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Background Studies suggest obesity is associated with decreased prostate cancer risk. We hypothesized obesity is biologically associated with increased risk, though this is obscured due to hemodilution of PSA and larger prostate size. Methods Retrospective study of 441 consecutive men undergoing prostate biopsy between 1999 and 2003 at two equal access centers. The association between obesity (body mass index ≥30 kg/m2) and positive biopsy and Gleason ≥4+3 were estimated using logistic regression analysis adjusting for multiple clinical characteristics. Results 123 men (28%) were obese and 149 men (34%) had cancer. Median PSA and age were 5.7 ng/ml and 63.9 years. Obese men had significantly lower PSA concentrations (p=0.02) and larger prostate volumes (p=0.04). Obesity was not significantly related to age (p=0.19) or race (p=0.37). On univariate analysis, obesity was not associated with prostate cancer risk (OR 1.13, 95% CI 0.73–1.75, p=0.58). However, after adjusting for multiple clinical characteristics, obesity was associated with significantly increased prostate cancer risk (OR 1.98, 95% CI 1.17–3.32, p=0.01). After multivariable adjustment, there was no significant association between obesity and high-grade disease (p=0.18). Conclusions Without adjustment for clinical characteristics, obesity was not significantly associated with prostate cancer risk in this equal access clinic-based population. However, after adjusting for the lower PSA levels and the larger prostate size, obesity was associated with a 98% increased prostate cancer risk. These findings support the fact current prostate cancer screening practices may be biased against obese men.

APOA1 is the most abundant protein in HDL. It modulates interactions that affect HDL's cardioprotective functions, in part via its activation of the enzyme, LCAT. On nascent discoidal HDL, APOA1 comprises 10 α-helical repeats arranged in an anti-parallel stacked-ring structure that encapsulates a lipid bilayer. Previous chemical cross-linking studies suggested that these APOA1 rings can adopt at least two different orientations, or registries, with respect to each other; however, the functional impact of these structural changes is unknown. Here, we placed cysteine residues at locations predicted to form disulfide bonds in each orientation and then measured APOA1's ability to adopt the two registries during HDL particle formation. We found that most APOA1 oriented with the fifth helix of one molecule across from fifth helix of the other (5/5 helical registry), but a fraction adopted a 5/2 registry. Engineered HDLs that were locked in 5/5 or 5/2 registries by disulfide bonds equally promoted cholesterol efflux from macrophages, indicating functional particles. However, unlike the 5/5 registry or the WT, the 5/2 registry impaired LCAT cholesteryl esterification activity ( < 0.001), despite LCAT binding equally to all particles. Chemical cross-linking studies suggest that full LCAT activity requires a hybrid epitope composed of helices 5-7 on one APOA1 molecule and helices 3-4 on the other. Thus, APOA1 may use a reciprocating thumbwheel-like mechanism to activate HDL-remodeling proteins.