Obese men have lower serum prostate-specific antigen (PSA) than comparably aged lean men, but the underlying mechanism remains unclear. The aim of this study was to determine the effect of obesity on PSA and the potential contributing mechanisms. A cohort of 1195 men aged 35 years and over at recruitment, with demographic, anthropometric (BMI, waist circumference (WC)) and serum hormone (serum testosterone, estradiol (E2)) PSA and hematology assessments obtained over two waves was assessed. Men with a history of prostate cancer or missing PSA were excluded, leaving 970 men for the final analysis. Mixed-effects regressions and mediation analyses adjusting for hormonal and volumetric factors explore the potential mechanisms relating obesity to PSA. After adjusting for age, PSA levels were lower in men with greater WC (P = 0.001). In a multivariable model including WC, age, E2/testosterone and PlasV as predictors, no statistically significant associations were observed between with PSA and either WC (P = 0.36) or PlasV (P = 0.49), while strong associations were observed with both E2/testosterone (P < 0.001) and age (P < 0.001). In the mediation analyses with PlasV as the mediator, the average causal mediation effect (ACME) explained roughly 20% of the total effect of WC on PSA (P = 0.31), while when E2/testosterone is a mediator, the ACME explained roughly 50% of the effect (P < 0.001). Our findings indicate that lower PSA levels in obese men, as compared to normal weight men, can be explained both by hormonal changes (elevated E2/testosterone ratio) and hemodilution. Hormonal factors therefore represent a substantial but underappreciated mediating pathway.
Adel T Aref, Andrew D Vincent, Michael E O’Callaghan, Sean A Martin, Peter D Sutherland, Andrew J Hoy, Lisa M Butler and Gary A Wittert
Deborah J Thompson, Tracy A O'Mara, Dylan M Glubb, Jodie N Painter, Timothy Cheng, Elizabeth Folkerd, Deborah Doody, Joe Dennis, Penelope M Webb, for the Australian National Endometrial Cancer Study Group (ANECS), Maggie Gorman, Lynn Martin, Shirley Hodgson, for the National Study of Endometrial Cancer Genetics Group (NSECG), Kyriaki Michailidou, Jonathan P Tyrer, Mel J Maranian, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Peter A Fasching, Alexander Hein, Matthias W Beckmann, Arif B Ekici, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Hui Zhao, Jeroen Depreeuw, Stefanie Schrauwen, Frederic Amant, Ellen L Goode, Brooke L Fridley, Sean C Dowdy, Stacey J Winham, Helga B Salvesen, Jone Trovik, Tormund S Njolstad, Henrica M J Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Luis Carvajal-Carmona, Emma Tham, Tao Liu, Miriam Mints, for RENDOCAS, Rodney J Scott, Mark McEvoy, John Attia, Elizabeth G Holliday, Grant W Montgomery, Nicholas G Martin, Dale R Nyholt, Anjali K Henders, John L Hopper, Nadia Traficante, for the AOCS Group, Matthias Ruebner, Anthony J Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Diether Lambrechts, Jenny Chang-Claude, Fergus J Couch, Graham G Giles, Vessela N Kristensen, Angela Cox, Manjeet K Bolla, Qin Wang, Stig E Bojesen, Mitul Shah, Robert Luben, Kay-Tee Khaw, Paul D P Pharoah, Alison M Dunning, Ian Tomlinson, Mitch Dowsett, Douglas F Easton and Amanda B Spurdle
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (P interaction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
Tracy A O'Mara, Dylan M Glubb, Jodie N Painter, Timothy Cheng, Joe Dennis, The Australian National Endometrial Cancer Study Group (ANECS), John Attia, Elizabeth G Holliday, Mark McEvoy, Rodney J Scott, Katie Ashton, Tony Proietto, Geoffrey Otton, Mitul Shah, Shahana Ahmed, Catherine S Healey, Maggie Gorman, Lynn Martin, National Study of Endometrial Cancer Genetics Group (NSECG), Shirley Hodgson, Peter A Fasching, Alexander Hein, Matthias W Beckmann, Arif B Ekici, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Matthias Dürst, Ingo Runnebaum, Peter Hillemanns, Thilo Dörk, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Hui Zhao, Ellen L Goode, Sean C Dowdy, Brooke L Fridley, Stacey J Winham, Helga B Salvesen, Tormund S Njølstad, Jone Trovik, Henrica M J Werner, Emma Tham, Tao Liu, Miriam Mints, RENDOCAS, Manjeet K Bolla, Kyriaki Michailidou, Jonathan P Tyrer, Qin Wang, John L Hopper, AOCS Group, Julian Peto, Anthony J Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang-Claude, Fergus J Couch, Graham G Giles, Vessela N Kristensen, Angela Cox, Paul D P Pharoah, Alison M Dunning, Ian Tomlinson, Douglas F Easton, Deborah J Thompson and Amanda B Spurdle
Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10−5), which was stronger for cancers of endometrioid subtype (P=3.76×10−6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.