Several prospective studies, including CPS-II (19
) and PLCO (4
), have found that men with diabetes have a 20–30% lower risk of prostate cancer compared to men without diabetes (2
). Using combined results from CPS-II and PLCO, we confirmed that three SNPs in HNF1B
and 2 SNPs in JAZF1
were significantly associated with a decreased risk of prostate cancer (13
). The two JAZF1
SNPs, which are not in LD with those previously associated with diabetes, were not associated with this disease in our study. However, the three HNF1B
SNPs, which represent two distinct loci, were marginally associated with an increased risk of diabetes. These findings, particularly for the rs4430796 and rs7501939 SNPs which have previously been shown to be associated with increased risk of diabetes (10
), likely lack statistical significance because they were obtained using only 407 diabetics. The other HNF1B
SNP, rs11649743, has not previously been associated with diabetes risk. Thus, our findings suggest for the first time that there are two distinct loci in the HNF1B
gene associated with increased risk of diabetes.
The different relationships of the SNPs from the two genes with the prostate cancer and diabetes, in which the HNF1B
SNPs are associated with both but the JAZF1
SNPs are only associated with prostate cancer, provide a useful comparison when probing how these genes influence the association between the two diseases. For HNF1B
, the nature of the associations of the SNPs with the two diseases, in which common variants are associated with an increased risk of diabetes and a decreased risk of prostate cancer, mirrors the inverse association between diabetes and prostate cancer risk. Therefore, the possibility that the SNP-prostate cancer relationship is mediated by diabetes requires consideration. If this were the case, then the association of the HNF1B
SNPs with prostate cancer should be substantially reduced or eliminated when diabetics are excluded from the analysis or when adjustment is made for diabetic status. We found that these associations persisted despite such exclusions and adjustments. The associations of the JAZF1 SNPs with prostate cancer, which shouldn’t be influenced by diabetes status, were also maintained after the same exclusions or adjustments. Although we cannot entirely rule out the possibility of an indirect association (20
), our findings are consistent with the HNF1B
variants being directly associated with prostate cancer. In addition, the association of diabetes with prostate cancer was not changed when the HNF1B
genotypes were included in the model, suggesting that the diabetes-prostate cancer relationship is not mediated through these gene variants. Thus, our findings suggest that the diabetes-prostate cancer association is not explained by the associated SNPs.
Understanding the expression and function of the HNF1B
gene products should help to explain their involvement in prostate cancer and diabetes and may shed light on the relationship between these two diseases. Both proteins are transcription factors that regulate the expression of numerous genes involved in a variety of cellular functions. HNF1B plays a key role in the development and function of several organs, particularly the pancreas (21
) and kidney (22
). It regulates the expression of numerous genes in the tissues in which it is expressed (23
), but whether it alters levels of the various metabolic and hormonal factors that may influence prostate cancer risk in diabetic men is unknown. JAZF1 is also a transcription factor that acts as a transcriptional repressor of an orphan nuclear receptor known as TR4 (also known as TAK1 or NR2C2) (24
) that contributes to the regulation of blood levels of glucose (25
) and IGF-1 (26
polymorphisms have been associated with human height (27
), further supporting a role for this gene in the regulation of growth and metabolism. Thus, it appears feasible that genetic variation in JAZF1
, may influence prostate cancer risk by altering the levels of hormones or growth-related proteins previously suggested to mediate the association between diabetes and this cancer.
The main strength of this study is the availability of men for whom both prostate cancer and diabetes status has been defined within two well-characterized, large cohorts. This allowed us to examine the association of the HNF1B
SNPs with both diseases in the same population. The limitations include the relatively low number of prostate cancer cases with diabetes, which limited the power of the stratified analyses. Additional limitations are the use of self-reported diabetes status and fact that diabetes status was not updated during the follow-up period. However, a recent study found that almost 80% of self-reports of diabetes were valid (28
), suggesting that misclassification of men as diabetic was minimal. The use of self-reported diabetes status also did not separate men with type I diabetes from those with type II diabetes and could result in some misclassification of disease status. However, this may be minimal because a previous study reported that approximately 95% of all diabetes cases in the US population with similar age distribution as in CPS-II and PLCO are type II (29
). Some misclassification could also arise because diabetes status was not updated during the follow-up period. This could potentially reduce the attenuation of the association of the SNPs with prostate cancer when testing whether diabetes status mediated this relationship. However, since few men are likely to be misclassified because of this and there was no attenuation of this association when diabetes status was included in the model, the lack of updating does not appear to influence the conclusions drawn from this study.
In summary, we have shown that the association of the HNF1B
SNPs with prostate cancer is not mediated by diabetes status and that these genetic variants are not responsible for the association of diabetes with reduced prostate cancer risk. We also found that the HNF1B
SNP rs11649743, which represents a distinct locus from the original one associated with prostate cancer (11
), may be associated with increased risk of diabetes. If this association holds up to replication in larger diabetes populations, then there will be two separate loci in the HNF1B
gene associated with both prostate cancer and diabetes. The JAZF1
SNPs associated with prostate cancer are not associated with diabetes. Further research into the functions of the HNF1B and JAZF1 transcription factors and the influence of the relevant SNPs on these functions is needed to clearly define the involvement of these genes in diabetes and prostate cancer.