Susan E Steck, Omonefe O Omofuma, L Joseph Su, Amanda A Maise, Anna Woloszynska-Learn, Candace S Johnson, Hongmei Zhang, Jeannette T Bensen, Elizabeth T H Fontham, James L Mohler, Lenore Arab, Calcium, magnesium, and whole-milk intakes and high-aggressive prostate most cancers within the North Carolina–Louisiana Prostate Most cancers Undertaking (PCaP), The American Journal of Medical Vitamin, Quantity 107, Situation 5, Might 2018, Pages 799–807, https://doi.org/10.1093/ajcn/nqy037
ABSTRACT
INTRODUCTION
Prostate most cancers is probably the most generally recognized malignancy and the second main explanation for most cancers mortality amongst American males (1). Prostate most cancers threat elements embrace age, household historical past of the illness, and race/ethnicity. African American males have the best charge of prostate most cancers mortality on the planet. This marked racial disparity could also be the results of variations in entry to and attitudes about screening and therapy, circulating androgens, genetics, environmental elements, socioeconomic elements, or weight loss program, or a mix of those elements (2).
Calcium consumption has been positively related to a analysis of prostate most cancers (3, 4), together with the next threat of extra aggressive types of prostate most cancers (5–11), in addition to localized or much less aggressive illness (10, 12). A hypothesized mechanism for calcium’s impact on prostate most cancers is the suppression of 1,25-dihydroxyvitamin D, the biologically energetic type of vitamin D. Our group beforehand reported that calcium consumption modified the affiliation between plasma 25-hydroxyvitamin D concentrations and prostate most cancers within the North Carolina–Louisiana Prostate Most cancers Undertaking (PCaP), from which the present examine originates (13). The proof associated to dairy merchandise and prostate most cancers threat is much less constant, with some exhibiting a nonsignificant inverse affiliation with prostate most cancers incidence (14–16) and others reporting vital elevated dangers of prostate most cancers for the best intakes of complete dairy merchandise (17, 18). The saturated fats content material of dairy merchandise has been urged to be a attainable explanatory issue within the constructive associations. Greater odds of aggressive prostate most cancers had been related to larger saturated fats consumption in PCaP (19). Nonetheless, few research have examined associations between dairy merchandise and prostate most cancers aggressiveness whereas accounting for fats content material.
Magnesium, the second-most plentiful cation within the physique, has been proven to manage glucose metabolism, irritation, and cell proliferation (20). When ingested, magnesium and calcium compete for absorption within the intestinal intraepithelial and reabsorption within the kidneys. Their concentrations within the physique are regulated via a destructive suggestions mechanism (21), such that low concentrations of both might improve the results of the opposite. Dietary calcium and magnesium intakes have elevated over the previous decade, with a >2-fold enhance noticed in calcium consumption (21). Nonetheless, roughly half of the US inhabitants nonetheless eat lower than the advisable day by day requirement for magnesium (22). The ratio of calcium to magnesium (Ca:Mg) could also be extra strongly related to illness threat than both mineral alone, though there are restricted information in relation to prostate most cancers in various populations (21, 23).
The present examine examined the relation between intakes of calcium and magnesium and Ca:Mg and prostate most cancers aggressiveness and investigated whether or not these relations differed by race. Moreover, the relations between dairy product intakes, together with whole-fat milk and non–whole-fat milk consumption, and prostate most cancers aggressiveness had been examined.
METHODS
Research inhabitants
The examine used information from the PCaP, a population-based, case-only examine designed to handle racial variations in prostate most cancers aggressiveness (24). Residents of the North Carolina and Louisiana examine areas with a primary analysis of histologically confirmed adenocarcinoma of the prostate had been eligible to take part in the event that they had been 40–79 y previous at analysis, might full the examine interview in English, didn’t reside in an establishment (nursing residence), and had been bodily and mentally capable of full the examine interview. Males self-identified as black/African American or white/Caucasian (European American) in response to the open-ended interview query on race (24). Sufferers eligible in North Carolina had been recognized by the Speedy Case Ascertainment Core Facility, a collaborative effort of the College of North Carolina–Lineberger Complete Most cancers Middle and the North Carolina Central Most cancers Registry. Sufferers eligible in Louisiana had been recognized by the Louisiana Tumor Registry within the Faculty of Public Well being on the Louisiana State College Well being Sciences Middle. Knowledgeable consent was obtained from all analysis individuals. Analysis protocols had been authorised by the institutional overview boards on the College of North Carolina, Louisiana State College Well being Providers Middle, and the Division of Protection Prostate Most cancers Analysis Program. The present evaluation additionally was authorised by the College of South Carolina Institutional Overview Board as exempt. The examine was registered at www.clinicaltrials.gov as NCT03289130.
Knowledge assortment
Analysis individuals had been visited of their residence or different location of their alternative by a skilled registered nurse. The vast majority of visits had been accomplished inside 14 wk of analysis. Individuals had been requested to quick for six h earlier than the examine go to, which was scheduled within the morning every time attainable, and to collect all medicines and dietary supplements used within the 2 wk earlier than the go to. The go to started by explaining the examine and acquiring HIPAA (Well being Insurance coverage Portability and Accountability Act of 1996) authorization and formal written knowledgeable consent, after which organic samples and anthropometric measurements had been collected and questionnaires administered. The structured questionnaires solicited info with regard to the next: background traits, occupation, household historical past, well being standing, well being care, prostate most cancers analysis and screening historical past, remedy use, nonsteroidal anti-inflammatory drug use, and vitamin and complement use. The 144-item Eating regimen Historical past Questionnaire (DHQ), developed by the Nationwide Most cancers Institute, was modified by PCaP investigators to incorporate Southern meals and interviewer-administered to analysis individuals to determine consumption frequency and traditional portion sizes. Analysis individuals had been requested to recall their traditional weight loss program for the yr earlier than analysis. Questionnaire responses had been linked to the up to date DHQ Nutrient Database via the Nationwide Most cancers Institute–developed Eating regimen*Calc software program to calculate common day by day intakes of dietary calcium, magnesium, and different vitamins. Data on dietary complement use, together with multivitamins and single calcium and magnesium dietary supplements, within the yr earlier than analysis was collected with using a validated questionnaire (25).
Medical information had been requested from the diagnosing doctor of consenting analysis individuals. Educated workers abstracted info regarding prostate most cancers analysis and therapy.
Final result evaluation
Data obtained from medical file abstraction was used to categorise circumstances into 3 aggressiveness classes on the idea of medical grade, medical stage, and prostate-specific antigen (PSA) at analysis. Excessive-aggressive circumstances had a Gleason rating ≥8, a PSA >20 ng/mL, or a Gleason rating ≥7 and medical stage T3–T4. Low-aggressive circumstances had a Gleason rating <7 and had been recognized at medical stage T1–T2 and had a PSA <10 ng/mL at analysis. All different circumstances had been thought-about intermediate aggressive. For the aim of this examine, circumstances had been categorized as high-aggressive circumstances or low-intermediate-aggressive circumstances (comparability group). Publicity evaluation Calcium, magnesium, and dairy merchandise (milk, cheese, yogurt, and complete dairy) served as the principle exposures. Ca:Mg intakes had been obtained by dividing calcium consumption by magnesium consumption. Three publicity variables had been created for calcium, magnesium, and Ca:Mg: dietary, supplemental, and complete (sum of dietary and supplemental intakes) intakes, which had been categorized into tertiles by utilizing cutoffs based mostly on distributions amongst analysis individuals within the comparability group. Common day by day intakes of milk, cheese, yogurt, and complete dairy had been calculated with using the knowledge on frequency of intakes and portion sizes obtained from the DHQ responses, and cutoffs for categorical variables had been decided on the idea of the distributions amongst analysis individuals with low-intermediate-aggressive prostate most cancers. Analysis individuals had been requested on the DHQ what sort of milk (complete; 2% fats; 1% fats; skim, nonfat, or 0.5% fats; soy; rice; or different) they normally consumed. Classes for whole-fat milk and non–whole-fat milk drinkers had been created, and whole-fat milk drinkers had been categorized additional into 3 ranges of consumption on the idea of day by day servings consumed. Non–whole-fat milk drinkers included analysis individuals who reported both no milk consumption or who reported normally consuming every other milk in addition to whole-fat milk. Statistical strategies PCaP enrolled a complete of 2258 analysis individuals. Individuals had been excluded for the next causes: lacking info on prostate most cancers aggressiveness, power consumption <500 kcal/d or >6000 kcal/d, lacking schooling or BMI information, or BMI (in kg/m2) <18.5 (underweight; see research subject flow chart in Supplemental Figure 1). The final sample size was 2060 participants of whom 359 were high-aggressive and 1701 were low-intermediate-aggressive cases. Descriptive statistics were calculated as means ± SDs for continuous variables, and frequencies and percentages for categorical variables. Multivariable logistic regression was used to study the relations between each exposure and prostate cancer aggressiveness. A minimally adjusted model controlling only for age and energy intake was examined. Other covariates were selected with the use of the ≥10% change-in-estimate criterion that compares a model with and without the potential confounder (26) and also were identified through literature review on potential confounders and risk factors. A second multivariable model included age (continuous), energy intake (continuous), BMI [weight (kg)/height (m2), categorized as normal (18.5–24.9), overweight (25.0–29.9), obese (30–39.9), or extremely obese (>40)], smoking standing (nonsmoker, former smoker, or present smoker), earlier screening (none, digital rectal examination solely, PSA solely, or PSA and digital rectal examination), examine web site (College of North Carolina or Louisiana State College), schooling (lower than eighth grade or some highschool, highschool graduate or vocational/technical college, some faculty or faculty graduate, or some graduate coaching or graduate or skilled diploma), revenue (11 classes), and Charlson comorbidity index (0, 1–3, or ≥4). A 3rd multivariable mannequin (recognized because the absolutely adjusted mannequin) additionally included different dietary variables: alcohol consumption (grams per day), lycopene consumption (micrograms per day from each weight loss program and dietary supplements), and saturated fats consumption (grams per day). The Ca:Mg consumption was included in a fourth mannequin within the whole-fat milk analyses to look at the potential mediating results of this dietary issue. Outcomes are introduced for your complete examine inhabitants and stratified by race. Within the race-stratified analyses, race-specific cutoffs for publicity variables had been decided by utilizing the distribution among the many low-intermediate-aggressive circumstances for every race.
Analyses had been performed with using SAS model 9.4 (SAS Institute), and significance was set at α = 0.05.
RESULTS
Analysis individuals with high-aggressive prostate most cancers had been extra more likely to be African American, previous or present people who smoke, and older and have the next BMI, decrease instructional attainment, fewer prostate most cancers screenings, and better day by day complete power, saturated fats, and alcohol intakes than individuals with low-intermediate-aggressive prostate most cancers (Desk 1). Calcium and magnesium intakes had been larger in European Individuals than in African Individuals. Analysis individuals with high-aggressive prostate most cancers had larger common day by day intakes of dietary, supplemental, and complete calcium and milk and complete dairy and the next Ca:Mg than low-intermediate-aggressive circumstances (Supplemental Desk 1).
There have been no associations between calcium consumption, both from meals alone or dietary supplements, and prostate most cancers aggressiveness (Desk 2). Greater dietary intakes of magnesium had been related to lowered odds of aggressive prostate most cancers within the highest tertile (OR for tertile 3 in contrast with tertile 1: 0.60; 95% CI: 0.39, 0.94) for all analysis individuals mixed, though the affiliation was attenuated with additional adjustment for different dietary variables (OR for tertile 3 in contrast with tertile 1: 0.71; 95% CI: 0.45, 1.12) (Desk 3).
Within the absolutely adjusted mannequin, larger dietary and complete Ca:Mgs had been considerably related to elevated odds of excessive aggressive prostate most cancers (dietary—OR for tertile 2 in contrast with tertile 1: 1.38; 95% CI: 1.01, 1.88; OR for tertile 3 in contrast with tertile 1: 1.46; 95% CI: 1.06, 2.02; and complete consumption—OR for tertile 2 in contrast with tertile 1: 1.63; 95% CI: 1.19, 2.24; OR for tertile 3 in contrast with tertile 1: 1.65; 95% CI: 1.19, 2.28) (Desk 4). When stratified by race, associations for complete (weight loss program+complement) Ca:Mg consumption had been extra pronounced for African Individuals (OR for tertile 3 in contrast with tertile 1: 1.80; 95% CI: 1.16, 2.80) than for European Individuals (OR for tertile 3 in contrast with tertile 1: 1.35; 95% CI: 0.84, 2.17).
Within the absolutely adjusted fashions, no vital relations had been detected between intakes of milk, cheese, yogurt, or complete dairy and prostate most cancers aggressiveness (Supplemental Desk 2). Within the evaluation of prostate most cancers aggressiveness amongst whole-fat milk and non–whole-fat milk drinkers, analysis individuals who reported consuming ≥1.25 servings of whole-fat milk/d had a 74% elevated odds of high-aggressive prostate most cancers when put next with non–whole-fat milk drinkers (OR: 1.74; 95% CI: 1.16, 2.62) (Desk 5). The affiliation was attenuated (OR: 1.37; 95% CI: 0.89, 2.11) after additional adjustment for different dietary variables which will mediate the affiliation, equivalent to saturated fats and the Ca:Mg consumption.
DISCUSSION – “magnesium in milk”
On this population-based examine of determinants of racial variations in aggressive prostate most cancers, the dietary consumption Ca:Mg was positively related to aggressive prostate most cancers, whereas calcium consumption alone had no affiliation. Dietary consumption of magnesium was modestly inversely related to aggressive prostate most cancers. As well as, males who reported normally consuming whole-fat milk had been at elevated odds of aggressive prostate most cancers in contrast with non-milk drinkers or those that eat normally different forms of milk, whereas dairy product consumption confirmed no affiliation.
Few research have examined Ca:Mg and most cancers outcomes. Beforehand, modifying results have been reported, such that larger intakes of magnesium and calcium had been related to lowered threat of two intermediate premalignant endpoints, colorectal adenoma (27) and Barrett esophagus (28), with extra pronounced associations amongst these with decrease Ca:Mg consumption. A major interplay between Ca:Mg consumption and transient receptor potential melastatin 7 (TRPM7) polymorphism was noticed in relation to threat of colorectal adenoma (27). In a current examine on serum calcium and magnesium concentrations, elevated serum Ca:Mg was considerably related to an elevated threat of high-grade prostate most cancers, and the next serum Ca:Mg was noticed amongst non–European American individuals than in European American individuals (23). One other examine noticed the next serum Ca:Mg in individuals with prostate most cancers than in age-matched controls with out prostate most cancers (29). Excessive calcium consumption could scale back the absorption of each calcium and magnesium (28, 30). Within the current examine, the next dietary Ca:Mg consumption was related to elevated odds of high-aggressive prostate most cancers. The outcomes counsel that the concentrations of calcium relative to magnesium intakes could have an effect on prostate most cancers aggressiveness, whereas calcium consumption alone is probably not as influential. In assist of this discovering, secondary analyses of a medical trial of calcium dietary supplements discovered no elevated threat of prostate most cancers after a mean of 10.3 y of follow-up amongst males randomly assigned to obtain 1200 mg Ca for 4 y (31).
The interdependence of calcium and magnesium might clarify the inconsistencies noticed in earlier epidemiologic research of calcium alone and prostate most cancers, and clarify the interactive function of calcium and magnesium within the improvement of high-aggressive illness. A urged organic mechanism has been proposed in experimental research wherein activation of TRPM7 as a consequence of an imbalance in Ca:Mg could stimulate prostate most cancers cell proliferation (29). Though no inverse affiliation was noticed for magnesium dietary supplements, using magnesium dietary supplements was probably too low to claim a definitive impact, notably amongst African-Individuals. Most analysis individuals who consumed supplemental magnesium additionally consumed supplemental calcium (338 African-Individuals and 534 European-Individuals in contrast with only one African-American and 13 European-Individuals who consumed supplemental magnesium and never supplemental calcium), and the Ca:Mg in complement customers was larger than in non-supplement customers (common Ca:Mg of two.55 in contrast with 2.36, respectively).
Within the evaluation of dairy merchandise, ORs tended to be >1.0 for larger intakes of milk and cheese, though CIs included the null worth. Nonetheless, when evaluating whole-fat milk drinkers with non–whole-fat milk drinkers, individuals who consumed probably the most whole-fat milk (≥1.25 servings/d) had considerably larger odds of high-aggressive prostate most cancers. Outcomes had been attenuated after adjustment for saturated fats and different dietary elements. Outcomes had been attenuated additional after adjustment for Ca:Mg consumption. These outcomes counsel a doubtlessly mediating impact of saturated fats and will assist clarify the blended outcomes obtained in earlier research of calcium and milk intakes on prostate most cancers aggressiveness (8, 32–35). As well as, males who eat whole-fat milk incessantly could also be much less health-conscious, much less more likely to be screened, and extra more likely to be recognized with aggressive illness. Nonetheless, the affiliation was maintained when earlier screening historical past was included as a covariate in our fashions to account for this potential confounder.
Few research have tried to match the results of full-fat with low- or no-fat dairy merchandise on most cancers threat or prognosis. Entire-fat milk consumption was positively related to deadly prostate most cancers within the Physicians’ Well being Research, whereas skim/low-fat milk consumption was positively related to low-grade, early-stage, and screen-detected prostate cancers (36). In a current examine from Sweden, males recognized with localized prostate most cancers who drank ≥3 servings of high-fat milk/d had been at elevated threat of prostate most cancers mortality, whereas low-fat milk drinkers had a borderline discount in prostate most cancers deaths (37). Comparable outcomes have been reported for breast most cancers, one other hormonally pushed most cancers. The Life After Most cancers Epidemiology (LACE) Research reported that the consumption of high-fat dairy, however not low-fat dairy, was related to larger mortality after a breast most cancers analysis (38), whereas an Italian examine reported no affiliation between high-fat dairy or low-fat dairy and mortality amongst girls recognized with breast most cancers, though there was a slightly vital elevated threat amongst milk drinkers (the examine didn’t distinguish between whole-fat and low- or no-fat milk) (39). Mechanisms by which high-fat milk could have an effect on prostate most cancers embrace deleterious results of saturated fats, rising C-peptide concentrations, or larger insulin-like development issue I (36). Future analysis in giant potential research that examine full-fat milk with different forms of milk is warranted to verify the present findings.
There are a number of benefits to PCaP. First, the case ascertainment was based mostly on most cancers registry information, medical information, and pathology experiences, thereby minimizing consequence misclassification bias. Second, the examine used info on a variety of potential confounders, equivalent to age, race, BMI, power consumption, schooling, household historical past of prostate most cancers, historical past of PSA screening, smoking standing, revenue, and Charlson comorbidity index. Third, the food-frequency questionnaire used to estimate nutrient intakes was modified to evaluate intakes of Southern meals, which can lower info bias as a consequence of measurement error of the publicity. Fourth, a comparatively giant pattern measurement (n = 2060) was used and was consultant of the inhabitants of males with prostate most cancers in 2 states, Louisiana and North Carolina; due to this fact, it has a great potential for the detection of small variations and for generalizability of the outcomes. Fifth, on this examine, 2 populations of curiosity, European Individuals and African Individuals, are equally nicely represented (n = 1064 and 996, respectively), which permits comparisons in prostate most cancers aggressiveness by race that, to our information, had not been achieved earlier than.
Limitations additionally must be famous. First, as a result of PCaP is a case-only examine, the comparability or management group consisted of males with low-intermediate-aggressive prostate most cancers. Though utilization of this management group permits necessary comparisons between low-intermediate and high-aggressive prostate cancers, it doesn’t enable comparability of results of threat elements in males who’re cancer-free. Second, the DHQ elicited details about traditional meals intakes through the yr previous the analysis of prostate most cancers. Intakes within the extra distant previous might have been completely different and have the next affect than newer weight loss program, as a result of prostate most cancers could take many years to develop. Third, information of illness standing could have biased DHQ responses by the individuals. Fourth, though all the variables and analyses had been deliberate a priori, and it has been urged that there isn’t a want for a number of testing adjustment on this state of affairs (40), there may be nonetheless a chance of false-positive conclusions. Lastly, though a number of confounders had been included within the mannequin, unmeasured or residual confounding is feasible in observational research.
The present examine suggests {that a} excessive Ca:Mg consumption and whole-fat milk consumption are related to larger prostate most cancers aggressiveness. Future research are warranted to discover the effect-modifying function of race on relations between vitamins, equivalent to calcium and magnesium, and prostate most cancers aggressiveness, and the interplay between calcium and magnesium within the pathogenesis and development of prostate most cancers.
Acknowledgements
The authors’ tasks had been as follows—SES, LJS, AW-R, CSJ, JTB, ETHF, JLM, and LA: designed the analysis; SES, OOO, and AAM: performed the analysis; SES, OOO, AAM, and HZ: analyzed the information; SES and OOO: wrote the manuscript; SES: had main duty for closing content material; and all authors: critically reviewed and revised the manuscript and browse and authorised the ultimate manuscript. Not one of the authors had a battle of curiosity to reveal.
Notes
The North Carolina–Louisiana Prostate Most cancers Undertaking (PCaP) was carried out as a collaborative examine supported by the Division of Protection contract DAMD 17-03-2-0052. The present analyses had been supported by DAMD 11-1-0568. SES and OOO had been supported by Susan G. Komen grant #GTDR17500160.
PCaP information assortment instruments might be accessed at: https://pcap.bioinf.unc.edu/.
Supplemental Determine 1 and Supplemental Tables 1 and a pair of can be found from the “Supplementary data” hyperlink within the on-line posting of the article and from the identical hyperlink within the on-line desk of contents at https://tutorial.oup.com/ajcn/.
Abbreviations used: Ca:Mg, ratio of calcium to magnesium; DHQ, Eating regimen Historical past Questionnaire; PCaP, North Carolina–Louisiana Prostate Most cancers Undertaking; PSA, prostate-specific antigen.