Human Molecular Genetics Advance Access originally published online on May 10, 2008
Human Molecular Genetics 2008 17(16):2456-2461; doi:10.1093/hmg/ddn145
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Published by Oxford University Press 2008
No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned
1 Department of Preventive Medicine 2 Norris Comprehensive Cancer Center 3 Department of Urology, University of Southern California, Los Angeles, CA 90033, USA 4 Tulane Cancer Center, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA 5 University of Sydney, Camperdown, NSW 2006, Australia 6 Cancer Research Center, University of Hawaii, Honolulu, HI 96813, USA
* To whom correspondence should be addressed at: 1441 Eastlake Avenue, MS44, Room 4425, Los Angeles, CA 90033, USA. Tel: +1 3238650437; Fax: +1 3238650127; Email: 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. A non-synonymous single-nucleotide polymorphism, 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) = 1.16, 95% confidence interval (CI) 0.79–1.69] 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 more than 6000 cases and 6000 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.
R.K.R. is deceased, but contributed significantly to the preparation of this manuscript prior to his death.