Kimberly A. Bertrand

Correlates of circulating 25-hydroxyvitamin D: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Low vitamin D status is common globally and is associated with multiple disease outcomes. Understanding the correlates of vitamin D status will help guide clinical practice, research, and interpretation of studies. Correlates of circulating 25-hydroxyvitamin D (25(OH)D) concentrations measured in a single laboratory were examined in 4,723 cancer-free men and women from 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, which covers a worldwide geographic area. Demographic and lifestyle characteristics were examined in relation to 25(OH)D using stepwise linear regression and polytomous logistic regression. The prevalence of 25(OH)D concentrations less than 25 nmol/L ranged from 3% to 36% across cohorts, and the prevalence of 25(OH)D concentrations less than 50 nmol/L ranged from 29% to 82%. Seasonal differences in circulating 25(OH)D were most marked among whites from northern latitudes. Statistically significant positive correlates of 25(OH)D included male sex, summer blood draw, vigorous physical activity, vitamin D intake, fish intake, multivitamin use, and calcium supplement use. Significant inverse correlates were body mass index, winter and spring blood draw, history of diabetes, sedentary behavior, smoking, and black race/ethnicity. Correlates varied somewhat within season, race/ethnicity, and sex. These findings help identify persons at risk for low vitamin D status for both clinical and research purposes.

Persistent Organic Pollutants and Type 2 Diabetes: A Prospective Analysis in the Nurses’ Health Study and Meta-analysis

Background: Prospective data regarding persistent organic pollutants (POPs) and risk of type 2 diabetes (T2D) are limited, and the results for individual POPs are not entirely consistent across studies. Objectives: We prospectively examined plasma POP concentrations in relation to incident T2D and summarized existing evidence in a meta-analysis. Methods: Plasma polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) concentrations were measured in 1,095 women who were free of diabetes at blood draw in 1989–1990 and participated in two case–control studies in the Nurses’ Health Study. We identified 48 incident T2D cases through 30 June 2008. We conducted a literature search in PubMed and EMBASE through December 2011 to identify prospective studies on POPs in relation to diabetes. We used a fixed-effects model to summarize results. Results: After multivariable adjustment, plasma HCB concentration was positively associated with incident T2D [pooled odds ratio (OR) 3.59 (95% CI: 1.49, 8.64, ptrend = 0.003) comparing extreme tertiles]. Other POPs were not significantly associated with diabetes. After pooling our results with those of six published prospective studies that included 842 diabetes cases in total, we found that HCB and total PCBs both were associated with diabetes: the pooled ORs were 2.00 (95% CI: 1.13, 3.53; I2 = 21.4%, pheterogeneity = 0.28) and 1.70 (95% CI: 1.28, 2.27; I2 = 16.3%, pheterogeneity = 0.30) for HCB and total PCBs, respectively. Conclusions: These findings support an association between POP exposure and the risk of T2D.

Circulating 25-hydroxyvitamin D and the risk of rarer cancers: design and methods of the Cohort Consortium Vitamin D Pooling Project of rarer cancers

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974–2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50–<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations.

Circulating 25-Hydroxyvitamin D and Risk of Non-Hodgkin Lymphoma Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Case-control studies generally suggesting an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) have led to speculation that vitamin D may protect against lymphomagenesis. To examine this hypothesis, the authors conducted a pooled investigation of circulating 25-hydroxyvitamin D (25(OH)D) and subsequent NHL risk within 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. The authors analyzed measurements from 1,353 cases and 1,778 controls using conditional logistic regression and other methods to estimate the association of 25(OH)D with NHL. No clear evidence of association between categories of 25(OH)D concentration and NHL was observed overall (Ptrend = 0.68) or by sex (men, Ptrend = 0.50; women, Ptrend = 0.16). Findings for other measures (continuous log(25(OH)D), categories of 25(OH)D using sex-/cohort-/season-specific quartiles as cutpoints, categories of season-adjusted residuals of predicted 25(OH)D using quartiles as cutpoints) were generally null, although some measures of increasing 25(OH)D were suggestive of an increased risk for women. Results from stratified analyses and investigations of histologic subtypes of NHL were also null. These findings do not support the hypothesis that elevated circulating 25(OH)D concentration is associated with a reduced risk of NHL. Future research investigating the biologic basis for the sunlight–NHL association should consider alternative mechanisms, such as immunologic effects.

Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses’ Health Study

Objective To examine the association between ultraviolet-B (UV-B) light exposure and rheumatoid arthritis (RA) risk among women in two large prospective cohort studies, the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII). Methods A total of 106 368 women from NHS, aged 30–55 years in 1976, and 115 561 women from NHSII, aged 25–42 in 1989, were included in the analysis. We identified women with incident RA from the start of each cohort until 2008 (NHS) and 2009 (NHSII). Cumulative average UV-B flux, a composite measure of ambient UV exposure based on latitude, altitude and cloud cover, was estimated according to state of residence and categorised as low, medium or high. Estimates of UV-B at birth and age 15 years were also examined. We used multivariable-adjusted Cox proportional hazards models to estimate HR and 95% CI. Results 1314 incident RA cases were identified in total. Among NHS participants, higher cumulative average UV-B exposure was associated with decreased RA risk; those in the highest versus lowest category had a 21% decreased RA risk (HR (95% CI); 0.79 (0.66 to 0.94)). UV-B was not associated with RA risk among younger women in NHSII (1.12 (0.87 to 1.44)). Results were similar for UV-B at birth and at age 15. Conclusions These results suggest that ambient UV-B exposure is associated with a lower RA risk in NHS, but not NHSII. Differences in sun-protective behaviours (eg, greater use of sun block in younger generations) may explain the disparate results.

Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics

Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages <55 years. To provide insight into these associations, we examined the components of PMD [dense area (DA) and nondense area (NDA)] with breast cancer subtypes. Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression. Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend <0.001] and NDA was associated with decreased risk [ORs for quartiles: 1.39, 1.00 (Ref), 0.88, 0.72; Ptrend <0.001] across all ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (Ptrend < 0.001) but no differences by nodal status. Among women <55 years, DA was more strongly associated with increased risk of ER+ versus ER− tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER− versus ER+ tumors (Phet = 0.03). Conclusions: DA and NDA have differential associations with ER+ versus ER− tumors that vary by age. Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.

Predicted Plasma 25-Hydroxyvitamin D and Risk of Renal Cell Cancer

BACKGROUND Although the kidney is a primary organ for vitamin D metabolism, the association between vitamin D and renal cell cancer (RCC) remains unclear. METHODS We prospectively evaluated the association between predicted plasma 25-hydroxyvitamin D [25(OH)D] and RCC risk among 72,051 women and 46,380 men in the period from 1986 to 2008. Predicted plasma 25(OH)D scores were computed using validated regression models that included major determinants of vitamin D status (race, ultraviolet B flux, physical activity, body mass index, estimated vitamin D intake, alcohol consumption, and postmenopausal hormone use in women). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. All statistical tests were two-sided. RESULTS During 22 years of follow-up, we documented 201 cases of incident RCC in women and 207 cases in men. The multivariable hazard ratios between extreme quintiles of predicted 25(OH)D score were 0.50 (95% CI = 0.32 to 0.80) in women, 0.59 (95% CI = 0.37 to 0.94) in men, and 0.54 (95% CI = 0.39 to 0.75; P trend < .001) in the pooled cohorts. An increment of 10 ng/mL in predicted 25(OH)D score was associated with a 44% lower incidence of RCC (pooled HR = 0.56, 95% CI = 0.42 to 0.74). We found no statistically significant association between vitamin D intake estimated from food-frequency questionnaires and RCC incidence. CONCLUSION Higher predicted plasma 25(OH)D levels were associated with a statistically significantly lower risk of RCC in men and women. Our findings need to be confirmed by other prospective studies using valid markers of long-term vitamin D status.

Body fatness during childhood and adolescence and breast density in young women: a prospective analysis

IntroductionOverweight and obesity in childhood and adolescence are associated with reduced breast cancer risk, independent of adult body mass index (BMI). These associations may be mediated through breast density.MethodsWe prospectively examined associations of early life body fatness with adult breast density measured by MRI in 182 women in the Dietary Intervention Study in Children (DISC) who were ages 25–29 at follow-up. Height, weight, and other factors were measured at baseline (ages 8–10) and annual clinic visits through adolescence. We used linear mixed-effects models to quantify associations of percent breast density and dense and non-dense breast volume at ages 25–29 with quartiles of age-specific youth body mass index (BMI) Z-scores, adjusting for clinic, treatment group, current adult BMI, and other well-established risk factors for breast cancer and predictors of breast density.ResultsWe observed inverse associations between age-specific BMI Z-scores at all youth clinic visits and percent breast density, adjusting for current adult BMI and other covariates (all p values <0.01). Women whose baseline BMI Z-scores (at ages 8–10 years) were in the top quartile had significantly lower adult breast density, after adjusting for current adult BMI and other covariates [least squares mean (LSM): 23.4 %; 95 % confidence interval (CI): 18.0 %, 28.8 %] compared to those in the bottom quartile (LSM: 31.8 %; 95 % CI: 25.2 %, 38.4 %) (p trend <0.01). Significant inverse associations were also observed for absolute dense breast volume (all p values <0.01), whereas there were no clear associations with non-dense breast volume.ConclusionsThese results support the hypothesis that body fatness during childhood and adolescence may play an important role in premenopausal breast density, independent of current BMI, and further suggest direct or indirect influences on absolute dense breast volume.Clinical Trials Registration NumberNCT00458588; April 9, 2007

Metabolic Syndrome and Mammographic Density in Mexican Women

Metabolic syndrome has been associated with an increased risk of breast cancer; however, little is known about the association between metabolic syndrome and percent mammographic density, a strong predictor of breast cancer. We analyzed cross-sectional data from 789 premenopausal and 322 postmenopausal women in the Mexican Teachers Cohort (ESMaestras). Metabolic syndrome was defined according to the harmonized definition. We measured percent density on mammograms using a computer-assisted thresholding method. Multivariable linear regression was used to estimate the association between density and metabolic syndrome, as well as its components by state (Jalisco, Veracruz) and menopausal status (premenopausal, postmenopausal). Among premenopausal women in Jalisco, women with metabolic syndrome had higher percent density than those without after adjusting for potential confounders including BMI [difference = 4.76; 95% confidence interval (CI), 1.72–7.81]. Among the metabolic syndrome components, only low high-density lipoprotein levels (<50 mg/dL) were associated with significantly higher percent density among premenopausal women in Jalisco (difference = 4.62; 95% CI, 1.73–7.52). Metabolic syndrome was not associated with percent density among premenopausal women in Veracruz (difference = −2.91; 95% CI, −7.19 to 1.38), nor among postmenopausal women in either state. Metabolic syndrome was associated with higher percent density among premenopausal women in Jalisco, Mexico, but was not associated with percent density among premenopausal women in Veracruz, Mexico, or among postmenopausal women in either Jalisco or Veracruz. These findings provide some support for a possible role of metabolic syndrome in mammographic density among premenopausal women; however, results were inconsistent across states and require further confirmation in larger studies. Cancer Prev Res; 6(7); 701–10. ©2013 AACR.

Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

Background Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. Methods and findings We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35–85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (–0.46 cm [95% CI: −0.53, −0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was −0.24 cm (95% CI: −0.34, −0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (−0.38 cm [95% CI: −0.44, −0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. Conclusions Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction.