Alison M. Mondul

Genome-wide association study of circulating vitamin D levels

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses’ Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10−5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

Genome-wide association study identifies new prostate cancer susceptibility loci

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.

Meat consumption among black and white men and risk of prostate cancer in the cancer prevention study II nutrition cohort

Previous epidemiologic studies have suggested that intake of red meat may be associated with increased risk of prostate cancer. Few studies, however, have examined these associations by race. We examined intake of red meat, processed meat, and poultry in relation to incident prostate cancer among Black and White men in the Cancer Prevention Study II Nutrition Cohort. Participants in the study completed a detailed questionnaire on diet, medical history, and lifestyle in 1992 to 1993. After excluding men with a history of cancer and incomplete dietary information, 692 Black and 64,856 White men were included in the cohort. During follow-up through August 31, 2001, we documented 85 and 5,028 cases of incident prostate cancer among Black and White men, respectively. Cox proportional hazards models were used to estimate rate ratios (RR) and 95% confidence intervals (95% CI). No measure of meat consumption was associated with risk of prostate cancer among White men. Among Black men, total red meat intake (processed plus unprocessed red meat) was associated with higher risk of prostate cancer (RR, 2.0; 95% CI, 1.0-4.2 for highest versus lowest quartile; Ptrend = 0.05); this increase in risk was mainly due to risk associated with consumption of cooked processed meats (sausages, bacon, and hot dogs; RR, 2.7; 95% CI, 1.3-5.3 for highest versus lowest quartile; Ptrend = 0.008). This study suggests that high consumption of cooked processed meats may contribute to prostate cancer risk among Black men in the United States.(Cancer Epidemiol Biomarkers Prev 2006;15(2):211–6)

Serum 25-Hydroxy Vitamin D and Prostate Cancer Risk in a Large Nested Case-Control Study

Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations. Methods: The 25-hydroxy vitamin D [25(OH)D]–prostate cancer relation was examined in a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (±1 year) and fasting blood collection date (±30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided. Results: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95–1.74), 1.34 (1.00–1.80), 1.26 (0.93–1.72), and 1.56 (1.15–2.12), with Ptrend = 0.01. Analyses based on prespecified clinical categories and season-adjusted values yielded similar results. These findings seemed stronger for aggressive disease [OR (95% CI) for fifth quintile of serum 25(OH)D [1.70 (1.05–2.76), Ptrend = 0.02], among men with greater physical activity [1.85 (1.26–2.72), Ptrend = 0.002], higher concentrations of serum total cholesterol [2.09 (1.36–3.21), Ptrend = 0.003] or α-tocopherol [2.00 (1.30–3.07), Ptrend = 0.01] and higher intakes of total calcium [1.82 (1.20–2.76), Ptrend = 0.01] or vitamin D [1.69 (1.04–2.75), Ptrend = 0.08], or among those who had received the trial α-tocopherol supplements [1.74 (1.15–2.64), Ptrend = 0.006]. Conclusion: Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer. Impact: Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels. Cancer Epidemiol Biomarkers Prev; 20(9); 1850–60. ©2011 AACR.

Cigarette Smoking and Prostate Cancer Recurrence After Prostatectomy

Toward the establishment of evidence-based recommendations for the prevention of prostate cancer recurrence after treatment, we examined the association between smoking and prostate cancer recurrence in a retrospective cohort study of 1416 men who underwent radical prostatectomy. Surgeries were performed by a single surgeon at Johns Hopkins Hospital between January 1, 1993, and March 31, 2006. Smoking status at 5 years before and 1 year after surgery was assessed by survey. Prostate cancer recurrence was defined as confirmed re-elevation of prostate-specific antigen levels, local recurrence, metastasis, or prostate cancer death. The cumulative incidence of recurrence was 34.3% among current smokers, 14.8% among former smokers, and 12.1% among never smokers, with a mean follow-up time of 7.3 years. Men who were current smokers at 1 year after surgery were more likely than never smokers to have disease recurrence after adjusting for pathological characteristics, including stage and grade (hazard ratio for recurrence = 2.31, 95% confidence interval = 1.05 to 5.10). This result suggests an association between cigarette smoking and risk of prostate cancer recurrence.

Dietary fat, fatty acids, and risk of prostate cancer in the NIH-AARP diet and health study.

Background: Observational studies report inconsistent associations of fat and fatty acids with prostate cancer. Methods: We investigated associations between dietary fats and fatty acids and risk of prostate cancer in the NIH-American Association of Retired Persons (AARP) Diet and Health Study. Diet was assessed at baseline with self-administered food-frequency questionnaires. Cases were determined by linkage with state cancer registries. HR and 95% confidence intervals (CI) were estimated with Cox proportional hazards models. Results: Among 288,268 men with average follow-up of nine years, 23,281 prostate cancer cases (18,934 nonadvanced and 2,930 advanced including 725 fatal cases) were identified. Total fat and mono- and polyunsaturated fat intakes were not associated with incidence of prostate cancer. Saturated fat intake was related to increased risk of advanced prostate cancer (HRQuintile 5 vs. Qunitile 1 (Q1 vs. Q5), 1.21; 95% CI, 1.00–1.46; Ptrend = 0.03) and fatal prostate cancer (HRQ5 vs. Q1, 1.47; 95% CI, 1.01–2.15; Ptrend = 0.04). α-Linolenic acid (ALA) intake was related to increased risk of advanced prostate cancer (HRQ5 vs. Q1, 1.17; 95% CI, 1.04–1.31; Ptrend = 0.01). Eicosapentanoic acid (EPA) intake was related to decreased risk of fatal prostate cancer (HRQ5 vs. Q1, 0.82; 95% CI, 0.64–1.04; Ptrend = 0.02). Conclusion: Our study suggests that the associations of fat and fatty acids differ by prostate cancer severity. Saturated fat, ALA, and EPA intakes were related to the risk of advanced or fatal prostate cancer but not to nonadvanced prostate cancer. Impact: Identifying factors associated with advanced prostate cancer could reduce morbidity and mortality. Cancer Epidemiol Biomarkers Prev; 22(4); 697–707. ©2013 AACR.

Body Fatness and Markers of Thyroid Function among U.S. Men and Women

Background We evaluated the association of central versus overall adiposity on levels of thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) among euthyroid subjects taken from a cross-sectional, representative sample of the adult non-institutionalized U.S. population. Methods The National Health and Nutrition Examination Survey 2007–2008 included 1,623 men and 1,491 women who were 20 years and older, with no history of thyroid or liver disease, kidney failure, diabetes, or thyroid function-altering prescription medication use (based on self-report), and having TSH, fT3, and fT4 levels between 0.5–4.49 mIU/L, 2.5–3.9 pg/mL, and 0.6–1.6 ng/dL, respectively. Associations between body mass index (BMI) and waist circumference (measures of overall and central adiposity, respectively) and TSH, fT3, and fT4 levels were estimated using multivariable linear regression models stratified by sex and adjusted for age, race, smoking status, and alcohol intake. Results An increase in serum TSH levels was observed for every 1-quartile increase in BMI in euthyroid men (3.8% [95% CI 0.8%, 6.8%]) and euthyroid women (4.0% [95% CI 1.6%, 6.5%]). Similar, albeit slightly weaker, associations were observed with waist circumference. We also found increases in fT3 levels with every 1-quartile increase in BMI (1.0% in men and 1.3% in women) and waist circumference (1.2% in men and 1.2% in women). No associations were observed with fT4. Conclusions Our results provide support that BMI and waist circumference are positively associated with levels of serum TSH and f T3 but not fT4 among euthyroid adults. Longitudinal studies are needed to define the temporality of these associations and their potential health implications.

Genome-wide association study identifies common variants associated with circulating vitamin E levels

In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10−8) and rs11057830 on 12q24.31 (P= 2.0 × 10−8) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10−10). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10−12 (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10−10 (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10−9 (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P< 1 × 10−4 identified.

Weight gain is associated with an increased risk of prostate cancer recurrence after prostatectomy in the PSA era

Although obesity at the time of prostatectomy has been associated with prostate cancer recurrence, it is unknown whether obesity before or after surgery, or weight change from the years prior to surgery to after surgery is associated with recurrence. Thus, we examined the influence of obesity and weight change on recurrence after prostatectomy. We conducted a retrospective cohort study of 1,337 men with clinically localized prostate cancer who underwent prostatectomy performed during 1993–2006 by the same surgeon. Men self-reported weight and physical activity at 5 years before and 1 year after surgery on a survey during follow-up. Mean follow-up was 7.3 years. We estimated multivariable-adjusted HRs of prostate cancer recurrence comparing obesity at 5 years before and at 1 year after surgery with normal weight, and a gain of more than 2.2 kg from 5 years before to 1 year after surgery with stable weight. During 9,797 person years of follow-up, 102 men recurred. Compared with men who had stable weight, those whose weight increased by more than 2.2 kg had twice the recurrence risk (HR = 1.94; 95% CI, 1.14–3.32) after taking into account age, pathologic stage and grade, and other characteristics. The HR of recurrence was 1.20 (95% CI, 0.64–2.23) and 1.72 (95% CI, 0.94–3.14) comparing obesity at 5 years before and at 1 year after surgery, respectively, with normal weight. Physical activity (≥5 h/wk) did not attenuate risk in men who gained more than 2.2 kg. By avoiding weight gain, men with prostate cancer may both prevent recurrence and improve overall well-being. Cancer Prev Res; 4(4); 544–51. ©2011 AACR.

Serum Vitamin D and Risk of Bladder Cancer

Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH)D; i.e., <25, 25 to <37.5, 37.5 to <50, ≥50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (versus ≥50 nmol/L; <25 nmol/L: OR, 1.73; 95% CI, 1.03-2.91; 25 to <37.5 nmol/L: OR, 1.81; 95% CI, 1.05-3.14; 37.5 to <50 nmol/L: OR, 1.76; 95% CI, 1.02-3.02; P trend=0.04). Similarly, increased risks for the lowest vitamin D category were observed when season-specific quartiles were used (Q1 versus Q4: OR, 1.63; 95% CI, 0.96-2.75; P trend=0.03). In this prospective study of male smokers, lower serum 25(OH)D was associated with an increased risk of bladder cancer. Future studies should examine the association in other populations, especially nonsmokers and women.