In this study of 563 healthy men, we found several SNPs in the 8q24 cancer risk regions associated with circulating levels of androgens. Specifically, SNPs centromeric to prostate cancer region 2 were associated with testosterone measures while those in prostate cancer region 1 were suggestively associated with androstenedione. Since many of the SNPs within each region are in strong LD with each other, the effect of the SNPs within each region on serum androgens may reflect their link with the same causal variant. These findings suggest a potential relationship between the 8q24 cancer risk regions and serum androgens, which in turn may provide some biological clues into the strong link between 8q24 variants and cancer risk. Future studies with larger sample size are needed to confirm these findings.
It is noteworthy that 8q24 SNPs identified in this study to be associated with androgens are also associated with or are in LD with SNPs that are associated with prostate cancer risk (2
), suggesting that serum testosterone may be related to the link between 8q24 variants and prostate cancer. Although the exact mechanism is unclear, data from a recent study showed that the 8q24 cancer risk regions harbor several androgen-responsive transcriptional enhancers, one of which contained a SNP, rs11986220, in prostate cancer region 1 that facilitated stronger androgen responsiveness in vitro
). This particular SNP was not genotyped in our study, but is in moderate to strong LD with several SNPs identified in the study to be associated with androstenedione (D′ =1 and r2
>0.54 based on the International HapMap Project data (29
)). Interactive effects of 8q24variants and serum androgens on prostate cancer risk warrants further investigation, in particular in studies with large samples size.
Our study has several strengths. First, we had high-quality genotyping data as suggested by high concordance and high completion rates, thereby minimizing misclassification of genotyping (4
). Second, we had high-quality serum assays of biomarkers, with low intra-and inter-assay variation (coefficients of variation <18%) (19
), which minimizes misclassification of the outcome. And third, effects of disease status (prostate cancer) is minimized by including only participants of the screening arm of the PLCO who have not been diagnosed with prostate cancer at the time of subject selection.
Limitations of the study should also be noted. Our findings are only borderline significant after adjusting for the tests on 164 SNPs with 5 biomarker measures. However, the 164 SNPs tested were over 5 distinct and independent regions, as defined by LD structure, and we conservatively accounted for these in our assessment of the statistical analyses. Given the relatively small sample size of our study and the existing strong evidence on the relevance of 8q24 region to various cancers, our findings require confirmation in studies with larger sample sizes to better understand the relationship between 8q24 and androgens. Future studies are also needed to determine the relationship between 8q24 and androgens in other ethnic groups.
In summary, our study showed that variations in the 8q24 cancer risk regions may be associated with serum androgen levels, which raises the intriguing hypothesis that serum androgens may be related to the reported association between the 8q24 risk regions and cancer, especially that of the prostate. Future studies with larger sample sizes and in other ethnic populations are needed to confirm these findings and enable generalization to other populations. In addition, future investigations into the mechanisms underlying the link between the 8q24 cancer risk variants, androgen levels and prostate carcinogenesis are warranted.