rs9282858), in SRD5A2 has been implicated in prostate cancer risk; however, results have been inconsistent. In 1999 we reported a strong association between the A49T variant and prostate cancer risk among African-Americans and Latinos in the Hawaii-Los Angeles Multiethnic Cohort (MEC). We report here an updated analysis of MEC data including the five major ethnic groups of the MEC, an increased sample size, improved genotyping technology, and a comprehensive meta-analysis of the published literature. We found a non-statistically significant positive association between prostate cancer risk and carrying either the AT or TT genotype (odds ratio (OR)=1.20, 95% confidence interval (CI) 0.82-1.77) in the MEC. This finding is in contrast to our previous results of ORs of 3.28 and 2.50 for the association between prostate cancer risk and the variant in African-American and Latino men respectively; this can be accounted for by genotyping error in our earlier study. Meta-analysis of the published literature, including the current MEC data, shows a summary OR of 1.13 (95% CI 0.95-1.34) for the A49T variant with prostate cancer risk among sporadic, unselected cases. After evaluating over 6,000 cases and 6,000 controls, there is little evidence of a role for the SRD5A2 A49T variant in prostate cancer risk. Overall, this report highlights the importance of rigorous genotyping quality control measures and replication efforts in genetic association studies.
** Ronald K. Ross is deceased, but contributed significantly to the preparation of this manuscript prior to his death.