https://orcid.org/0000-0002-3834-1535
Figures
Abstract
Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component). We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariable-adjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform. Separately, the GC-cancer risk association was examined using proportional hazards regression among 109,746 individuals with genetic data and 26,713 diagnosed with cancer. Specific vitamin D binding protein isoform subtypes were delineated and analyzed, including Gc1-1 subtypes (Gc1s-Gc1s, Gc1f-Gc1s, and Gc1f-Gc1f) and Gc2 subtypes (Gc1s-Gc2, Gc1f-Gc2, and Gc2-Gc2). For most cancers, the GC genotype did not modify the risk associations for 25(OH)D; e.g., the OR for high vs. low vitamin D quintile was 1.09 (0.89–1.33) for overall cancer risk among individuals with the Gc1-1 isoform and 1.04 (0.83–1.31) among those with either the Gc1-2 or Gc2-2 isoforms. ORs for high compared to low vitamin D tertile for colorectal, lung, breast, and prostate cancer among those with the Gc1-1 vs. any Gc2 isoforms were, respectively, 0.60 vs. 0.73, 1.96 vs. 1.03, 1.30 vs. 1.18, and 1.19 vs. 1.22 (all p-interaction ≥0.36). However, GC qualitatively modified the vitamin D-bladder cancer risk association: OR = 1.70 (95% CI 0.96–2.98) among those with the Gc1-1 isoform and 0.52 (0.28–0.96) among those with any Gc2 isoforms (p-interaction = 0.03). When modeled without regard for 25(OH)D, Gc isoforms were generally not associated with cancer risk, although melanoma risk was significantly lower among individuals with the “f” subtype of the Gc1-1 isoform, specifically HR = 0.83 (95% CI 0.70–0.98) for Gc1f-1s and 0.67 (0.45–1.00) for Gc1f-1f, compared to individuals with the Gc1s-Gc1s isoform. Vitamin D binding protein genetic isoforms may be associated with melanoma risk but do not modify the association between vitamin D status and cancer, with the possible exception of bladder cancer.
Citation: Weinstein SJ, Parisi D, Mondul AM, Layne TM, Huang J, Stolzenberg-Solomon RZ, et al. (2024) Vitamin D binding protein genetic isoforms, serum vitamin D, and cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. PLoS ONE 19(12): e0315252. https://doi.org/10.1371/journal.pone.0315252
Editor: Michal Zmijewski, Medical University of Gdańsk, POLAND
Received: July 15, 2024; Accepted: November 21, 2024; Published: December 20, 2024
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: To protect the personal health information of participants within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), data are only available through the PLCO Cancer Data Access System. PLCO data can be shared via this proposal submission and approval process system and after an appropriate Data Transfer Agreement is in place. Instructions to request access to PLCO data and specimens can be found here: https://cdas.cancer.gov/learn/plco/instructions/. Note that cancer data collected via certain state cancer registries are not permitted to be shared outside of NCI as required by those registries. Access to genotyping data can be requested here: https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs001286.v3.p2.
Funding: The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The genetics work by the Cancer Genomics Research Laboratory was funded under NCI Contract No. 75N910D00024.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Vitamin D has been extensively examined in regard to cancer risk. Studies suggest that higher circulating 25-hydroxyvitamin concentrations [25(OH)D, the accepted biomarker of vitamin D status] are associated with lower risk of colorectal cancer [1], but not breast [2] or lung cancer [3], or cancer at other sites [4–9], and may be associated with higher risk of prostate cancer [10]. Vitamin D binding protein is responsible for the transport of vitamin D and its metabolites through the circulation [11], and two single nucleotide polymorphisms (SNPs), rs7041 and rs4588 [12], define three isoforms: Gc1s, Gc1f, and Gc2. (Vitamin D binding protein was originally known as “group-specific component” or Gc, the acronym its encoding gene retains.) The affinity of vitamin D binding protein for 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D, the active form of vitamin D] varies by isoform, with Gc1f having the strongest affinity, Gc2 having the weakest, and Gc1s having intermediate affinity [11]. This results in differences in actual concentrations of 25(OH)D and 1,25(OH)2D, with highest concentrations found for Gc1-1, intermediate for Gc1-2, and lowest for Gc2-2 [13, 14]. We recently showed in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial that associations between vitamin D and both overall cancer survival and lung cancer survival were modified by Gc isoforms such that circulating vitamin D was associated with increased survival only for those cases with the Gc2 isoform [15]. A similar pattern was noted by Gibbs et al. for colorectal adenoma and cancer risk, as well as for colorectal cancer mortality [16–18] and for vitamin D supplementation and colorectal adenoma recurrence [19], and by another group for vitamin D intake and colorectal cancer risk [20]. However, data from three other studies did not find effect modification of the vitamin D-cancer association by Gc isoform for colorectal [21, 22] or breast cancer [12], and associations with other sites are unknown. Therefore, the rationale for this analysis was to examine the genetic influence of GC, which encodes the vitamin D binding protein, on the risk of cancer overall and multiple specific organ sites, and to further assess whether GC acts as an effect modifier of the relationship between circulating vitamin D and overall and site-specific cancer risk. Accordingly, we examined whether Gc isoforms modify the association between serum 25(OH)D and site-specific and overall cancer risk within the PLCO Trial.
Materials and methods
Study population
The PLCO Trial was a randomized trial of prostate, lung, colorectal, and ovarian cancer screening conducted within 10 centers in the United States from November 16, 1993 to July 2, 2001. Men and women (n = 154,987) aged 55–74 years completed a self-administered questionnaire at baseline, which gathered information on sociodemographic and risk factor characteristics including age, race, ethnicity, height, weight, smoking history, family history of cancer, and personal medical history. Non-fasting serum samples were collected and stored at –70°C. Written informed consent was obtained from each participant and the PLCO Trial was approved by the Institutional Review Boards of the National Cancer Institute and the 10 PLCO centers [23–25].
Only participants with available genetic data (n = 109,746) were included in this analysis. Of these, 26,713 had a cancer diagnosis during follow-up. The majority of the analyses conducted here used a subset of participants (n = 7,651) with both available genetic data and previously measured circulating vitamin D in nested matched case-control sets [3–6, 8, 9, 24, 26–30]. These included the following cancer sites, listed here first with their total number of cases and then the number of cases with both available circulating vitamin D and genotype data: biliary (195/NA), bladder (1,223/342), breast (4,013/862), male breast (40/NA), colorectum (2,322/416), endometrium (838/135), glioma (306/NA), hematopoietic cancer (3,660/278), head and neck (689/NA), kidney (983/145), liver (305/NA), lung (3,394/389), melanoma (1,389/NA), ovary (515/58), pancreas (865/194), prostate (8282/912), thyroid (380/NA), and upper gastrointestinal tract (646/75).
Cancer diagnoses and control selection
Incident cancer cases were identified through 2017 using a variety of methods including linkage to state cancer registries, physician reports, death certificates, self-report, and/or next-of-kin report. Trained medical record specialists confirmed the diagnoses with medical record abstractions. For the vitamin D nested sets, censor dates for cancer diagnoses varied, as listed in the original reports [3–6, 8, 9, 24, 26–31].
All nested case-control sets were matched on age (+/- 1 year, +/- 5 years, or 5-year intervals) and sex (or were only one sex). For race, one prostate case-control set included only non-Hispanic white participants [24] and another included only non-Hispanic black participants (1:2 case:control ratio) [27]. All but two [3, 26] of the remaining studies were matched on race, and all but two [24, 26] were matched on date of blood collection (+/- 30 days or 2-month blocks).
Vitamin D status
Circulating 25(OH)D was measured using radioimmunoassay (for breast, prostate among non-Hispanic white individuals, and 76% of the pancreas set) [32, 33], liquid chromatography/mass spectrometry (for prostate among non-Hispanic black individuals and lung) [27, 34] and chemiluminescence immunoassay (all other case-control sets including the remaining pancreas set) [35]. Coefficients of variation ranged from 3.7%-13.2% [3–6, 8, 9, 24, 26–31].
Genotyping
Genotyping was conducted using Illumina arrays and imputed against the TopMed reference panel 5b through the Michigan Imputation Server. All imputed genotypes were converted to the bgen v1.2 format with plink2. Imputed genotypes (range 0–2) for the vitamin D binding protein SNPs rs7041 and rs4588 were converted to categorical variables (i.e., 0, 1, 2) using cutpoints <0.15, >0.85 & <1.15, and >1.85, respectively. Values outside these ranges were excluded and only participants with data for both SNPs were used in the analyses. S1 Table displays how cross tabulations of rs4588 and rs7041 define the six vitamin D binding protein Gc isoforms (Gc1s-Gc1s, Gc1f-Gc1s, Gc1f-Gc1f, Gc1s-Gc2, Gc1f-Gc2, and Gc2-Gc2.) Empty cells indicate rare combinations not found in our data. Across the rows, “Gc1-1” includes isoforms with only Gc1 (i.e., Gc1s-Gc1s, Gc1f-Gc1s, or Gc1f-Gc1f), “Gc1-2” includes Gc1s-Gc2 and Gc1f-Gc2 and “Gc2” includes only Gc2-2. The term “any Gc2” means having any Gc2 isoform, i.e., Gc1s-Gc2, Gc1f-Gc2, or Gc2-Gc2. Results for the gene-only analyses with over 100,000 participants are presented for each of the six isoforms separately, while results for the analyses using the vitamin D data (n = 7,651) are presented with the isoforms collapsed as Gc1-1, Gc1-2, and Gc2-2 because of the smaller number.
Statistical analysis
For analyses among the 109,746 participants with GC SNP data, cases were defined based on the 2017 cancer incidence censor date. For analyses including circulating 25(OH)D data, cases and controls were defined as they were when originally selected for each nested case-control set. Characteristics of cancer cases vs. controls were compared using Wilcoxon rank sum tests (for continuous variables) and chi-square tests (for categorical variables). Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for vitamin D quantiles, stratified by GC SNP, and adjusted for factors potentially associated with cancer risk including age at randomization, sex, race, body mass index (BMI), smoking status, physical activity, history of diabetes, and family history of cancer. The lung cancer models were additionally adjusted for cigar smoking, pipe smoking, and packyears of cigarette smoking. Using separate smoking duration and intensity variables in the lung cancer model or adding the smoking-related covariates to the overall cancer models did not materially change the risk estimates. The breast, endometrial, and ovarian cancer models were additionally adjusted for parity, duration of oral contraceptive use, and menopausal status/duration of menopausal hormone use, but these covariate adjustments did not materially change the risk estimates and were therefore not retained. Vitamin D quintiles were calculated separately for each cancer site by sex and season (December–May vs. June–November) and merged for the overall cancer model. For the organ-specific models, due to small samples sizes in the Gc2 strata, vitamin D was categorized into tertiles and Gc1-2 and Gc2-2 groups were combined to produce more stable risk estimates. See S2 and S3 Tables for quintile and tertile cut points, respectively. Persons with missing BMI were assigned the median BMI value and missing codes were included for categorical variables.
Tests for linear trend were conducted by coding each category either 1–5 (for quintiles) or 1–3 (for tertiles) and treating these as continuous variables. The log-likelihood test was used to statistically evaluate effect modification of the Gc isoform on the vitamin D/cancer association, by comparing models with and without a cross-product term of the vitamin D quantiles (n = 5 or n = 3) and the Gc isoform (n = 2 or n = 3 categories).
Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs to examine the association between the Gc SNPs and cancer risk, without regard to circulating vitamin D (total n = 109,746, n with cancer = 26,713). Models were adjusted for the same factors as above, except for physical activity which was only ascertained in the screening arm of the trial. Because 2.8% of the participants had more than one cancer diagnosis, the follow-up time for these participants was censored at the date of the first cancer diagnosis to account for competing risks; however, this did not change the results compared with censoring at the date of the cancer diagnosis for each particular cancer site model (whether or not it was the first cancer diagnosis).
Statistical analyses were conducted using SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina) and all P-values were 2-sided. The data were last accessed on November 30, 2023.
Results
Cancer cases were significantly older at randomization than controls and more likely to be current or former smokers (Table 1). The cases also included a lower percentage of Black individuals compared with controls owing to the 2:1 control:case ratio in that study set. Median serum 25(OH)D was similar in cases compared with controls, as was the distribution of the Gc isoform (Table 1). As expected, the distribution of Gc isoform differs by race, with the Gc1f isoform being more common in persons of African ancestry (S4 Table). Within the entire PLCO dataset with GC SNP data, cancer cases were more likely to be older, male, current smokers, and to have reported a family history of cancer (S5 Table). The distribution of Gc isoform did not differ by case status.
Circulating vitamin D was not associated with overall cancer, although risk was suggestively elevated in quintiles three through five vs. quintile one, with a significant trend test (p-trend = 0.04; Table 2). Risk of overall cancer was significantly elevated in quintile four for individuals with any Gc-2, with a marginally significant trend (p-trend = 0.06), but the statistical test for a 25(OH)D-Gc isoform interaction was not significant (p-interaction = 0.46; Table 2).
For colorectal cancer, we observed the expected pattern of reduced risk with higher 25(OH)D, but this did not differ significantly by Gc isoform (p-interaction = 0.92; Table 3). Risks between circulating 25(OH)D and breast and prostate cancer also did not differ by Gc isoform (p-interaction = 0.41 and 0.36, respectively), whereas lung cancer risk was significantly higher for elevated vitamin D among individuals with the Gc1-1 isoform (OR for highest vs. lowest tertile of vitamin D = 1.96, 95% CI 1.14–3.37, p-trend = 0.01), but not for those with the Gc1-2 or Gc2-2 isoform (OR = 1.03, 95% CI 0.60–1.80, p-trend = 0.90), although the interaction was not significant (p = 0.45). The Gc isoform did modify the association between circulating vitamin D and bladder cancer risk: OR’s for the highest vs. lowest tertile of vitamin D were 1.70, 95% CI 0.96–2.98 (p-trend = 0.07) for individuals with the Gc1 isoform and 0.52, 95% CI 0.28–0.96 (p-trend = 0.04) for individuals with the Gc1-2 or Gc2-2 isoforms (p-interaction = 0.03). Vitamin D was not associated with overall bladder cancer risk, however, with OR (95% CI) 1.11 (0.76–1.62) and 1.00 (0.67–1.50) for 25(OH)D tertiles 2 and 3, respectively (vs. tertile 1). Risks did not differ by Gc isoform for other cancer sites.
Compared to individuals with the Gc1s-Gc1s isoform, those with other isoforms (Gc1f-Gc1s, Gc1f-Gc1f, Gc1s-Gc2, Gc1f-Gc2, Gc2-Gc2) experienced similar risks of overall and site-specific cancer, with HRs for overall cancer ranging from 0.96–0.99 (Table 4). An increased risk of biliary tract cancer was noted for individuals with the Gc2-Gc2 isoform (HR = 1.67, 95% CI 1.00–2.78) and an increased risk for breast cancer was noted for men with the Gc1f-Gc1s or Gc1f-Gc1f isoforms (HR = 2.52, 95% CI 1.02–6.20 and HR = 3.75, 95% CI = 1.06–13.29, respectively), but these were based on a small number of incident cases. We observed a reduced risk of melanoma for individuals with the Gc1f-Gc1s or Gc1f-Gc1f isoforms (HR = 0.83, 95% CI 0.70–0.98 and HR = 0.67, 95% CI 0.45–1.00, respectively). While we noted above that the Gc isoforms modified the vitamin D-bladder cancer association, there were no direct associations between the Gc isoforms and bladder cancer risk. When restricting the analysis to Black individuals, the various isoforms were also not associated with risk of overall cancer or any specific cancer site examined (S6 Table). Many HRs had wide CIs and several could not be calculated due to small numbers.
Discussion
Based on data from 3,795 cancer cases and 3,856 controls in the PLCO Trial, we observed significant effect modification of the circulating vitamin D-cancer risk association by Gc isoform (Gc1-2 and Gc2-2 vs. Gc1-1) for bladder cancer, but not for other cancer sites, including colorectal and lung cancer, for which prior studies have noted interactions [15, 18], or for all cancers combined. Furthermore, with a few exceptions, we did not observe associations between the six Gc isoforms and cancer risk among 109,746 participants with GC genetic data.
We have previously noted in PLCO effect modification by Gc isoforms of the associations between circulating 25(OH)D and overall and lung cancer survival, whereby the benefit from higher vitamin D was only evident for cases with the Gc2 isoform [15] (HR = 0.38 for overall cancer mortality for those with the Gc2-2 isoform vs. 0.94 for those with the Gc1-1 isoform, and HR = 0.30 for lung cancer mortality for those with either the Gc1-2 or Gc2-2 isoform vs. 0.95 for those with the Gc1-1 isoform). Factors that influence the risk of developing cancer can differ from those impacting survival. For example, smoking is associated with a lower risk of prostate cancer but also adversely impacts prostate cancer survival [36]. Similarly, higher vitamin D status is associated with elevated prostate cancer risk [10] but with improved prostate cancer survival [37], with the latter difference not being due to detection or collider biases [38]. The opposite outcomes for risk and survival in our PLCO analyses could also suggest differential inhibitory effects of vitamin D/Gc isoform on tumor initiation vs. growth, invasion, or metastasis via vitamin D receptor (VDR) response elements. For example, there could be a greater impact on genes regulated by VDR related to angiogenesis, invasion, and metastasis (e.g., HIF1α and IL-8) [39] compared with genes that influence tumor initiation (i.e., malignant transformation) (e.g. MYC and RB) [39].
Others have previously noted effect modification by Gc isoforms of the associations between circulating 25(OH)D and cancer risk or survival. Gibbs et al. found a similar genetic effect modification pattern for 25(OH)D and colorectal adenoma and colorectal cancer risk, and colorectal cancer mortality outcomes [16–18], as well as for vitamin D supplementation (1000 IU/day) and colorectal adenoma recurrence [19]. For example, the HR for colorectal cancer mortality for deficient vs. sufficient circulating vitamin D was 2.24 for cases with the Gc2 isoform and 0.94 among cases without the Gc2 isoform (p-interaction = 0.0002) [16]. Similarly, in the Danish Diet, Cancer, and Health prospective cohort study, the reduced risk for higher vitamin D intake and colorectal cancer was only noted among participants with the Gc2 isoform (IRR for 3 ug/day increase in vitamin D intake = 0.90 for Gc2-2 vs. 0.99 for Gc1-1), while the isoform itself was not associated with colorectal cancer [20]. In contrast, data from the UK Biobank showed reduced colorectal cancer risk with higher serum 25(OH)D concentration but no significant interaction with the Gc isoform [21], and an analysis of the Nurses’ Health Study and Health Professionals Follow-up Study did not find effect modification of the vitamin D-colorectal cancer association by Gc isoform [22]. Finally, a population-based case-control study in Germany showed an inverse association for breast cancer risk for women with the Gc2-2 isoform compared with the Gc1s-1s isoform, but no interaction with 25(OH)D [12]. Differences in the observed effect modification across studies may be due to population differences, with participants being drawn from different countries, having different races/ethnicities, sex, and likely other risk factors such as smoking, physical activity, anthropometry, or diets. Such differences may be relevant as vitamin D binding protein concentrations have been associated with factors such as oral contraceptive use, BMI, long-term smoking, and triglyceride and cholesterol levels [40]. In addition, participants in the various studies may have different ranges of low vs. adequate circulating vitamin D.
With the exception of bladder cancer, we found no significant effect modification of the 25(OH)D-cancer risk association by Gc isoforms, and although we did observe reduced colorectal cancer risk for higher 25(OH)D, there was no interaction with GC. In contrast, individuals with higher 25(OH)D and any Gc2 isoform had a better lung cancer outcome (i.e., no increased risk) compared with individuals with only Gc1 isoforms (higher risk), and even though the interaction was not statistically significant, it was similar in direction to our previous finding of improved lung cancer survival in cases with higher 25(OH)D and any Gc2 isoform [15]. Regarding bladder cancer, we observed inverse vitamin D risk associations in participants with any Gc2 isoform (Gc1-2 or Gc2) but not in those with the Gc1-1 isoform. Why this effect modification might exist for bladder cancer, but not other cancers, can only be speculated. For example, genes related to inflammation (e.g. COX2) [39] could be particularly affected by the interaction between vitamin D and Gc isoform. Alternatively, the finding could be due to chance and should be examined in additional studies.
For the genotype-only examination of GC and cancer risk, we noted increased risks of biliary tract and male breast cancer for individuals with various Gc isoforms, but these were based on very small case numbers. We also observed reduced risk for melanoma for individuals with the Gc1f-Gc1s and Gc1f-Gc1f isoforms, findings consistent with data from a pooled analysis of two previous studies that encompassed 4,490 cases diagnosed in Australia, Canada, Italy, and the United States that showed lower melanoma-specific death among cases with any Gc1f isoform vs. no Gc1f (HR = 0.63, 95% CI 0.47–0.83) [41].
Our study has strengths and limitations. It is among the largest prospective studies to examine effect modification by Gc isoforms on the association between vitamin D and cancer risk. The analyses among the nested case-control sets with vitamin D biomarker data included nearly 3,800 cases and over 7,600 individuals, while the genetic-only analysis included over 26,700 cases among nearly 110,000 participants. Even with these sample sizes, however, there was limited power to detect associations within strata of Gc isoform for uncommon and rare cancers, and the number of statistical tests that were run could have increased the type one error rate. The PLCO population consists of mainly White individuals, which limited our ability to examine associations in other racial and ethnic groups and limited the generalizability of our findings to those populations. This is particularly relevant because circulating 25(OH)D concentrations and Gc isoforms differ by race and could be related to disparate vitamin D/cancer incidence and survival associations by race [42, 43]. Circulating 25(OH)D measurements in PLCO were calibrated to a standard assay within an international pooling project of 17 cohorts and empirically were at the median of all the cohorts combined (median, 10-90th percentiles in PLCO = 55 (29–87) and for all 17 cohorts = 56 (31–85). All cancers were prospectively diagnosed, which minimized reverse causality. Although vitamin D concentrations vary by season, we accounted for this using season-specific 25(OH)D quantiles. We also created quantiles separately for each nested case-control set because the vitamin D assays for these sets were conducted at laboratories using different methods. We adjusted our models for several covariates that could potentially be associated with cancer risk, but the possibility of residual confounding cannot be eliminated. While vitamin D was assayed in blood samples from single time points, a common limitation of most observational studies, methodological studies have demonstrated 25(OH)D concentrations to be moderately correlated over 14 years [44–47] and to be stable up to 30 years [48, 49].
Conclusions
Gc isoforms of the vitamin D binding protein did not modify the association between circulating vitamin D and cancer risk within the PLCO Trial, either for overall cancer or specific cancer sites such as lung, colorectum, breast and prostate, although an interaction was noted for bladder cancer. Gc isoforms alone were not significantly associated with overall or site-specific cancer, with the possible exceptions of increased risk of biliary tract and male breast cancer for individuals with the Gc2-Gc2 isoform and the Gc1f-Gc1s or Gc1f-Gc1f isoforms, respectively, and a reduced risk of melanoma for individuals with the Gc1f-Gc1s or Gc1f-Gc1f isoforms. Additional large studies that include more racially and ethnically diverse populations are needed.
Supporting information
S1 Table. Cross tabulation of rs4588 and rs7041 to define the vitamin D binding protein Gc groups.
https://doi.org/10.1371/journal.pone.0315252.s001
(DOCX)
S2 Table. Serum 25(OH)D quintile cut-points based on the controls, stratified by cancer site, season, and sex.
https://doi.org/10.1371/journal.pone.0315252.s002
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S3 Table. Serum 25(OH)D tertile cutpoints based on the controls, stratified by cancer site, season, and sex.
https://doi.org/10.1371/journal.pone.0315252.s003
(DOCX)
S4 Table. Distribution of Gc isoform by race and ethnicity.
https://doi.org/10.1371/journal.pone.0315252.s004
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S5 Table. Selected baseline characteristics of cases and non-cases with GC SNP data.
https://doi.org/10.1371/journal.pone.0315252.s005
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S6 Table. Association between Gc isoform and overall and organ-specific cancer risk in 4,408 black individuals.
https://doi.org/10.1371/journal.pone.0315252.s006
(DOCX)
Acknowledgments
The authors acknowledge the research contributions of the Cancer Genomics Research Laboratory of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, for their expertise, execution, and support of this research in the areas of project planning, wet laboratory processing of specimens, and bioinformatics analysis of generated data. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Cancer incidence data have been provided by the Alabama Statewide Cancer Registry, Arizona Cancer Registry, Colorado Central Cancer Registry, District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Cancer Data Registry of Idaho, Maryland Cancer Registry, Michigan Cancer Surveillance Program, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Ohio Cancer Incidence Surveillance System, Pennsylvania Cancer Registry, Texas Cancer Registry, Utah Cancer Registry, Virginia Cancer Registry, and Wisconsin Cancer Reporting System. The results reported here and the conclusions derived are the sole responsibility of the authors.
References
- 1. McCullough ML, Zoltick ES, Weinstein SJ, Fedirko V, Wang M, Cook NR, et al. Circulating vitamin D and colorectal cancer risk: An international pooling project of 17 cohorts. J Natl Cancer Inst. 2019;111(2):158–69. pmid:29912394
- 2. Visvanathan K, Mondul AM, Zeleniuch-Jacquotte A, Wang M, Gail MH, Yaun SS, et al. Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts. Eur J Epidemiol. 2023;38(1):11–29. pmid:36593337.
- 3. Muller DC, Hodge AM, Fanidi A, Albanes D, Mai XM, Shu XO, et al. No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3). Ann Oncol. 2018;29(6):1468–75. pmid:29617726.
- 4. Abnet CC, Chen Y, Chow WH, Gao YT, Helzlsouer KJ, Le Marchand L, et al. Circulating 25-hydroxyvitamin D and risk of esophageal and gastric cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):94–106. pmid:20562192.
- 5. Gallicchio L, Moore LE, Stevens VL, Ahn J, Albanes D, Hartmuller V, et al. Circulating 25-hydroxyvitamin D and risk of kidney cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):47–57. pmid:20562187.
- 6. Purdue MP, Freedman DM, Gapstur SM, Helzlsouer KJ, Laden F, Lim U, et al. Circulating 25-hydroxyvitamin D and risk of non-hodgkin lymphoma: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):58–69. pmid:20562184.
- 7. 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. pmid:20562185.
- 8. Zeleniuch-Jacquotte A, Gallicchio L, Hartmuller V, Helzlsouer KJ, McCullough ML, Setiawan VW, et al. Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):36–46. pmid:20562189.
- 9. Zheng W, Danforth KN, Tworoger SS, Goodman MT, Arslan AA, Patel AV, et al. Circulating 25-hydroxyvitamin D and risk of epithelial ovarian cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):70–80. pmid:20562186.
- 10. Travis RC, Perez-Cornago A, Appleby PN, Albanes D, Joshu CE, Lutsey PL, et al. A collaborative analysis of individual participant data from 19 prospective studies assesses circulating vitamin D and prostate cancer risk. Cancer Res. 2019;79(1):274–85. pmid:30425058.
- 11. Chun RF. New perspectives on the vitamin D binding protein. Cell Biochem Funct. 2012;30(6):445–56. pmid:22528806.
- 12. Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss EJ, Flesch-Janys D, et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status. Cancer Epidemiol Biomarkers Prev. 2008;17(6):1339–43. pmid:18559548.
- 13. Lauridsen AL, Vestergaard P, Hermann AP, Brot C, Heickendorff L, Mosekilde L, et al. Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women. Calcif Tissue Int. 2005;77(1):15–22. pmid:15868280
- 14. Gozdzik A, Zhu J, Wong BY, Fu L, Cole DE, Parra EJ. Association of vitamin D binding protein (VDBP) polymorphisms and serum 25(OH)D concentrations in a sample of young Canadian adults of different ancestry. J Steroid Biochem Mol Biol. 2011;127(3–5):405–12. pmid:21684333.
- 15. Weinstein SJ, Mondul AM, Layne TM, Yu K, Huang J, Stolzenberg-Solomon RZ, et al. Prediagnostic serum vitamin D, vitamin D binding protein isoforms, and cancer survival. JNCI Cancer Spectr. 2022;6(2):pkac019. pmid:35603848.
- 16. Gibbs DC, Bostick RM, McCullough ML, Um CY, Flanders WD, Jenab M, et al. Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common, inherited vitamin D-binding protein isoforms. Int J Cancer. 2020;147(10):2725–34. pmid:32391587.
- 17. Gibbs DC, Fedirko V, Um C, Gross MD, Thyagarajan B, Bostick RM. Associations of circulating 25-hydroxyvitamin D3 concentrations with incident, sporadic colorectal adenoma risk according to common vitamin D-binding protein isoforms. Am J Epidemiol. 2018;187(9):1923–30. pmid:29788105.
- 18. Gibbs DC, Song M, McCullough ML, Um CY, Bostick RM, Wu K, et al. Association of circulating vitamin D with colorectal cancer depends on vitamin D-binding protein isoforms: A pooled, nested, case-control study. JNCI Cancer Spectr. 2020;4(1):pkz083. pmid:32337495.
- 19. Gibbs DC, Barry EL, Fedirko V, Baron JA, Bostick RM. Impact of common vitamin D-binding protein isoforms on supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence risk: A secondary analysis of a randomized clinical trial. JAMA Oncol. 2023;9(4):546–51. pmid:36701139.
- 20. Kopp TI, Vogel U, Andersen V. Associations between common polymorphisms in CYP2R1 and GC, Vitamin D intake and risk of colorectal cancer in a prospective case-cohort study in Danes. PLoS One. 2020;15(2):e0228635. pmid:32012190.
- 21. Li J, Qin S, Zhang S, Lu Y, Shen Q, Cheng L, et al. Serum vitamin D concentration, vitamin D-related polymorphisms, and colorectal cancer risk. Int J Cancer. 2023;153(2):278–89. pmid:36946647.
- 22. Kim H, Yuan C, Nguyen LH, Ng K, Giovannucci EL. Prediagnostic vitamin D status and colorectal cancer survival by vitamin D binding protein isoforms in US cohorts. J Clin Endocrinol Metab. 2023;108(6):e223–e9. pmid:36550068.
- 23. Black A, Huang WY, Wright P, Riley T, Mabie J, Mathew S, et al. PLCO: Evolution of an epidemiologic resource and opportunities for future studies. Rev Recent Clin Trials. 2015;10(3):238–45. pmid:26435289.
- 24. Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, et al. Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst. 2008;100(11):796–804. pmid:18505967.
- 25. Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, Crawford ED, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials. 2000;21(6 Suppl):273S–309S. pmid:11189684.
- 26. Freedman DM, Chang SC, Falk RT, Purdue MP, Huang WY, McCarty CA, et al. Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev. 2008;17(4):889–94. pmid:18381472.
- 27. Layne TM, Weinstein SJ, Graubard BI, Ma X, Mayne ST, Albanes D. Serum 25-hydroxyvitamin D, vitamin D binding protein, and prostate cancer risk in black men. Cancer. 2017;123(14):2698–704. pmid:28369777.
- 28. Weinstein SJ, Purdue MP, Smith-Warner SA, Mondul AM, Black A, Ahn J, et al. Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer. 2015;136(6):E654–64. pmid:25156182.
- 29. Mondul AM, Weinstein SJ, Horst RL, Purdue M, Albanes D. Serum vitamin D and risk of bladder cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial. Cancer Epidemiol Biomarkers Prev. 2012;21(7):1222–5. pmid:22623707.
- 30. 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. pmid:19208842.
- 31. Gallicchio L, Helzlsouer KJ, Chow WH, Freedman DM, Hankinson SE, Hartge P, et al. Circulating 25-hydroxyvitamin D and the risk of rarer cancers: Design and methods of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):10–20. pmid:20562188.
- 32. Hollis BW. Quantitation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D by radioimmunoassay using radioiodinated tracers. Methods Enzymol. 1997;282:174–86. pmid:9330287.
- 33. Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer. Clin Chem. 1993;39(3):529–33. pmid:8448871.
- 34. Midttun O, Ueland PM. Determination of vitamins A, D and E in a small volume of human plasma by a high-throughput method based on liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2011;25(14):1942–8. pmid:21698677.
- 35. Wagner D, Hanwell HE, Vieth R. An evaluation of automated methods for measurement of serum 25-hydroxyvitamin D. Clin Biochem. 2009;42(15):1549–56. pmid:19631201.
- 36. Al-Fayez S, El-Metwally A. Cigarette smoking and prostate cancer: A systematic review and meta-analysis of prospective cohort studies. Tob Induc Dis. 2023;21:19. pmid:36762260.
- 37. Mondul AM, Weinstein SJ, Moy KA, Mannisto S, Albanes D. Circulating 25-hydroxyvitamin D and prostate cancer survival. Cancer Epidemiol Biomarkers Prev. 2016;25(4):665–9. pmid:26809275.
- 38. Etievant L, Gail MH, Albanes D. Disentangling discordant vitamin D associations with prostate cancer incidence and fatality in a large, nested case-control study. Int J Epidemiol. 2024;53(5). pmid:39180769.
- 39. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14(5):342–57. pmid:24705652.
- 40. Delanghe JR, Speeckaert R, Speeckaert MM. Behind the scenes of vitamin D binding protein: More than vitamin D binding. Best Practice & Research Clinical Endocrinology & Metabolism. 2015;29(5):773–86. pmid:26522461
- 41. Gibbs DC, Thomas NE, Kanetsky PA, Luo L, Busam KJ, Cust AE, et al. Association of functional, inherited vitamin D-binding protein variants with melanoma-specific death. JNCI Cancer Spectr. 2023;7(5):pkad051. pmid:37494457.
- 42. Powe CE, Karumanchi SA, Thadhani R. Vitamin D-binding protein and vitamin D in blacks and whites. N Engl J Med. 2014;370(9):880–1. pmid:24571762.
- 43. Mondul AM, Weinstein SJ, Layne TM, Albanes D. Vitamin D and cancer risk and mortality: state of the science, gaps, and challenges. Epidemiol Rev. 2017;39(1):28–48. pmid:28486651.
- 44. Hofmann JN, Yu K, Horst RL, Hayes RB, Purdue MP. Long-term variation in serum 25-hydroxyvitamin D concentration among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomarkers Prev. 2010;19(4):927–31. pmid:20332255.
- 45. Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, Grimnes G. Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. Am J Epidemiol. 2010;171(8):903–8. pmid:20219763.
- 46. 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. pmid:15090720.
- 47. Sonderman JS, Munro HM, Blot WJ, Signorello LB. Reproducibility of serum 25-hydroxyvitamin d and vitamin D-binding protein levels over time in a prospective cohort study of black and white adults. Am J Epidemiol. 2012;176(7):615–21. pmid:22975199.
- 48. Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem. 2013;59(5):771–80. pmid:23503722.
- 49. Agborsangaya C, Toriola AT, Grankvist K, Surcel HM, Holl K, Parkkila S, et al. The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione. Nutr Cancer. 2010;62(1):51–7. pmid:20043259.