Abstract
Background
Laboratory studies suggest vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting.
Methods
To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D) (IDS Inc. enzymeimuunoassay) were associated with risk of pancreatic cancer, we performed a pooled analysis of nested case-control studies with 451 cases and 1167 controls from five cohorts through 2008. Median follow-up among controls was 14.1 years in HPFS, 18.3 years in NHS, 25.3 years in PHS, 12.2 years in WHI, and 14.4 years in WHS. Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D.
Results
Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L, P=0.005). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. Participants in quintiles two through five had multivariable-adjusted odds ratios (OR [95% confidence intervals]) of 0.79 (0.56–1.10), 0.75 (0.53–1.06), 0.68 (0.48–0.97), and 0.67 (0.46–0.97); P-trend=0.03), respectively, compared to the bottom quintile. Compared to those with insufficient levels (25[OH]D<50 nmol/L), ORs were 0.75 (0.58–0.98) for subjects with relative insufficiency (25[OH]D 50–<75 nmol/L) and 0.71 (0.52–0.97) for those with sufficient levels (25[OH]D≥75 nmol/L). No increased risk was noted in subjects with 25(OH)D≥100 nmol/L, as suggested in a prior study. In subgroup analyses, ORs for the top versus bottom quartile of 25(OH)D were 0.72 (0.48–1.08) for women, 0.73 (0.40–1.31) for men, and 0.73 (0.51–1.03) for Whites.
Conclusions
Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer.
Impact
Low circulating 25(OH)D may predispose individuals to the development of pancreatic cancer.
Keywords: Pancreatic cancer, Vitamin D, Prospective cohort, Epidemiology
INTRODUCTION
Epidemiologic evidence has suggested that adequate circulating vitamin D is associated with health benefits, leading to proposals to increase vitamin D intake in the general population (1–3). Based principally on studies of bone health, a recent report from the Institute of Medicine recommended dietary intake to achieve circulating 25-hydroxyvitamin D (25[OH]D) of >20 ng/ml (50 nmol/L) (4). Laboratory studies suggest that vitamin D and its analogues may inhibit cancer development and growth, including pancreatic adenocarcinoma (5–7). Despite these data, epidemiologic investigations of vitamin D and incident pancreatic cancer have been inconsistent. Ecological studies of latitude variation and ultraviolet B radiation have suggested a possible inverse relationship between vitamin D and pancreatic cancer risk and mortality (8, 9). Studies of vitamin D intake and predicted vitamin D status have also suggested an association between higher vitamin D and reduced pancreatic cancer risk and mortality (10–12). However, studies evaluating circulating 25(OH)D have been conflicting, with some studies reporting an elevated risk for pancreatic cancer among those with the highest levels of plasma 25(OH)D (13–15).
Given the strong laboratory data and conflicting epidemiologic studies, we prospectively examined the association between plasma 25(OH)D and pancreatic cancer risk in five large cohorts of initially healthy men and women, in which plasma samples were collected prior to cancer diagnosis.
MATERIALS AND METHODS
Study Population
Our study population included pancreatic cancer cases and controls from five large, prospective studies: Health Professionals Follow-Up Study (HPFS), Nurses’ Health Study (NHS), Physicians’ Health Study (PHS), Women’s Health Initiative-Observational Study (WHI), and Women’s Health Study (WHS). HPFS was initiated in 1986 when 51,529 U.S. men aged 40–75 years working as dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, or podiatrists responded to a mailed questionnaire. NHS was established in 1976 when 121,700 female registered nurses aged 30–55 years responded to a mailed questionnaire. The participants in these cohorts have subsequently responded to biennial questionnaires to update exposures and disease diagnoses. PHS is a completed randomized trial initiated in 1982 of aspirin and β-carotene among 22,071 male physicians between 40 and 84 years of age. After completion of the randomized components, study participants were followed as an observational cohort. WHI consists of 93,676 postmenopausal women, aged 50 to 79 years, enrolled between 1994 and 1998. The health of these participants is tracked via annual health forms and clinic visits. WHS is a completed randomized trial initiated in 1992 of low-dose aspirin and vitamin E among 39,876 female professionals 45 years of age or older. The trial was closed in 2004, with all study participants followed as an observational cohort. Further details for these cohorts have been provided previously (HPFS (16), NHS (17), PHS (18), WHI (19), WHS (20)). The study was approved by the Human Research Committee at the Brigham and Women’s Hospital, Boston, MA, and participants provided informed consent.
We included all cases of incident pancreatic adenocarcinoma diagnosed through 2008 with available plasma and no prior history of cancer, except non-melanoma skin cancer. Eligible controls were alive, free of cancer at of the date of the case’s diagnosis, and provided a blood sample. We randomly selected 2 or 3 controls for each case, matching on cohort, year of birth, smoking status, fasting status, and month of blood draw. Median follow-up among controls was 14.1 years in HPFS, 18.3 years in NHS, 25.3 years in PHS, 12.2 years in WHI, and 14.4 years in WHS.
Incident cases of pancreatic cancer were identified by self-report or during follow-up of a participant’s death. Deaths were ascertained from next-of-kin or the postal service and by searching the National Death Index; this method has been shown to capture >98% of deaths (21). For all cases, medical records were reviewed by study physicians blinded to exposure data. Of the 451 pancreatic cancer cases in the analysis, 448 (99.6%) were confirmed by review of medical records, tumor registry data, or death certificates.
Our pooled analysis of nested case-control studies included 501 cases of pancreatic adenocarcinoma and 1175 matched controls from five prospective cohorts. Two cases and five controls were removed due to failure of the assay. One case (and its two matched controls) and one control were removed due to outlier values for 25(OH)D (>300 nmol/L). Due to concern regarding the possible influence of subclinical malignancy on lifestyle choices and plasma 25(OH)D, we excluded 47 cases diagnosed within 2 years of blood draw. To maximize power, matched controls for these cases were maintained in the dataset, resulting in 451 cases and 1167 controls for analysis.
Assessment of Covariates
Individual characteristics and habits were obtained from baseline questionnaires at study enrollment in PHS, WHI, and WHS and from questionnaires preceding the date of blood draw in HPFS and NHS. In all cohorts, data were available for age at blood draw, sex, race/ethnicity, weight, height, smoking status, history of diabetes, multivitamin use, and region of residence. We used body mass index (BMI) as a measure of total adiposity. For HPFS, NHS, WHI, and WHS, energy-adjusted intakes (22) of vitamin D, calcium and retinol were available from validated food frequency questionnaires (23–25).
In HPFS, NHS, and WHI, alcohol intake was calculated in grams/day. In PHS and WHS, participants were asked number of drinks consumed by pre-specified categories. Since 1 standard drink = 13.7 grams of alcohol, harmonized categories included: rarely/never, 1–3 drinks/month, 1–6 drinks/week, and 1+ drinks/day. In HPFS, NHS, WHI, and WHS, physical activity was calculated in metabolic equivalent task-hours/week (MET-hr/week), as previously described and validated.(26, 27) In PHS, participants were asked number of times per week they exercised vigorously (rarely/never, 1–3/month, 1/week, 2–4/week, 5–6/week, 7/week). Assuming a MET score of 6 for vigorous activity and 60-minutes of exercise per episode, we assigned 6 MET-hours for each episode of activity per week to determine the MET-hr/week for PHS participants.
Plasma Samples
Blood samples were collected from 18,225 men in HPFS from 1993–1995, 32,826 women in NHS from 1989–1990, 14,916 men in PHS from 1982–1984, 93,676 women in WHI-OS from 1994–1998, and 28,345 women in WHS from 1992–1995. All blood samples were continuously stored in well-monitored freezers. Details on blood draw procedures, transportation, and storage of plasma samples in these cohorts have been described previously (HPFS (28), NHS (29), PHS (30), WHI (31), WHS (32)).
Plasma levels of 25(OH)D were assayed in the laboratory of Dr. Nader Rifai (Children’s Hospital, Boston, MA), using the Immunodiagnostic Systems (Fountain Hills, AZ) 25-Hydroxyvitamin D enzymeimmunoassay kit, as per manufacturer’s instructions. All samples were handled identically in a single batch and laboratory personnel were blinded to case, control, or quality control sample. The mean intra-assay coefficients of variance were ≤9% for blinded, replicate, quality control samples
Statistical Analysis
Quintiles of 25(OH)D were created from control subjects in all five cohorts jointly and in each cohort separately. In our primary analysis, we computed odds ratios to estimate relative risks and 95% confidence intervals using unconditional logistic regression, since the case-control match was broken due to exclusion of cases with short lag time between blood draw and cancer diagnosis. We also performed conditional logistic regression among all subjects and after exclusion of cases and matched controls with blood drawn within 2, 3, and 5 years of pancreatic cancer diagnosis. Furthermore, we evaluated cohort-specific quintiles by meta-analysis in age-adjusted models, using a random effects model (33). Of note, due to small numbers in one cohort (WHS: 29 cases/69 controls), multivariable adjustment led to an unstable logistic regression model, precluding meta-analysis of the multivariable-adjusted data. To evaluate whether one cohort unduly influenced the pooled results, we conducted a sensitivity analysis, whereby risk estimates were assessed after individually excluding each cohort in turn. Tests for trend using two-sided P-values were calculated by entering the pooled quintile-specific median values for 25(OH)D as a variable in logistic regression models. Given that 25(OH)D was not normally distributed, we also evaluated a “global” trend test by including log-transformed 25(OH)D as a continuous variable in logistic regression models.
By adding each covariate in turn to age-adjusted models, we investigated possible confounders, including sex, cohort, BMI (World Health Organization categories), smoking status (never, past, current), history of diabetes, multivitamin use, physical activity (continuous, MET-hr/wk), alcohol intake (never/rare, 1–3 drinks/month, 1–6 drinks/week, ≥1 drink/day), and total and dietary intakes of calcium (quartiles), retinol (quartiles), and calories (quartiles). In no instance did addition of the covariate change the point estimate of risk by more than 10%. Given that no strong confounders of the relationship between 25(OH)D and pancreatic cancer risk were found, we investigated three models incorporating covariates, as in previous studies (14, 15, 34). The first model adjusted for age. The second adjusted for covariates thought a priori to have the greatest potential for confounding, including age, cohort (which also adjusts for sex), BMI (35), smoking status (36), history of diabetes (37), and multivitamin use (38), plus month of blood draw. The third additionally adjusted for fasting time, physical activity (39), alcohol intake (40), and dietary intakes of calcium (41), retinol (41), and calories (41). In our analysis of multivariable-adjusted quintiles of plasma 25(OH)D and pancreatic cancer risk, no change was noted in risk estimates between the second and third models, so results from the second model are presented.
Although optimal levels of 25(OH)D have not been definitively determined, plasma 25(OH)D <50 nmol/L has been defined as “insufficiency”, 50 to <75 nmol/L as “relative insufficiency”, and ≥75 nmol/L as “sufficient” (42, 43). Therefore, we investigated the risk of pancreatic cancer for relatively insufficient and sufficient subjects compared to insufficient subjects, using the above cut-points. We also investigated risk among subjects with 25(OH)D ≥100 nmol/L, given a previous study suggesting increased risk specifically among these subjects (15).
We assessed the association of pancreatic cancer risk with plasma 25(OH)D in specific subgroups using cohort-specific quartiles of 25(OH)D, given fewer subjects within these subgroups. Since plasma levels of 25(OH)D may differ by race/ethnicity and gender, we performed separate analyses in Whites, men, and women. In stratified analyses, we assessed for statistical interaction, by entering the main effect terms and a cross-product term of the 25(OH)D quintile trend and binary stratification variable into the model, evaluating likelihood ratio tests. We assessed heterogeneity in the association between 25(OH)D and pancreatic cancer risk across the cohorts using Cochran’s Q-statistic (44); the Cochran’s Q-statistic P-value was 0.12 for the comparison of the fifth versus the first quintile of plasma 25(OH)D across the cohorts. All statistical analyses were performed with the SAS 9.1 statistical package (SAS Institute, Cary, North Carolina) and all P-values are two-sided.
RESULTS
Baseline characteristics of controls by quintile of 25(OH)D and by cohort are shown in Table 1 and Supplemental Table 1, respectively. Mean 25(OH)D was 64.5 nmol/L in control subjects and 61.3 nmol/L in case subjects (Wilcoxon rank-sum P=0.005). The global tests for trend were P-trend=0.01 in the age-adjusted logistic regression model and P-trend=0.03 in the multivariable-adjusted model, evaluating log-transformed, continuous 25(OH)D. Compared to participants in the bottom quintile of 25(OH)D, those in the second, third, fourth, and fifth quintiles had multivariable-adjusted odds ratios (OR [95% confidence intervals]) of 0.79 (0.56–1.10), 0.75 (0.53–1.06), 0.68 (0.48–0.97), and 0.67 (0.46–0.97), respectively (Table 2).
Table 1.
Baseline characteristics of nested control subjects by quintile of plasma 25-hydroxyvitamin D
| Characteristic* | Quintiles of Plasma 25(OH)D
|
||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| Median plasma 25(OH)D, nmol/L | 37.3 | 51.7 | 62.2 | 73.9 | 93.7 |
| Range of plasma 25(OH)D, nmol/L | < 45.6 | 45.6 – 56.9 | 56.9 – 66.9 | 66.9 – 81.1 | > 81.1 |
| No. of cases | 117 | 93 | 87 | 79 | 75 |
| No. of controls | 233 | 234 | 233 | 233 | 234 |
| Age, years | 63.0 (9.0) | 63.4 (8.2) | 62.5 (8.1) | 62.7 (8.4) | 60.8 (8.8) |
| Female sex, % | 81.1 | 70.9 | 68.7 | 64.4 | 54.7 |
| Race/ethnicity | |||||
| White, % | 88.0 | 91.0 | 93.1 | 94.4 | 94.0 |
| Black, % | 6.0 | 3.9 | 0 | 0.4 | 0.9 |
| Other/Missing, % | 6.0 | 5.1 | 6.9 | 5.2 | 5.1 |
| Height, inches | 65.4 (3.4) | 66.3 (3.6) | 66.4 (3.6) | 66.4 (3.8) | 67.2 (4.2) |
| Body mass index, kg/m2 | 27.8 (5.4) | 26.3 (4.8) | 25.7 (3.9) | 25.2 (3.8) | 24.6 (3.8) |
| Physical activity, MET-hr/week | 12.8 (18.1) | 15.4 (17.8) | 21.7 (32.6) | 23.1 (28.1) | 24.5 (23.4) |
| Tobacco use | |||||
| Never, % | 42.9 | 42.7 | 44.6 | 45.9 | 39.3 |
| Past, % | 37.8 | 46.2 | 42.1 | 42.1 | 50.0 |
| Current, % | 18.4 | 11.1 | 12.9 | 10.7 | 9.8 |
| Missing, % | 0.9 | 0 | 0.4 | 1.3 | 0.9 |
| History of diabetes mellitus, % | 4.7 | 4.3 | 2.6 | 3.9 | 1.7 |
| Regular multivitamin use, % | 25.3 | 40.2 | 44.6 | 45.1 | 42.3 |
| Total vitamin D intake, IU/day† | 289 (239) | 416 (284) | 424 (274) | 430 (242) | 446 (292) |
| Dietary vitamin D intake, IU/day† | 176 (107) | 221 (145) | 230 (134) | 230 (119) | 232 (120) |
| Total calcium intake, mg/day† | 977 (525) | 1107 (500) | 1196 (585) | 1293 (803) | 1192 (547) |
| Dietary calcium intake, mg/day† | 727 (275) | 784 (305) | 813 (318) | 851 (309) | 839 (308) |
| Total retinol intake, IU/day† | 2814 (3073) | 4440 (4620) | 4460 (5260) | 4552 (4585) | 4370 (4598) |
| Dietary retinol intake, IU/day† | 1526 (982) | 1882 (1335) | 1995 (1701) | 2000 (1595) | 1919 (1333) |
| Total calories, kcal/day† | 1648 (719) | 1738 (632) | 1719 (527) | 1735 (593) | 1702 (565) |
| Alcohol (≥1 drink/day), % | 17.6 | 17.5 | 20.6 | 24.9 | 28.2 |
| Season of blood draw‡ | |||||
| Winter, % | 29.2 | 23.5 | 19.7 | 15.5 | 9.4 |
| Spring, % | 30.9 | 24.8 | 19.3 | 20.1 | 17.1 |
| Summer, % | 15.0 | 26.5 | 25.8 | 29.2 | 35.5 |
| Fall, % | 24.9 | 25.2 | 35.2 | 35.2 | 38.0 |
| Fasting time, hours | 11.2 (4.2) | 10.5 (4.6) | 10.9 (4.3) | 10.0 (4.7) | 9.2 (4.8) |
Continuous variables presented as mean (standard deviation)
Not including PHS participants; data are not available for dietary covariates among PHS participants.
Winter: December, January, February; Spring: March, April, May; Summer: June, July, August; Fall: September, October, November
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; MET-hr/wk, metabolic equivalent task-hours per week; PHS, Physicians’ Health Study
Table 2.
Odds ratios (95% confidence intervals) for pancreatic cancer by quintile of plasma 25-hydroxyvitamin D
| Quintiles of Plasma 25(OH)D
|
P-value, trend† | |||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| Quintiles from all Controls | ||||||
| Range, nmol/L | < 45.64 | 45.64 – 56.92 | 56.93 – 66.94 | 66.95 – 81.05 | > 81.05 | |
| Median, nmol/L | 37.7 | 51.6 | 61.9 | 73.9 | 93.6 | |
| No. of cases/controls | 117/233 | 93/234 | 87/233 | 79/233 | 75/234 | |
| Age-adjusted OR (95% CI) | 1.0 | 0.79 (0.57–1.10) | 0.74 (0.53–1.04) | 0.68 (0.48–0.95) | 0.65 (0.46–0.92) | 0.009 |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.79 (0.56–1.10) | 0.75 (0.53–1.06) | 0.68 (0.48–0.97) | 0.67 (0.46–0.97) | 0.03 |
| Cohort-Specific Quintiles‡ | ||||||
| Median, nmol/L | 37.6 | 51.2 | 61.3 | 73.6 | 93.6 | |
| No. of cases/controls | 114/232 | 95/234 | 85/234 | 79/234 | 78/233 | |
| Age-adjusted OR (95% CI) | 1.0 | 0.83 (0.60–1.15) | 0.74 (0.53–1.03) | 0.68 (0.49–0.96) | 0.69 (0.49–0.97) | 0.02 |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.82 (0.59–1.15) | 0.71 (0.51–1.01) | 0.69 (0.48–0.98) | 0.70 (0.49–1.01) | 0.04 |
Adjusted for age (continuous), cohort (HPFS, NHS, PHS, WHI, WHS; which also adjusts for sex), body mass index (WHO categories), smoking status (never, past, current), history of diabetes mellitus (yes, no), multivitamin use (yes, no), and month of blood draw (2-month intervals).
Cohort-specific quintile ranges of plasma 25(OH)D: HPFS: <53, 53–<63.5, 63.5–<72.8, 72.8–<86.6, ≥86.6; NHS: <47, 47–<58.5, 58.5–<67, 67–<80.5, ≥80.5; PHS: <50, 50–<63.1, 63.1–<75, 75–<89.6, ≥89.6; WHI: <40.4, 40.4–<51.9, 51.9–<61.7, 61.7–<75.2, ≥75.2; WHS: <39, 39–<50, 50–<65, 65–<77, ≥77.
Tests for trend calculated by entering quintile-specific median values for 25(OH)D as a single variable in logistic regression models.
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; OR, odds ratio; PHS, Physicians’ Health Study; WHI, Women’s Health Initiative; WHO, World Health Organization; WHS, Women’s Health Study
In both a pooled analysis of the raw data (Table 2) and a meta-analysis of the risk estimates, this inverse association was highly similar utilizing cohort-specific quintiles. In the meta-analysis, the age-adjusted OR for the fifth versus first quintile of plasma 25(OH)D was 0.70 (0.43–1.14; P-trend=0.03). Finally, the use of conditional logistic regression also resulted in highly similar inverse associations, even after exclusion of cases with successively greater time between blood draw and pancreatic cancer diagnosis and their matched controls (Table 3).
Table 3.
Odds ratios (95% confidence intervals) for pancreatic cancer by quintile of plasma 25-hydroxyvitamin D and time between plasma collection and diagnosis
| Time between Plasma Collection and Cancer Diagnosis | No. of Cases | Quintiles of Plasma 25(OH)D
|
P-value, trend† | ||||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |||
| ≥ 0 years | |||||||
| Age-adjusted OR (95% CI) * | 498 | 1.0 | 0.92 (0.66–1.28) | 0.78 (0.55–1.10) | 0.74 (0.52–1.04) | 0.72 (0.50–1.03) | 0.04 |
| Multivariable-adjusted OR (95% CI)‡ | 1.0 | 0.90 (0.64–1.25) | 0.77 (0.54–1.09) | 0.72 (0.51–1.02) | 0.73 (0.50–1.05) | 0.05 | |
| ≥ 2 years | |||||||
| Age-adjusted OR (95% CI) * | 451 | 1.0 | 0.82 (0.58–1.16) | 0.74 (0.52–1.06) | 0.69 (0.48–0.98) | 0.67 (0.46–0.97) | 0.02 |
| Multivariable-adjusted OR (95% CI) ‡ | 1.0 | 0.80 (0.57–1.14) | 0.74 (0.51–1.06) | 0.68 (0.47–0.98) | 0.67 (0.46–0.99) | 0.03 | |
| ≥ 3 years | |||||||
| Age-adjusted OR (95% CI) * | 417 | 1.0 | 0.84 (0.59–1.22) | 0.79 (0.54–1.14) | 0.70 (0.49–1.02) | 0.69 (0.47–1.02) | 0.04 |
| Multivariable-adjusted OR (95% CI) ‡ | 1.0 | 0.83 (0.57–1.20) | 0.78 (0.54–1.14) | 0.70 (0.48–1.02) | 0.70 (0.47–1.05) | 0.06 | |
| ≥ 5 years | |||||||
| Age-adjusted OR (95% CI) * | 331 | 1.0 | 0.85 (0.56–1.29) | 0.63 (0.42–0.97) | 0.58 (0.38–0.89) | 0.65 (0.42–0.99) | 0.02 |
| Multivariable-adjusted OR (95% CI) ‡ | 1.0 | 0.83 (0.54–1.26) | 0.61 (0.40–0.94) | 0.56 (0.37–0.86) | 0.63 (0.41–0.99) | 0.02 | |
Matched on year of birth, cohort (HPFS, NHS, PHS, WHI, WHS; which also matches for sex), smoking status (never, past, current), fasting status (<8 hours, ≥ 8 hours), month of blood draw, and adjusted for age (continuous).
Matched on year of birth, cohort (HPFS, NHS, PHS, WHI, WHS; which also matches for sex), smoking status (never, past, current), fasting status (<8 hours, ≥ 8 hours), month of blood draw, and adjusted for age (continuous), body mass index (WHO categories), history of diabetes mellitus (yes, no), and multivitamin use (yes, no).
Tests for trend calculated by entering quintile-specificmedian values for 25(OH)D as a single variable in logistic regression models.
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; OR, odds ratio; PHS, Physicians’ Health Study; WHI, Women’s Health Initiative; WHO, World Health Organization; WHS, Women’s Health Study
We next investigated clinically-defined cut-points for 25(OH)D (Table 4) (42, 43). Compared to those with insufficient levels of vitamin D, ORs were 0.75 (0.58–0.98) for those with relative insufficiency and 0.71 (0.52–0.97) for those with sufficient levels. After exclusion of each cohort in turn, ORs for pancreatic cancer were similar comparing those with sufficient levels of 25(OH)D to those with insufficient levels: 0.70 (0.51–0.97) when excluding HPFS, 0.63 (0.45–0.88) when excluding NHS, 0.73 (0.53–1.00) when excluding PHS, 0.77 (0.54–1.11) when excluding WHI, and 0.65 (0.48–0.88) when excluding WHS. Given prior data suggesting a possible elevated risk for pancreatic cancer among subjects with high 25(OH)D (13, 15), we performed an analysis using cutpoints as defined in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (Table 5) (15). No increased risk for pancreatic cancer was noted among subjects with 25(OH)D levels ≥100 nmol/L.
Table 4.
Odds ratios (95% confidence intervals) for pancreatic cancer by clinically-defined cut-points of plasma 25-hydroxyvitamin D
| Clinically-Defined Cut-Points of Plasma 25(OH)D
|
|||
|---|---|---|---|
| Insufficient | Relative Insufficiency | Sufficient | |
| Range | |||
| ng/ml | < 20 | 20 – <30 | ≥ 30 |
| nmol/L | < 50 | 50 – <75 | ≥ 75 |
| No. of cases/controls | 154/317 | 189/524 | 108/326 |
| Age-adjusted OR (95% CI) | 1.0 | 0.74 (0.58–0.96) | 0.69 (0.52–0.93) |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.75 (0.58–0.98) | 0.71 (0.52–0.97) |
Adjusted for age (continuous), cohort (HPFS, NHS, PHS, WHI, WHS; which also adjusts for sex), body mass index (WHO categories), smoking status (never, past, current), history of diabetes mellitus (yes, no), multivitamin use (yes, no), and month of blood draw (2-month intervals).
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; OR, odds ratio; PHS, Physicians’ Health Study; WHI, Women’s Health Initiative; WHO, World Health Organization; WHS, Women’s Health Study
Table 5.
Odds ratios (95% confidence intervals) for pancreatic cancer by cut-points of plasma 25-hydroxyvitamin D and referent group defined by the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
| Plasma 25(OH)D, nmol/L
|
||||||
|---|---|---|---|---|---|---|
| Insufficient | Relative Insufficiency | Sufficient | ||||
|
| ||||||
| < 25 | 25 – <37.5 | 37.5 – <50 | 50 – <75 | 75 – <100 | ≥ 100 | |
| No. of cases/controls | 8/21 | 44/98 | 102/198 | 189/524 | 81/247 | 27/79 |
| Age-adjusted OR (95% CI) | 1.05 (0.46–2.41) | 1.25 (0.84–1.85) | 1.42 (1.07–1.91) | 1.0 (referent) | 0.92 (0.68–1.25) | 0.96 (0.60–1.53) |
| Multivariable-adjusted OR (95% CI)* | 0.97 (0.41–2.29) | 1.23 (0.82–1.86) | 1.41 (1.05–1.90) | 1.0 (referent) | 0.93 (0.69–1.27) | 1.01 (0.63–1.62) |
Adjusted for age (continuous), cohort (HPFS, NHS, PHS, WHI, WHS; which also adjusts for sex), body mass index (WHO categories), smoking status (never, past, current), history of diabetes mellitus (yes, no), multivitamin use (yes, no), and month of blood draw (2-month intervals).
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; OR, odds ratio; PHS, Physicians’ Health Study; WHI, Women’s Health Initiative; WHO, World Health Organization; WHS, Women’s Health Study
Similar inverse associations were noted in analyses limited to women, men, and Whites (Table 6). No statistically significant interaction of 25(OH)D and pancreatic cancer risk was seen by other potential predisposing factors for pancreatic cancer, or by month of blood draw, region of residence, or fasting status (Supplemental Table 2; all P-interaction≥0.18).
Table 6.
Odds ratios (95% confidence intervals) for pancreatic cancer in study subpopulations by quartile of plasma 25-hydroxyvitamin D
| Characteristic | Quartiles of Plasma 25(OH)D‡
|
P-value, trend∫ | |||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | ||
| All | |||||
| Median | 39.6 | 55.4 | 68.3 | 89.3 | |
| No. of cases/controls | 133/290 | 114/292 | 112/292 | 92/293 | |
| Age-adjusted OR (95% CI) | 1.0 | 0.86 (0.63–1.15) | 0.84 (0.62–1.13) | 0.69 (0.51–0.94) | 0.02 |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.85 (0.62–1.15) | 0.83 (0.61–1.13) | 0.70 (0.51–0.98) | 0.04 |
| Whites | |||||
| Median | 39.9 | 55.6 | 68.2 | 89.3 | |
| No. of cases/controls | 114/258 | 102/267 | 99/273 | 87/277 | |
| Age-adjusted OR (95% CI) | 1.0 | 0.87 (0.63–1.20) | 0.82 (0.60–1.13) | 0.72 (0.52–0.99) | 0.04 |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.87 (0.62–1.20) | 0.81 (0.58–1.13) | 0.73 (0.51–1.03) | 0.07 |
| Women† | |||||
| Median | 37.2 | 52.8 | 65.2 | 85.3 | |
| No. of cases/controls | 91/197 | 79/198 | 78/199 | 63/199 | |
| Age-adjusted OR (95% CI) | 1.0 | 0.87 (0.60–1.24) | 0.84 (0.59–1.21) | 0.69 (0.47–1.00) | 0.06 |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.86 (0.59–1.25) | 0.85 (0.58–1.25) | 0.72 (0.48–1.08) | 0.12 |
| Men† | |||||
| Median | 45.2 | 60.8 | 75.0 | 96.0 | |
| No. of cases/controls | 42/93 | 35/94 | 34/93 | 29/94 | |
| Age-adjusted OR (95% CI) | 1.0 | 0.84 (0.49–1.43) | 0.82 (0.48–1.41) | 0.69 (0.40–1.21) | 0.21 |
| Multivariable-adjusted OR (95% CI)* | 1.0 | 0.83 (0.48–1.44) | 0.84 (0.48–1.48) | 0.73 (0.40–1.31) | 0.32 |
Adjusted for age (continuous), cohort (HPFS, NHS, PHS, WHI, WHS; which also adjusts for sex), body mass index (WHO categories), smoking status (never, past, current), history of diabetes mellitus (yes, no), multivitamin use (yes, no), and month of blood draw (2-month intervals).
P-value for interaction by sex = 0.95.
Cohort-specific quartile ranges of plasma 25(OH)D: HPFS: <55.8, 55.8–<66.9, 66.9–<83.4, ≥83.4; NHS: <50.4, 50.4–<62.3, 62.3–<77.3, ≥77.3; PHS: <53.1, 53.1–<67.8, 67.8–<85.9, ≥85.9; WHI: <43.9, 43.9–<57.2, 57.2–<71.2, ≥71.2; WHS: <43.5, 43.5–<56.6, 56.6–<74.2, ≥74.2.
Tests for trend calculated by entering quartile-specific median values for 25(OH)D as a single variable in logistic regression models.
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; OR, odds ratio; PHS, Physicians’ Health Study; WHI, Women’s Health Initiative; WHO, World Health Organization; WHS, Women’s Health Study
DISCUSSSION
In this pooled analysis of five nested case-control studies, we noted a statistically significant inverse association between prediagnostic plasma 25(OH)D and the subsequent risk of pancreatic cancer. A similar inverse relationship was seen across a wide variety of subgroups, including Whites, women, and men. Furthermore, the inverse association was similar regardless of whether blood was drawn in months with low or high ultraviolet light exposure. Analyses of clinically-defined categories of 25(OH)D demonstrated that those subjects with “sufficient” 25(OH)D had an approximate 30% lower risk for pancreatic cancer, compared to those who were vitamin D “insufficient”. No increase in risk for pancreatic cancer was seen among subjects with 25(OH)D ≥100 nmol/L.
Laboratory studies have demonstrated that pancreatic cancer cells express 25(OH)D-1α-hydroxylase (5) which metabolizes 25(OH)D to the active form of 1,25-dihydroxyvitamin D (1,25[OH]2D). These cells also express vitamin D receptors (VDR) (6), which translocate to the nucleus and bind vitamin D response elements to regulate gene expression, upon engagement by 1,25(OH)2D. Thus, VDR-target genes may be regulated locally at the site of a developing cancer, with important implications for cellular proliferation, apoptosis, and angiogenesis (45). Lending support to a role for vitamin D in tumorigenesis, vitamin D and its analogues can slow proliferation of pancreatic cancer cells both in cell culture and in xenograft mouse models (5, 6). Clinical studies are underway to exploit these effects of vitamin D and its analogues in patients with pancreatic cancer (46, 47).
Several epidemiologic approaches have investigated vitamin D and the risk of pancreatic cancer. Ecological studies have suggested an increased risk of pancreatic cancer with greater distance from the equator and lesser exposure to ultraviolet B radiation, both within countries and worldwide (8, 9). A study of vitamin D intake demonstrated a reduced risk for pancreatic cancer in subjects with greater total and dietary vitamin D (10). Two studies have examined the risk of pancreatic cancer in relation to predicted vitamin D status, as calculated using a validated predictive model for plasma level of 25(OH)D (11, 12). This model integrated five independent predictors of plasma 25(OH)D, including race/ethnicity, geographic region, vitamin D intake, body-mass index, and physical activity. In the larger of the two studies (12), the top quintile of predicted 25(OH)D was associated with a relative risk of 0.66 (95% CI, 0.46–0.96), compared with the bottom quintile.
In contrast to the above work, two initial studies examining serum 25(OH)D have generated inconsistent results (13, 14). A nested case-control study of male, Finnish smokers from Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study reported a statistically significant elevated risk of pancreatic cancer among subjects in quintiles 3 and 5 of plasma 25(OH)D, compared to quintile 1 (13). In contrast, a nested analysis of men and women within the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Screening trial demonstrated no statistically significant difference in risk of pancreatic cancer by quintile of plasma 25(OH)D (14). Nevertheless, these studies were relatively small in size (200 cases in ATBC and 184 cases in PLCO).
A pooled analysis has also been performed of 952 pancreatic cancer cases, including subjects previously examined from ATBC and PLCO and cases and controls added from several other prospective cohorts in U.S. and China (15). In contrast to the two previous studies, clinically-defined cut-points were used for 25(OH)D (<25, 25–<37.5, 37.5–<50, 50–<75, 75–<100, ≥100 nmol/L), rather than quintiles, and the referent group consisted of subjects with 25(OH)D levels of 50 to <75 nmol/L. As a result of the post-hoc pooled approach of this study, 25(OH)D was measured in multiple batches and in two separate laboratories. This pooled analysis found no association between circulating 25(OH)D and pancreatic cancer risk. However, in the small subset of subjects with 25(OH)D levels ≥100 nmol/L (39 cases and 30 controls), an increase in the risk of pancreatic cancer was observed (OR, 2.12; 95% CI, 1.23–3.64), when compared to those subjects with 25(OH)D levels between 50 and <75 nmol/L.
In light of these conflicting data, the current study has a number of important strengths. Its prospective design and exclusion of cases diagnosed within 2 years of blood draw greatly reduced the likelihood of bias due to reverse causation. The large number of pancreatic cancer cases and controls from diverse geographic locations across the U.S. allowed for the investigation of a wide spectrum of plasma 25(OH)D values, including subjects with 25(OH)D ≥100 nmol/L. All plasma assays for 25(OH)D were performed in a single batch in a single laboratory, and blinded to any identifiers of case and control status. Furthermore, coefficients of variance were low for repeated measures of quality control samples interspersed within participant samples. Pancreatic cancer cases were rigorously coded, with greater than 99% confirmed by review of medical records, state tumor registries or death certificates. Data on covariates were also rigorously collected from all five cohorts, allowing for robust control of confounding and evaluation of effect modification.
Limitations of the current study include having only a single measure of 25(OH)D. However, we have previously demonstrated a correlation of 0.70 for repeated measures of plasma 25(OH)D within individuals over time (48), suggesting that a single measurement is a reasonable proxy for long-term levels of 25(OH)D. We cannot rule out that our findings may be influenced in part by residual confounding. This may be more likely in an analysis involving multiple cohorts, as not all covariate data are collected identically. However, we evaluated multiple possible confounding covariates and did not observe meaningful changes in our risk estimates. Our sample consisted primarily of White subjects and we did not have adequate power to examine the association of 25(OH)D in non-Whites. Nevertheless, the use of five large cohorts with participants from across the U.S. allows for reasonable generalizability of our results to individuals of European descent. Further studies in non-Whites are warranted.
In this pooled analysis of five nested case-control studies, we observed a statistically significant inverse association between plasma 25(OH)D levels and the subsequent risk of pancreatic cancer. As compared to subjects who were vitamin D insufficient (<50 nmol/L; <20 ng/ml), those with relatively insufficient or sufficient levels (≥50 nmol/L; ≥ 20 ng/ml) experienced an approximate 30% lower risk for pancreatic cancer. In light of the high prevalence of vitamin D insufficiency in the population, further studies should examine whether increasing vitamin D levels impacts the incidence of this highly lethal malignancy.
Supplementary Material
Acknowledgments
Sources of Funding:
The NHS and HPFS are supported by the National Cancer Institute, National Institutes of Health (Grants No. P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908). Brian Wolpin, MD, MPH is supported by NCI K07 CA140790, an American Society of Clinical Oncology Career Development Award, and a Howard Hughes Medical Institute Early Career Physician-Scientist Award.
The PHS is supported by grants CA 97193, CA 34944, CA 40360, HL 26490, and HL 34595 from the National Institutes of Health (Bethesda, MD).
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators is available (49).
The WHS is supported by grants CA047988, HL043851, and HL080467 from the National Institutes of Health (Bethesda, MD).
Role of the Funding Sources:
The sponsors had no role in the design, data collection, data analysis, interpretation, or writing of the report. The authors had full access to all data in the study and had final responsibility for decision to submit for publication.
The authors would like to thank the subjects of the Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative and Women’s Health Study for their participation and steadfast dedication.
Footnotes
Conflicts of Interest: None
References
- 1.Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: global perspective. Ann Epidemiol. 2009;19(7):468–83. doi: 10.1016/j.annepidem.2009.03.021. [DOI] [PubMed] [Google Scholar]
- 2.Guallar E, Miller ER, 3rd, Ordovas JM, Stranges S. Vitamin D supplementation in the age of lost innocence. Ann Intern Med. 2010;152(5):327–9. doi: 10.7326/0003-4819-152-5-201003020-00013. [DOI] [PubMed] [Google Scholar]
- 3.Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007;85(3):649–50. doi: 10.1093/ajcn/85.3.649. [DOI] [PubMed] [Google Scholar]
- 4.Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–8. doi: 10.1210/jc.2010-2704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Schwartz GG, Eads D, Rao A, Cramer SD, Willingham MC, Chen TC, et al. Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. Carcinogenesis. 2004;25(6):1015–26. doi: 10.1093/carcin/bgh086. [DOI] [PubMed] [Google Scholar]
- 6.Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Grant AG. Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. Br J Cancer. 1997;76(8):1017–20. doi: 10.1038/bjc.1997.501. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Persons KS, Eddy VJ, Chadid S, Deoliveira R, Saha AK, Ray R. Anti-growth effect of 1,25-dihydroxyvitamin D3-3-bromoacetate alone or in combination with 5-amino-imidazole-4-carboxamide-1-beta-4-ribofuranoside in pancreatic cancer cells. Anticancer Res. 2010;30(6):1875–80. [PubMed] [Google Scholar]
- 8.Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC. Ultraviolet B irradiance and vitamin D status are inversely associated with incidence rates of pancreatic cancer worldwide. Pancreas. 2010;39(5):669–74. doi: 10.1097/MPA.0b013e3181ce654d. [DOI] [PubMed] [Google Scholar]
- 9.Neale RE, Youlden DR, Krnjacki L, Kimlin MG, van der Pols JC. Latitude variation in pancreatic cancer mortality in Australia. Pancreas. 2009;38(4):387–90. doi: 10.1097/MPA.0b013e31819975f4. [DOI] [PubMed] [Google Scholar]
- 10.Skinner HG, Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Vitamin D intake and the risk for pancreatic cancer in two cohort studies. Cancer Epidemiol Biomarkers Prev. 2006;15(9):1688–95. doi: 10.1158/1055-9965.EPI-06-0206. [DOI] [PubMed] [Google Scholar]
- 11.Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98(7):451–9. doi: 10.1093/jnci/djj101. [DOI] [PubMed] [Google Scholar]
- 12.Bao Y, Ng K, Wolpin BM, Michaud DS, Giovannucci E, Fuchs CS. Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br J Cancer. 2010;102(9):1422–7. doi: 10.1038/sj.bjc.6605658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P, Taylor PR, Virtamo J, et al. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res. 2006;66(20):10213–9. doi: 10.1158/0008-5472.CAN-06-1876. [DOI] [PubMed] [Google Scholar]
- 14.Stolzenberg-Solomon RZ, Hayes RB, Horst RL, Anderson KE, Hollis BW, Silverman DT. Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial. Cancer Res. 2009;69(4):1439–47. doi: 10.1158/0008-5472.CAN-08-2694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, Qi D, Patel AV, Helzlsouer KJ, et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):81–93. doi: 10.1093/aje/kwq120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med. 1995;122(5):327–34. doi: 10.7326/0003-4819-122-5-199503010-00002. [DOI] [PubMed] [Google Scholar]
- 17.Colditz GA, Hankinson SE. The Nurses’ Health Study: lifestyle and health among women. Nat Rev Cancer. 2005;5(5):388–96. doi: 10.1038/nrc1608. [DOI] [PubMed] [Google Scholar]
- 18.Manson JE, Grobbee DE, Stampfer MJ, Taylor JO, Goldhaber SZ, Gaziano JM, et al. Aspirin in the primary prevention of angina pectoris in a randomized trial of United States physicians. Am J Med. 1990;89(6):772–6. doi: 10.1016/0002-9343(90)90220-8. [DOI] [PubMed] [Google Scholar]
- 19.Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M. The Women’s Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol. 2003;13(9 Suppl):S107–21. doi: 10.1016/s1047-2797(03)00047-4. [DOI] [PubMed] [Google Scholar]
- 20.Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294(1):47–55. doi: 10.1001/jama.294.1.47. [DOI] [PubMed] [Google Scholar]
- 21.Rich-Edwards JW, Corsano KA, Stampfer MJ. Test of the National Death Index and Equifax Nationwide Death Search. Am J Epidemiol. 1994;140(11):1016–9. doi: 10.1093/oxfordjournals.aje.a117191. [DOI] [PubMed] [Google Scholar]
- 22.Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol. 1986;124(1):17–27. doi: 10.1093/oxfordjournals.aje.a114366. [DOI] [PubMed] [Google Scholar]
- 23.Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol. 1985;122(1):51–65. doi: 10.1093/oxfordjournals.aje.a114086. [DOI] [PubMed] [Google Scholar]
- 24.Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol. 1992;135(10):1114–26. doi: 10.1093/oxfordjournals.aje.a116211. discussion 27–36. [DOI] [PubMed] [Google Scholar]
- 25.Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women’s Health Initiative food frequency questionnaire. Ann Epidemiol. 1999;9(3):178–87. doi: 10.1016/s1047-2797(98)00055-6. [DOI] [PubMed] [Google Scholar]
- 26.Chasan-Taber S, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E, et al. Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals. Epidemiology. 1996;7(1):81–6. doi: 10.1097/00001648-199601000-00014. [DOI] [PubMed] [Google Scholar]
- 27.Wolf AM, Hunter DJ, Colditz GA, Manson JE, Stampfer MJ, Corsano KA, et al. Reproducibility and validity of a self-administered physical activity questionnaire. Int J Epidemiol. 1994;23(5):991–9. doi: 10.1093/ije/23.5.991. [DOI] [PubMed] [Google Scholar]
- 28.Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros CS. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst. 2005;97(22):1688–94. doi: 10.1093/jnci/dji376. [DOI] [PubMed] [Google Scholar]
- 29.Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, et al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst. 1995;87(17):1297–302. doi: 10.1093/jnci/87.17.1297. [DOI] [PubMed] [Google Scholar]
- 30.Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med. 1989;321(3):129–35. doi: 10.1056/NEJM198907203210301. [DOI] [PubMed] [Google Scholar]
- 31.Anderson GL, Manson J, Wallace R, Lund B, Hall D, Davis S, et al. Implementation of the Women’s Health Initiative study design. Ann Epidemiol. 2003;13(9 Suppl):S5–17. doi: 10.1016/s1047-2797(03)00043-7. [DOI] [PubMed] [Google Scholar]
- 32.Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327–34. doi: 10.1001/jama.286.3.327. [DOI] [PubMed] [Google Scholar]
- 33.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
- 34.Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE, et al. Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer. Cancer Res. 2007;67(16):7923–8. doi: 10.1158/0008-5472.CAN-07-0373. [DOI] [PubMed] [Google Scholar]
- 35.Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies. Int J Cancer. 2007;120(9):1993–8. doi: 10.1002/ijc.22535. [DOI] [PubMed] [Google Scholar]
- 36.Fuchs CS, Colditz GA, Stampfer MJ, Giovannucci EL, Hunter DJ, Rimm EB, et al. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med. 1996;156(19):2255–60. [PubMed] [Google Scholar]
- 37.Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92(11):2076–83. doi: 10.1038/sj.bjc.6602619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Schernhammer E, Wolpin B, Rifai N, Cochrane B, Manson JA, Ma J, et al. Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts. Cancer Res. 2007;67(11):5553–60. doi: 10.1158/0008-5472.CAN-06-4463. [DOI] [PubMed] [Google Scholar]
- 39.Bao Y, Michaud DS. Physical activity and pancreatic cancer risk: a systematic review. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2671–82. doi: 10.1158/1055-9965.EPI-08-0488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Michaud DS, Vrieling A, Jiao L, Mendelsohn JB, Steplowski E, Lynch SM, et al. Alcohol intake and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium (PanScan) Cancer Causes Control. 2010;21(8):1213–25. doi: 10.1007/s10552-010-9548-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Dietary meat, dairy products, fat, and cholesterol and pancreatic cancer risk in a prospective study. Am J Epidemiol. 2003;157(12):1115–25. doi: 10.1093/aje/kwg098. [DOI] [PubMed] [Google Scholar]
- 42.Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–81. doi: 10.1056/NEJMra070553. [DOI] [PubMed] [Google Scholar]
- 43.Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84(1):18–28. doi: 10.1093/ajcn/84.1.18. [DOI] [PubMed] [Google Scholar]
- 44.Cochran WG. The combination of estimates from different experiments. Bio metrics. 1954;10:101–29. [Google Scholar]
- 45.Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005;26(5):662–87. doi: 10.1210/er.2004-0002. [DOI] [PubMed] [Google Scholar]
- 46.Chiang KC, Chen TC. Vitamin D for the prevention and treatment of pancreatic cancer. World J Gastroenterol. 2009;15(27):3349–54. doi: 10.3748/wjg.15.3349. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Blanke CD, Beer TM, Todd K, Mori M, Stone M, Lopez C. Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Invest New Drugs. 2009;27(4):374–8. doi: 10.1007/s10637-008-9184-6. [DOI] [PubMed] [Google Scholar]
- 48.Platz EA, Leitzmann MF, Hollis BW, Willett WC, Giovannucci E. Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer. Cancer Causes Control. 2004;15(3):255–65. doi: 10.1023/B:CACO.0000024245.24880.8a. [DOI] [PubMed] [Google Scholar]
- 49.http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.