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BACKGROUND: alpha-Linolenic acid (ALA) is associated with a low risk of cardiovascular disease; however, the underlying mechanism is not completely known. OBJECTIVE: The objective was to examine whether habitual dietary ALA intake is associated with plasma concentrations of inflammatory biomarkers after control for shared genetic and common environmental factors. DESIGN: We cross-sectionally studied 353 middle-aged male twins. Habitual diet was assessed with the Willett food-frequency questionnaire. Fasting plasma concentrations of interleukin-6 (IL-6) and its soluble receptor (sIL-6R), high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) were measured. Linear mixed-effect regression analysis was used to partition the overall association into within- and between-pair associations. RESULTS: A 1-g increment in habitual dietary ALA intake was associated with 11.0% lower concentrations of sIL-6R (P = 0.004) but not of IL-6 (P = 0.31), TNF-alpha (P = 0.16), or hsCRP (P = 0.36) after adjustment for energy intake, nutritional factors, known cardiovascular disease risk factors, and medications. After further control for shared genetic and common environmental factors by comparison of brothers within a twin pair, a twin with a 1-g higher ALA intake was likely to have 10.9% (95% CI: 3.7%, 17.6%; P = 0.004) lower sIL-6R concentrations than his co-twin with a low intake, whereas ALA intake was not significantly associated with plasma concentrations of IL-6, TNF-alpha, or hsCRP. These results were validated by using 1000 bootstrap samples. CONCLUSIONS: Habitual dietary ALA intake is inversely associated with plasma sIL-6R concentrations independent of shared genetic and common environmental influences. Lowering sIL-6R may be a mechanism underlying the cardioprotective properties of habitual dietary ALA. This study was registered at clinicaltrials.gov as NCT00017836. © 2010 American Society for Nutrition. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D supplementation may be required for certain subgroups in the United States in whom status and intake are inadequate, but the impact of various doses, and whether calcium administration jointly or independently influences vitamin D metabolite levels, is unclear.Methods: In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma, we measured the impact of vitamin D supplementation and/or calcium supplementation on plasma vitamin D metabolite concentrations. Ninety-two adult men and women living in the southeastern United States were randomized to 800 IU vitamin D(3), 2000 mg elemental calcium, both, or placebo daily for 6 months. We examined vitamin D status at baseline and postintervention and compared the change in plasma 25-hydroxyvitamin D (25(OH)D) and 1,25(OH)(2)D levels by intervention group using general linear models.Results: Eighty-two percent of the study population had insufficient plasma 25(OH)D concentrations (<75 nmol/L) at baseline, with the lowest levels observed among African American participants. Vitamin D supplements, with or without calcium supplementation, raised plasma 25(OH)D concentrations, on average, by 25 to 26 nmol/L. Half of the study participants were classified as having sufficient 25(OH)D status after 6 months of 800 IU of vitamin D(3) daily. Calcium alone did not influence 25(OH)D concentrations.Conclusion: In this southeastern U.S. population, half of the study participants receiving 800 IU vitamin D(3) daily had blood 25(OH)D concentrations of

Background:The cardioprotective property of the Mediterranean diet has been attributed to its antioxidant capacity, but direct investigation of this mechanism has been limited.Objective:We examined the association between the Mediterranean diet and an established plasma marker of oxidative stress, the ratio of reduced to oxidized glutathione (GSH/GSSG), in a well-controlled study of twins.Design:We administered the Willett food-frequency questionnaire to 138 monozygotic and dizygotic twin pairs and to 21 unpaired twins and derived a score measuring adherence to the Mediterranean diet. Fasting plasma GSH and GSSG concentrations were measured to calculate the GSH/GSSG ratio. The higher the ratio, the lower the oxidative stress. Mixed-effect regression analysis was used to partition the association into between- and within-twin pair differences. When within-pair effects are examined, twins are matched for sociodemographic and familial factors.Results:A one-unit increment in the diet score was associated with a 7% higher GSH/GSSG ratio (P = 0.03) after adjustment for energy intake, other nutritional factors, cardiovascular disease risk factors, and medication use. The association persisted within twin pairs: a one-unit within-pair absolute difference in the diet score was associated with a 10% (95% CI: 2.7, 18.0) higher GSH/GSSG ratio in the twin with the higher score than in the co-twin with the lower score (P = 0.007). Results were similar in monozygotic and dizygotic twin pairs.Conclusions:The association between the Mediterranean diet and plasma oxidative stress is robust and is not confounded by genetic or shared environmental factors. Decreased oxidative stress is a plausible mechanism linking the Mediterranean diet to reduced cardiovascular disease risk. © American Society for Nutrition [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate associations of APOE, APOE promoter (G-219T), and tau protein exon 6 polymorphisms (47 and 53) and a history of self-reported concussion in college athletes. DESIGN: Multi-center cross-sectional study. SETTING: Male football and male and female soccer programs at the University of South Carolina, Jacksonville University, Benedict College, and the College of Charleston. PARTICIPANTS: Active 18- to 30-year-old (n = 195) intercollegiate male football players and male and female soccer players during 2001 and 2002. ASSESSMENT OF RISK FACTORS: Written questionnaires and blood or mouthwash samples for DNA for genotyping by RFLP/PCR. MAIN OUTCOME MEASUREMENT: Self-reported history of concussions over the previous 8 years. RESULTS: A statistically significant, nearly 3-fold increase in risk of a history of concussion for those with the APOE promoter G-219T TT genotype relative to the GG genotype (OR, 2.8; 95% CI, 1.1 to 6.9) adjusted for age, sport, school, and years in their primary sport, a finding that was stronger for Cantu grade 2 and 3 concussions. CONCLUSIONS: These results suggest that college athletes with an APOE promoter G-219T TT genotype may be at increased risk for having a history of concussions, especially more severe concussions. Although there was some support for the possibility that the tau 53 polymorphism may be associated with increased risk of prior concussion (OR, 2.1; 95% CI, 0.3 to 14.5), there was no support for an association with APOE genotypes. The results of this cross-sectional study support the need for a prospective study of genetic factors, such as APOE promoter polymorphisms, and the incidence of and sequelae from concussions in college athletes. [ABSTRACT FROM AUTHOR]

Lycopene has been associated with reduced prostate cancer risk, although the results of epidemiological studies have varied. We hypothesize that an effect of lycopene may be modified by XRCC1 genotype and other antioxidants. We used a food-frequency questionnaire to assess lycopene intake in a case-control study of prostate cancer in North Carolina. Plasma alpha-tocopherol and beta-carotene levels were measured using high-performance liquid chromatography. XRCC1 genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism. The final dataset included 77 cases and 174 controls with complete questionnaires, genotyping, and plasma analyses. Among men with the Arg/Arg genotype at codon 399, odds ratios (ORs) for prostate cancer risk associated with medium (732-1,529 mug/day) and high (>1,529 mug/day) lycopene intake were 0.59 (95% confidence interval = 0.23-1.50) and 0.21 (0.06-0.71), respectively (P(trend) < 0.01). Similar analyses for persons with Arg/Gln or Gln/Gln genotypes produced null results. Above-median (1,048 mug/day) lycopene intake combined with above-median levels of alpha-tocopherol and beta-carotene was associated with an OR of 0.11 (0.02-0.65) among men with the Arg/Arg genotype but not those with at least one Gln allele (P(interaction) = 0.01). Although limited by small sample size, these findings indicate that the association between lycopene and prostate cancer is complex and may be modified by other antioxidants and by XRCC1 genotype. [ABSTRACT FROM AUTHOR]

Although high vegetable intakes have been associated with a lower risk of colorectal cancer, this relation is less well established for the precursor lesions, adenomatous polyps. With a case-control design involving adenomatous polyp cases (n = 564), colonoscopy-negative controls who were polyp free at colonoscopy (n = 682), and community controls (n = 535), this 1991-1994 Minnesota Cancer Prevention Research Unit study investigated the relation between fruit and vegetable consumption and first incident adenomatous polyps. Dietary intake was assessed using a food frequency questionnaire. For women, adenoma risk was approximately halved in the highest versus lowest quintile of juice consumption (cases vs. colonoscopy-negative controls: odds ratio (OR) = 0.50, 95% confidence interval (CI): 0.27, 0.92; cases vs. community controls: OR = 0.56, 95% CI: 0.30, 1.06). The association was stronger for adenomas with moderate or severe dysplasia compared with mild dysplasia. Juice was not associated with adenoma risk in men. The results for fruits, vegetables, total fruits and vegetables, green leafy vegetables, and several botanically and phytochemically defined subgroups generally were not statistically significant. Because elevated vegetable consumption has been associated with a lower risk of colorectal cancer, vegetables may have a stronger role in preventing the progression of adenomas to carcinomas rather than in preventing the initial appearance of adenomas. [ABSTRACT FROM AUTHOR]

Gravidity and parity have strong inverse relations with endometrial cancer occurrence. To determine whether gravidity masks an association with other reproductive factors, the authors analyzed data from a cohort study of 24,848 postmenopausal Iowa women aged 55-69 years who were cancer free at baseline in 1986 and who had not had a hysterectomy. During 5 years of follow-up, 167 incident endometrial cancer cases were documented. As expected, the mean gravidity of cases was lower than that of noncases (2.6 vs. 3.5, p < 0.0001). Endometrial cancer occurrence was associated positively with early age at menarche, late age natural menopause, and total length of ovulation span, but history of infertility and ages at first and last pregnancy were unrelated to risk after adjustment for gravidity. Two additional factors remained statistically significant independent of gravidity: a history of ever (vs. never) having had an induced abortion (relative risk = 2.5, 95% confidence interval 1.1-5.7) and timing of spontaneous abortions (miscarriages). Results suggest that a miscarriage late in reproductive life, followed by lack of a subsequent full-term pregnancy, may be marker for progesterone deficiency. If so, the findings support the 'unopposed' estrogen hypothesis for the etiology of endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is hypothesized to contribute to the pathogenesis of several chronic diseases. Numerous dietary and lifestyle factors are associated with oxidative stress; however, little is known about associations of genetic factors, individually or jointly with dietary and lifestyle factors, with oxidative stress in humans. Methods: We genotyped 22 haplotype-tagging single nucleotide polymorphisms (SNPs) in 3 antioxidant enzyme (AE) genes and 79 SNPs in 14 DNA base excision repair (BER) genes to develop oxidative stress-specific AE and BER genetic risk scores (GRS) in two pooled cross-sectional studies ( n = 245) of 30-74-year-old, White, cancer- and inflammatory bowel disease-free adults. Of the genotypes, based on their associations with a systemic oxidative stress biomarker, plasma F 2 -isoprostanes (FiP) concentrations, we selected 4 GSTP1 SNPs for an AE GRS, and 12 SNPs of 5 genes ( XRCC1 , TDG , PNKP , MUTYH , and FEN1 ) for a BER GRS. We also calculated a previously-reported, validated, questionnaire-based, oxidative stress biomarker-weighted oxidative balance score (OBS) comprising 17 anti- and pro-oxidant dietary and lifestyle exposures, with higher scores representing a higher predominance of antioxidant exposures. We used general linear regression to assess adjusted mean FiP concentrations across GRS and OBS tertiles, separately and jointly. Results: The adjusted mean FiP concentrations among those in the highest relative to the lowest oxidative stress-specific AE and BER GRS tertiles were, proportionately, 11.8% ( p = 0.12) and 21.2% ( p = 0.002) higher, respectively. In the joint AE/BER GRS analysis, the highest estimated mean FiP concentration was among those with jointly high AE/BER GRS. Mean FiP concentrations across OBS tertiles were similar across AE and BER GRS strata. Conclusion: Our pilot study findings suggest that DNA BER, and possibly AE, genotypes collectively may be associated with systemic oxidative stress in humans, and support further research in larger, general populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mao, Gray, Thyagarajan and Bostick.)

Importance: Variants in the vitamin D-binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies., Objective: To estimate supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 (NG&#95;012837.3:g.57904T>G NP&#95;001191235.1:p.Asp432Glu) and rs4588 (NG&#95;012837.3:g.57915C>A NP&#95;001191235.1:p.Thr436Lys)., Design, Setting, and Participants: Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022., Interventions: Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo., Main Outcomes and Measures: One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis., Results: Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D3 relative to no vitamin D3, 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D3 relative to no vitamin D3, 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent., Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform-encoding rs4588*A allele may particularly benefit from vitamin D3 and/or calcium supplementation for colorectal adenoma prevention., Trial Registration: ClinicalTrials.gov Identifier: NCT00153816.

One potential mechanism by which diet and lifestyle may affect chronic disease risk and subsequent mortality is through chronic systemic inflammation. In this study, we investigated whether the inflammatory potentials of diet and lifestyle, separately and combined, were associated with all-cause, all-CVD and all-cancer mortality risk. We analysed data on 18 484 (of whom 4103 died during follow-up) Black and White men and women aged ≥45 years from the prospective REasons for Geographic and Racial Differences in Stroke study. Using baseline (2003-2007) Block 98 FFQ and lifestyle questionnaire data, we constructed the previously validated inflammation biomarker panel-weighted, 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS) to reflect the overall inflammatory potential of diet and lifestyle. From multivariable Cox proportional hazards models, the hazards ratios (HR) and their 95 % CI for the DIS-all-cause mortality and LIS-all-cause mortality risk associations were 1·32 (95 % CI (1·18, 1·47); P for trend < 0·01) and 1·25 (95 % CI (1·12, 1·38); P for trend < 0·01), respectively, among those in the highest relative to the lowest quintiles. The findings were similar by sex and race and for all-cancer mortality, but weaker for all-CVD mortality. The joint HR for all-cause mortality among those in the highest relative to the lowest quintiles of both the DIS and LIS was 1·91 (95 % CI 1·57, 2·33) ( P for interaction < 0·01). Diet and lifestyle, via their contributions to systemic inflammation, separately, but perhaps especially jointly, may be associated with higher mortality risk among men and women.

Dietary and lifestyle evolutionary discordance is hypothesised to play a role in the aetiology of CVD, including CHD and stroke. We aimed to investigate associations of a previously reported, total (dietary plus lifestyle) evolutionary-concordance (EC) pattern score with incident CVD, CHD and stroke. We used multivariable Cox proportional hazards regression to investigate associations of the EC score with CVD, CHD and stroke incidence among USA Black and White men and women ≥45 years old in the prospective REasons for Geographic and Racial Differences in Stroke study (2003-2017). The EC score comprised seven equally weighted components: a previously reported dietary EC score (using Block 98 FFQ data) and six lifestyle characteristics (alcohol intake, physical activity, sedentary behaviour, waist circumference, smoking history and social network size). A higher score indicates a more evolutionary-concordant dietary/lifestyle pattern. Of the 15 467 participants in the analytic cohort without a CVD diagnosis at baseline, 1563 were diagnosed with CVD (967 with CHD and 596 with stroke) during follow-up (median 11·0 years). Among participants in the highest relative to the lowest EC score quintile, the multivariable-adjusted hazards ratios and their 95 % CI for CVD, CHD and stroke were, respectively, 0·73 (0·62, 0·86; P trend < 0·001), 0·72 (0·59, 0·89; P trend < 0·001) and 0·76 (0·59, 0·98; P trend = 0·01). The results were similar by sex and race. Our findings support that a more evolutionary-concordant diet and lifestyle pattern may be associated with lower risk of CVD, CHD and stroke.

Background: Inflammation is implicated in the etiology of various aging-related diseases. Numerous dietary and lifestyle factors contribute to chronic systemic inflammation; genetic variation may too. However, despite biological plausibility, little is known about associations of antioxidant enzyme (AE) and DNA base excision repair (BER) genotypes with human systemic inflammation. Methods: We genotyped 22 single nucleotide polymorphisms (SNPs) in 3 AE genes, and 79 SNPs in 14 BER genes to develop inflammation-specific AE and BER genetic risk scores (GRS) in two pooled cross-sectional studies ( n = 333) of 30-74-year-old White adults without inflammatory bowel disease, familial adenomatous polyposis, or a history of cancer or colorectal adenoma. Of the genotypes, based on their associations with a biomarker of systemic inflammation, circulating high sensitivity C-reactive protein (hsCRP) concentrations, we selected 2 SNPs of 2 genes ( CAT and MnSoD ) for an AE GRS, and 7 SNPs of 5 genes ( MUTYH , SMUG1 , TDG , UNG , and XRCC1 ) for a BER GRS. A higher GRS indicates a higher balance of variant alleles directly associated with hsCRP relative to variant alleles inversely associated with hsCRP. We also calculated previously-reported, validated, questionnaire-based dietary (DIS) and lifestyle (LIS) inflammation scores. We used multivariable general linear regression to compare mean hsCRP concentrations across AE and BER GRS categories, individually and jointly with the DIS and LIS. Results: The mean hsCRP concentrations among those in the highest relative to the lowest AE and BER GRS categories were, proportionately, 13.9% ( p = 0.30) and 57.4% ( p = 0.009) higher. Neither GRS clearly appeared to modify the associations of the DIS or LIS with hsCRP. Conclusion: Our findings suggest that genotypes of DNA BER genes collectively may be associated with systemic inflammation in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mao, Gray, Gross, Thyagarajan and Bostick.)

Purpose: Plasma F 2 -isoprostanes (FiP) concentration, a reliably measured, valid, systemic oxidative stress biomarker, has been associated with multiple health-related outcomes; however, associations of most individual dietary and lifestyle exposures with FiP are unclear, and there is no reported oxidative balance score (OBS) comprising multiple dietary and/or lifestyle components weighted by their associations with FiP., Methods: To investigate cross-sectional associations of dietary and lifestyle characteristics with plasma FiP concentrations, we used multivariable general linear models to compare adjusted mean FiP concentrations across categories of dietary nutrient and whole-food intakes and lifestyle characteristics in two pooled cross-sectional studies (n = 386). We also developed equal-weight and weighted OBS (nutrient- and foods-based dietary OBS, lifestyle OBS, and total OBS), and compared adjusted mean FiP concentrations across OBS tertiles., Results: Among men and women combined, adjusted mean FiP concentrations were statistically significantly, proportionately 28.1% higher among those who were obese relative to those who were normal weight; among those in the highest relative to the lowest total nutrient intake tertiles, FiP concentrations were statistically significantly lower by 9.8% for carotenes, 13.6% for lutein/zeaxanthin, 10.9% for vitamin C, 12.2% for vitamin E, 11.5% for glucosinolates, and 5% for calcium. Of the various OBS, the weighted OBS that combined total nutrient intakes and lifestyle exposures was most strongly associated with FiP concentrations: among those in the highest relative to the lowest total OBS, mean FiP concentrations were statistically significantly 29.7% lower (P < 0.001)., Conclusion: Multiple dietary and lifestyle characteristics, individually, and especially collectively, may contribute to systemic oxidative stress., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Diet and lifestyle may affect risk for metabolic-associated fatty liver disease (MAFLD) by chronically elevating systemic inflammation., Objectives: In this study we investigated the separate and joint associations of dietary and lifestyle inflammation scores (DIS and LIS, respectively) with MAFLD risk., Methods: For this nested case-control study we identified and recruited 968 patients with MAFLD (defined as having a fatty liver index ≥60 plus ≥1 of the following conditions: overweight or obese, type II diabetes mellitus, evidence of metabolic dysregulation) and 964 controls from among 35-70-y-old men and women in the baseline phase of the Sabzevar Persian Cohort Study. We collected demographic, lifestyle, anthropometric, biochemical, and dietary intake information (via a validated FFQ) from which we calculated a circulating inflammation biomarker-weighted, predominantly whole foods and beverages-based, 19-component DIS and a 3-component LIS. We estimated DIS- and LIS-MAFLD associations using multivariable unconditional logistic regression. We also calculated equal-weight DIS and LIS to capture all potential mechanisms (inflammation plus other mechanisms) for associations of diet and lifestyle with MAFLD risk., Results: Among those in the highest relative to the lowest DIS and LIS tertiles, the multivariable-adjusted ORs and their 95% CIs were OR: 1.84; 95% CI: 1.61, 2.07; Ptrend < 0.001, and OR: 1.96; 95% CI: 1.69, 2.21; Ptrend < 0.001, respectively. For those in the highest relative to the lowest joint DIS and LIS tertile, the values were OR: 2.56; 95% CI: 2.19, 2.93; Pinteraction < 0.001. The findings were similar by sex. The third tertile values for the equal-weight DIS- and LIS-MAFLD associations were OR: 1.87; 95% CI: 1.41, 2.34; and OR: 2.16; 95% CI: 1.85, 2.46, respectively., Conclusions: Our results suggest that higher balances of pro- relative to anti-inflammatory dietary and lifestyle exposures, separately and especially jointly, may be associated with higher MAFLD risk among adults. Also, inflammation may be the primary mechanism through which diet affects MAFLD risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Chronic inflammation, associated with lifestyle and dietary factors, may contribute to colorectal carcinogenesis. To address this, we investigated associations of previously validated, inflammation biomarker panel-weighted, novel, 4-component lifestyle (LIS) and 19-component predominately whole foods-based dietary (DIS) inflammation scores with incident colorectal cancer (CRC) in the prospective Iowa Women's Health Study (IWHS; 1986-2012; n  = 34,254, of whom 1,632 developed CRC)., Methods: We applied the published scores' components' weights, summed the weighted components to constitute the scores (higher scores reflect a higher balance of pro-inflammatory exposures), and investigated LIS- and DIS-CRC associations using multivariable Cox proportional hazards regression., Results: The multivariable-adjusted hazards ratios (HR) and their 95% confidence intervals (CI) for CRC among participants in the highest relative to the lowest LIS and DIS quintiles were 1.47 (1.26, 1.72; P trend  < 0.01) and 1.07 (0.91, 1.25; P trend  = 0.22), respectively. The corresponding findings for distal colon cancers were HR 1.78 (1.29, 2.47) and HR 1.34 (0.98, 1.84), respectively. Among those in the highest relative to the lowest joint LIS/DIS quintile, the HR for CRC was 1.60 (95% CI 1.30, 1.98)., Conclusions: Our results suggest that a more pro-inflammatory lifestyle, alone and jointly with a more pro-inflammatory diet, may be associated with higher CRC risk.

Background: High sucrose intakes are hypothesized to increase colorectal cancer (CRC) risk by several mechanisms, and sucrose intakes have been consistently positively associated with CRC risk in case-control studies. However, all but one prospective study reported a null sucrose-CRC association. The only prospective study to report a positive association was the Iowa Women's Health Study (IWHS) of 35,221 cancer-free Iowa women, aged 55 - 69 years old at baseline in 1986, after four years of follow up., Materials and Methods: To address the discrepant findings in the literature, after 26 years of follow up in the IWHS, we updated and expanded on our earlier reported analyses. During follow up through 2012, 1,731 women were diagnosed with CRC. Baseline dietary intakes were assessed with a Willett semiquantitative food frequency questionnaire. We used multivariable Cox proportional hazards regression models to estimate adjusted hazards ratios (HRs) and their 95% confidence intervals (CI)., Results: For those in the highest relative to the lowest intake quintiles, the adjusted HRs (95% CI) for CRC were 1.04 (0.87-1.23; P trend = 0.59) for sucrose, 1.00 (0.82-1.21; P trend = 0.67) for sucrose-containing foods, and 1.01, (0.83-1.22; P trend = 0.56) for nondairy sucrose-containing foods, respectively. These findings did not differ substantially by colorectal site or according to categories of selected participant characteristics., Conclusions: Our findings do not support that intakes of sucrose or sucrose-containing foods are substantially associated with CRC risk among older women.

Differences in diet and lifestyle relative to those of our Paleolithic-era ancestors may explain current high incidences of chronic diseases, including colorectal cancer (CRC), in Westernized countries. Previously reported evolutionary-concordance diet and lifestyle pattern scores, reflecting closeness of diet and lifestyle patterns to those of Paleolithic-era humans, were associated with lower CRC incidence. Separate and joint associations of the scores with colorectal adenoma among men and women are unknown. To address this, we pooled data from three case-control studies of incident, sporadic colorectal adenomas ( n  = 771 cases, 1,990 controls), used participants' responses to food frequency and lifestyle questionnaires to calculate evolutionary-concordance diet and lifestyle pattern scores, and estimated the scores' associations with adenomas using multivariable unconditional logistic regression. The multivariable-adjusted odds ratios comparing those in the highest relative to the lowest diet and lifestyle score quintiles were 0.84 (95% confidence interval [CI] 0.62, 1.12; P trend :0.03) and 0.41 (95% CI 0.29, 0.59; P trend :<0.0001), respectively. The inverse associations were stronger for high-risk adenomas, and among those with both high relative to those with both low diet and lifestyle scores. These results suggest that more evolutionary-concordant diet and lifestyle patterns, separately and jointly, may be associated with lower risk for incident, sporadic colorectal adenoma.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.2002919 .

Introduction: We previously showed that the rectal mucosal immune environment among men who have sex with men (MSM) engaging in condomless receptive anal intercourse (CRAI) is immunologically distinct from that of men who do not engage in anal intercourse (AI). Here, we further examined these differences with quantitative immunohistochemistry to better understand the geographic distribution of immune markers of interest., Methods: We enrolled a cohort of MSM engaging in CRAI (n = 41) and men who do not engage in AI (n = 21) between October 2013 and April 2015. Participants were healthy, HIV-negative men aged 18-45 from the metro Atlanta area. We performed rectal mucosal sampling via rigid sigmoidoscopy during two study visits separated by a median of nine weeks and timed with sexual activity for MSM engaging in CRAI. We used standardized, automated immunohistochemistry and quantitative image analysis to investigate the rectal mucosal distribution of neutrophils (MPO), IL-17-producing cells (IL-17) and T regs (FOXP3) in the lamina propria, and cellular proliferation (Ki67) and adherens junction protein (E-cadherin) in the epithelium. We examined associations between biomarker expression and the rectal mucosal microbiota composition by 16s rRNA sequencing., Results: Relative to the colonic crypt base, IL-17, FOXP3, and MPO expression increased towards the rectal lumen, while Ki67 decreased and E-cadherin was more uniformly distributed. Throughout the rectal mucosa distribution examined, MSM engaging in CRAI had higher mean lamina propria MPO expression (p = 0.04) and epithelial Ki67 (p = 0.04) compared to controls. There were no significant differences in IL-17, FOXP3 or E-cadherin expression. We found no significant associations of the five biomarkers with the global rectal microbiota composition or the individual taxa examined., Conclusions: Understanding the mucosal distribution of inflammatory mediators can enhance our knowledge of the earliest events in HIV transmission. Neutrophil enrichment and crypt epithelial cell proliferation likely represent sub-clinical inflammation in response to CRAI in the rectal mucosa of MSM, which could increase the risk for HIV acquisition. However, the contributory role of the microbiota in mucosal inflammation among MSM remains unclear. HIV prevention may be enhanced by interventions that reduce inflammation or capitalize on the presence of specific inflammatory mechanisms during HIV exposure., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Purpose: Substantial basic science evidence suggests that oxidative stress may play a role in aging-related health outcomes, including cardiovascular diseases (CVD) and cancer, and oxidative stress markers were linked with all-cause and cause-specific mortality in epidemiologic studies. However, the associations of many individual dietary and lifestyle anti-/pro-oxidant exposures with mortality are inconsistent. Oxidative balance scores (OBS) that incorporated multiple dietary and lifestyle factors were previously developed and reported to reflect the collective oxidative effects of multiple exposures., Methods: We investigated associations of 11-component dietary and 4-component (physical activity, adiposity, alcohol, and smoking) lifestyle OBS (higher scores were considered more anti-oxidative) with all-cause and cause-specific mortality among women 55-69 years of age at baseline in the prospective Iowa Women's Health Study (1986-2012). We assessed OBS-mortality associations using multivariable Cox proportional hazards regression., Results: Of the 34,137 cancer-free women included in the analytic cohort, 18,058 died (4521 from cancer, and 6825 from CVD) during a mean/median 22.0/26.1 person-years of follow-up. Among participants in the highest relative to the lowest lifestyle OBS quintiles, the adjusted hazards ratios and their 95% confidence intervals for all-cause, all-cancer, and all-CVD mortality were 0.50 (0.48, 0.53), 0.47 (0.43, 0.52), and 0.54 (0.50, 0.58) (all P trend  < 0.001), respectively. The associations of the dietary OBS with mortality were close to null., Conclusion: Our findings, combined with results from previous studies, suggest that a predominance of antioxidant over pro-oxidant lifestyle exposures may be associated with lower all-cause, all-CVD, and all-cancer mortality risk., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Evolutionary discordance may contribute to the high burden of chronic disease-related mortality in modern industrialized nations. We aimed to investigate the associations of a 7-component, equal-weight, evolutionary-concordance lifestyle (ECL) score with all-cause and cause-specific mortality., Methods: Baseline data were collected in 2003-2007 from 17,465 United States participants in the prospective REasons for Geographic and Racial Differences in Stroke (REGARDS) study. The ECL score's components were: a previously reported evolutionary-concordance diet score, alcohol intake, physical activity, sedentary behavior, waist circumference, smoking history, and social network size. Diet was assessed using a Block 98 food frequency questionnaire and anthropometrics by trained personnel; other information was self-reported. Higher scores indicated higher evolutionary concordance. We used multivariable Cox proportional hazards regression models to estimate ECL score-mortality associations., Results: Over a median follow-up of 10.3 years, 3771 deaths occurred (1177 from cardiovascular disease [CVD], 1002 from cancer). The multivariable-adjusted hazard ratios (HR) (95% confidence intervals [CI]) for those in the highest relative to the lowest ECL score quintiles for all-cause, all-CVD, and all-cancer mortality were, respectively, 0.45 (0.40, 0.50), 0.47 (0.39, 0.58), and 0.42 (0.34, 0.52) (all P trend < 0.01). Removing smoking and diet from the ECL score attenuated the estimated ECL score-all-cause mortality association the most, yielding fifth quintile HRs (95% CIs) of 0.56 (0.50, 0.62) and 0.50 (0.46, 0.55), respectively., Conclusions: Our findings suggest that a more evolutionary-concordant lifestyle may be inversely associated with all-cause, all-CVD, and all-cancer mortality. Smoking and diet appeared to have the greatest impact on the ECL-mortality associations., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Exogenous exposures collectively may contribute to chronic, low-grade inflammation and increase risks for major chronic diseases and mortality. We previously developed, validated, and reported a novel, FFQ-based and lifestyle questionnaire-based, inflammation biomarker panel-weighted, predominantly whole foods-based 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS; comprising physical activity, alcohol intake, BMI, and current smoking status). Both scores were more strongly associated with circulating biomarkers of inflammation in 3 populations than were previously reported dietary inflammation indices. Associations of the DIS and LIS with mortality risk have not been reported., Objectives: To investigate separate and joint associations of the DIS and LIS with all-cause, all-cancer, and cardiovascular disease (CVD) mortality risks in the prospective Iowa Women's Health Study (1986-2012; n = 33,155 women, ages 55-69 years, of whom 17,431 died during follow-up, including 4379 from cancer and 6574 from CVD)., Methods: We summed each study participant's scores' components, weighted by their published weights, to yield the participant's inflammation score; a higher score was considered more pro-inflammatory. We assessed DIS and LIS mortality associations using multivariable Cox proportional hazards regression., Results: Among participants in the highest relative to the lowest DIS and LIS quintiles, the adjusted HRs for all-cause mortality were 1.11 (95% CI: 1.05-1.16) and 1.60 (95% CI: 1.53-1.68), respectively; for all-cancer mortality were 1.07 (95% CI: 0.97-1.17) and 1.51 (95% CI: 1.38-1.66), respectively; and for CVD mortality were 1.12 (95% CI: 1.03-1.21) and 1.79 (95% CI: 1.66-1.94), respectively (all Ptrend values < 0.01). Among those in the highest relative to the lowest joint LIS/DIS quintiles, the HRs for all-cause, all-cancer, and all-CVD mortality were 1.88 (95% CI: 1.71-2.08), 1.82 (95% CI: 1.50-2.20), and 1.92 (95% CI: 1.64-2.24), respectively., Conclusions: More pro-inflammatory diets and lifestyles, separately but especially jointly, may be associated with higher all-cause, all-cancer, and all-CVD mortality risks among women., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D 3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D 3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women ( P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none ( P trend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m 2 relative to those with a BMI < 22.5 kg/m 2 ( P trend = 0.17). Our results suggest that daily supplemental vitamin D 3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3-5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability. PREVENTION RELEVANCE: Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies., (©2020 American Association for Cancer Research.)

Background: Basic science literature strongly supports a role of oxidative stress in colorectal cancer (CRC) etiology, but in epidemiologic studies, associations of most individual exposures with CRC have been weak or inconsistent. However, recent epidemiologic evidence suggests that the collective effects of these exposures on oxidative balance and CRC risk may be substantial., Methods: Using food frequency and lifestyle questionnaire data from the prospective Iowa Women's Health Study (1986-2012), we investigated associations of 11-component dietary and 4-component lifestyle oxidative balance scores (OBS) with incident CRC using multivariable Cox proportional hazards regression., Results: Of the 33,736 cancer-free women aged 55-69 years at baseline, 1,632 developed CRC during follow-up. Among participants in the highest relative to the lowest dietary and lifestyle OBS quintiles (higher anti-oxidant relative to pro-oxidant exposures), the adjusted hazard ratios (HRs) and their 95% confidence intervals (CI) were, respectively, 0.77 (0.63, 0.94) ( P trend =0.02) and 0.61 (0.52, 0.71) ( P trend <0.0001). Among those in the highest relative to the lowest joint lifestyle/dietary OBS quintile, the HR was 0.45 (95% CI 0.26, 0.77)., Conclusions: Our findings suggest that a predominance of antioxidant over pro-oxidant dietary and lifestyle exposures-separately and especially jointly-may be inversely associated with CRC risk among older women.

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group ( P = 0.001), 46% in the calcium group ( P = 0.002), and 34% in the calcium + vitamin D group ( P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 ( GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% ( P = 0.0006), 75% ( P = 0.0002), and 60% ( P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer., (©2020 American Association for Cancer Research.)

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)-considered the best marker of total vitamin D exposure-is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [<30], insufficient [30 - <50], sufficient [≥50 nmol/L]). In the pooled analysis, multivariable-adjusted hazard ratios (HRs) for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI 1.44-3.49) among cases with the Gc2 isoform, and 0.94 (95% CI 0.68-1.22) among cases without Gc2 (P interaction = .0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (P interaction = .004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis., (© 2020 UICC.)

Background: Colorectal carcinogenesis is mechanistically linked to inflammation and is highly associated with diet and lifestyle factors that may affect chronic inflammation. We previously developed dietary (DIS) and lifestyle (LIS) inflammation scores, comprising inflammation biomarker-weighted components, to characterize the collective contributions of 19 food groups and four lifestyle exposures to systemic inflammation. Both scores were more strongly directly associated with circulating inflammation biomarkers in three validation populations, including a subset of the study population described below, than were the previously reported dietary inflammatory index and empirical dietary inflammatory pattern., Methods: We calculated the DIS and LIS in three pooled case-control studies of incident, sporadic colorectal adenoma ( N = 765 cases and 1,986 controls) with extensive dietary and lifestyle data, and investigated their associations with adenoma using multivariable unconditional logistic regression., Results: For those in the highest (more proinflammatory) relative to the lowest (more anti-inflammatory) quintiles of the DIS and LIS, the multivariable-adjusted ORs were 1.31 [95% confidence interval (CI), 0.98-1.75; P trend = 0.09] and 1.98 (95% CI, 1.48-2.66; P trend < 0.001), respectively. These associations were strongest for adenomas with high-risk characteristics and among men. Those in the highest relative to the lowest joint DIS/LIS quintile had a 2.65-fold higher odds (95% CI, 1.77-3.95) of colorectal adenoma., Conclusions: These results support that diets and lifestyles with higher balances of pro- to anti-inflammatory exposures may be associated with higher risk for incident, sporadic colorectal adenoma., Impact: Our findings support further investigation of the DIS and LIS in relation to colorectal neoplasms., (©2020 American Association for Cancer Research.)

Background: Chronically higher inflammation, likely contributed to by dietary and lifestyle exposures, may increase risk for colorectal cancer (CRC). To address this, we investigated associations of novel dietary (DIS) and lifestyle (LIS) inflammation scores with incident CRC in the prospective National Institutes of Health-American Association of Retired Persons Diet and Health Study (N = 453 465)., Methods: The components of our previously developed and externally validated 19-component DIS and 4-component LIS were weighted based on their strengths of associations with a panel of circulating inflammation biomarker concentrations in a diverse subset (N = 639) of participants in the REasons for Geographic and Racial Differences in Stroke Study cohort. We calculated the components and applied their weights in the National Institutes of Health-American Association of Retired Persons cohort at baseline, summed the weighted components (higher scores reflect a higher balance of proinflammatory exposures), and investigated associations of the scores with incident CRC using Cox proportional hazards regression. All statistical tests were two-sided., Results: Over a mean 13.5 years of follow-up, 10 336 participants were diagnosed with CRC. Among those in the highest relative to the lowest DIS and LIS quintiles, the multivariable-adjusted hazards ratios (HRs) and their 95% confidence intervals (CIs) were HR = 1.27 (95% CI = 1.19 to 1.35; P trend < .001) and 1.38 (95% CI = 1.30 to 1.48; P trend < .001), respectively. The associations were stronger among men and for colon cancers. The hazards ratio for those in the highest relative to the lowest joint DIS and LIS quintile was HR = 1.83 (95% CI = 1.68 to 1.99; P interaction < .001)., Conclusions: Aggregates of proinflammatory dietary and lifestyle exposures may be associated with higher risk for CRC., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Chronically higher inflammation, which may partly result from diet and lifestyle, is implicated in risk for multiple chronic diseases. The dietary inflammatory index (DII) and empirical dietary inflammatory pattern (EDIP), developed to characterize dietary contributions to systemic inflammation, have several limitations. There are no scores to characterize contributions of lifestyle to inflammation., Objectives: To reflect dietary/lifestyle contributions to inflammation, we developed novel, inflammation biomarker panel-weighted, dietary (DIS) and lifestyle (LIS) inflammation scores in a subset (n = 639) of the Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) cohort., Methods: We selected a priori 19 food groups and 4 lifestyle characteristics to comprise the DIS and LIS, respectively. We calculated the components' weights based on their strengths of association with an inflammation biomarker score [comprising high-sensitivity C-reactive protein (hsCRP), IL-6, IL-8, and IL-10] using multivariable linear regression. The sums of the weighted components constitute the scores, such that higher scores reflect, on balance, more proinflammatory exposures. We calculated the DIS, LIS, DII, and EDIP with cross-sectional data from the remaining REGARDS cohort (  n = 14,210 with hsCRP measurements) and 2 other study populations with hsCRP and/or an 8-component inflammation biomarker panel, and investigated their associations with circulating inflammation biomarker concentrations using multivariable logistic regression., Results: In REGARDS, those in the highest relative to the lowest DIS, LIS, DII, and EDIP quintiles had statistically significant 1.66-, 4.29-, 1.56-, and 1.32-fold higher odds of a high hsCRP concentration (>3 mg/dL), respectively (all P-trend < 0.001). Those in the highest relative to the lowest joint DIS/LIS quintile had a statistically significant 7.26-fold higher odds of a high hsCRP concentration. Similar findings were noted in the other 2 validation populations., Conclusion: Our results support that dietary and lifestyle exposures collectively contribute substantially to systemic inflammation, and support the use of our novel DIS and LIS., (Copyright © American Society for Nutrition 2019.)

Background: Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC- rs4588*A (Thr436Lys) variant encoding the vitamin D-binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability., Methods: We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided., Results: The odds of having 25(OH)D concentrations less than 50 nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588*A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, P trend = 1.2 × 10 -8 ). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (≥ 50 nmol/L), relative to deficient (< 30 nmol/L), were associated with a 53% lower CRC risk among individuals with the DBP2 isoform (RR = 0.47, 95% CI = 0.33 to 0.67), but with a non-statistically significant 12% lower risk among individuals without it (RR = 0.88, 95% CI = 0.61 to 1.27) ( P heterogeneity = .01)., Conclusions: Our results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotype linked to vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention., (© The Author(s) 2020. Published by Oxford University Press.)

The physical gut barrier, comprised of a thick mucus layer and the epithelium, plays an important role in defense against microbes and foreign antigens. Calcium and vitamin D may be involved in maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which may lead to endotoxemia and inflammation, and contribute to colorectal carcinogenesis. We investigated supplemental calcium (1200 mg, daily) and/or vitamin D 3 (1000 IU daily) effects on intestinal barrier function-related biomarkers in a subset of 105 participants from a large colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of the tight junction proteins claudin-1 (CLDN1), occludin (OCLD), and mucin-12 (MUC12) in the normal-appearing colorectal mucosa using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, in the calcium relative to the no calcium group, the CLDN1, OCLD, and MUC12 expression increased by 14% (P = 0.17), 23% (P = 0.11), and 22% (P = 0.07), respectively. In secondary analyses, the estimated calcium treatment effects were greater among participants with baseline serum 25-OH-vitamin D concentrations below the median value of 22.69 ng/mL (CLDN1: 29%, P = 0.04; OCLD: 36%, P = 0.06; MUC12: 35%, P = 0.05). There were no biomarker expression changes in the vitamin D 3 alone group; however, modest increases were found in the combined calcium/vitamin D 3 group. At baseline, obesity, history of a sessile-serrated adenoma, colorectal MIB-1/Ki-67 expression, and a family history of colorectal cancer were associated with CLDN1, OCLD, and MUC12 expression. Our study supports continued investigation of factors that could affect intestinal mucosal barrier integrity relevant to colorectal carcinogenesis., (© 2019 Wiley Periodicals, Inc.)

Ca and dairy product intakes may be inversely associated with all-cause and cause-specific mortality, and non-Ca components of dairy products, such as insulin-like growth factor-1, may be independently associated with mortality. We investigated associations of Ca and dairy product intakes with all-cause, all-cancer, colorectal cancer (CRC) and CHD mortality among 35 221 55- to 69-year-old women in the prospective Iowa Women's Health Study, who were cancer-free in 1986. We assessed diet using a Willett FFQ, and associations using multivariable Cox proportional hazards regression. We estimated residuals from linear regression models of dairy products with dietary Ca to investigate total and specific dairy products independent of their Ca content. Through 2012, 18 687 participants died, including 4665 from cancer (including 574 from CRC) and 3603 from CHD. For those in the highest relative to the lowest quintiles of intake, the multivariable-adjusted hazard ratios (HR) and 95 % CI for total Ca (dietary plus supplemental) were 0·88 (0·83, 0·93; P trend=0·001) for all-cause mortality, 0·91 (0·81, 1·02; P trend=0·34) for all-cancer mortality, 0·60 (0·43, 0·83; P trend=0·002) for CRC mortality and 0·73 (0·64, 0·83; P trend &lt;0·0001) for CHD mortality. The corresponding HR for associations of whole milk, whole milk residuals, and low-/non-fat milk residuals with all-cause mortality were 1·20 (95 % CI 1·13, 1·27), 1·20 (95 % CI 1·13, 1·28) and 0·91 (95 % CI 0·86, 0·96), respectively. These results suggest that Ca may be associated with lower risk of all-cause, CRC and CHD mortality, and that non-Ca components of milk may be independently associated with mortality.

Vitamin D and calcium supplementation are postulated to have chemopreventive effects against colorectal neoplasia, yet in our previously reported randomized trial, there was no overall efficacy of calcium and/or vitamin D 3 against colorectal adenoma recurrence. It is possible vitamin D 3 and calcium chemopreventive effects are not detectable until beyond the 3- to 5-year follow-up captured in that trial. Accordingly, we explored possible vitamin D and calcium effects on posttreatment (observational) adenoma occurrence. In this secondary analysis of the observational follow-up phase of the Vitamin D/Calcium Polyp Prevention Study, participants who completed the treatment phase were invited to be followed for one additional surveillance colonoscopy cycle. We evaluated adenoma occurrence risk at surveillance colonoscopy, with a mean of 55 ± 15 months after treatment follow-up, according to randomized treatment with vitamin D versus no vitamin D, calcium versus no calcium, and calcium plus vitamin D versus calcium alone. Secondary outcomes included advanced and multiple adenomas. Among the 1,121 participants with observational follow-up, the relative risk (95% confidence interval, CI) of any adenoma was 1.04 (0.93-1.17) for vitamin D versus no vitamin D; 0.95 (0.84-1.08) for calcium versus no calcium; 1.07 (0.91-1.25) for calcium plus vitamin D versus calcium; and 0.96 (0.81-1.15) for calcium plus vitamin D versus neither. Risks of advanced or multiple adenomas also did not differ by treatment. Our results do not support an association between supplemental calcium and/or vitamin D 3 for 3 to 5 years and risk of recurrent colorectal adenoma at an average of 4.6 years after treatment., (©2019 American Association for Cancer Research.)

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ 1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D 3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D 3 and vitamin D 3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFβ 1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ 1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D 3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ 1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ 1 alone, and TGFα relative to TGFβ 1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms., (© 2018 Wiley Periodicals, Inc.)

Background: Despite considerable biological plausibility, other than for calcium, there are few reported epidemiologic studies on mineral intake-colorectal cancer associations, none of which investigated multiple minerals in aggregate., Methods: Accordingly, we incorporated 11 minerals into a mineral score and investigated its association with incident colorectal cancer in the Iowa Women's Health Study, a prospective cohort study of 55- to 69-year-old women who completed a food frequency questionnaire in 1986. In the analytic cohort ( n = 35, 221), 1,731 incident colorectal cancer cases were identified via the State Health Registry of Iowa. Participants' calcium, magnesium, manganese, zinc, selenium, potassium, and iodine intakes were ranked 1 to 5, with higher ranks indicating higher, potentially anticarcinogenic, intakes, whereas for iron, copper, phosphorus, and sodium intakes, the rankings were reversed to account for their possible procarcinogenic properties. The rankings were summed to create each woman's mineral score. The mineral score-incident colorectal cancer association was estimated using multivariable Cox proportional hazards regression., Results: There was decreasing risk with an increasing score ( P trend = 0.001). The hazard ratios and 95% confidence intervals (CI) for those in mineral score quintiles 2 to 5 relative to those in the lowest were 0.91 (CI, 0.88-1.08), 0.85 (CI, 0.75-0.95), 0.86 (CI, 0.75-0.97), and 0.75 (CI, 0.71-0.95), respectively., Conclusions: Our findings suggest that a predominance of putative anti- relative to pro-colorectal carcinogenic mineral intakes may be inversely associated with colorectal cancer risk., Impact: These results support further investigation of colorectal cancer etiology using composite mineral intake scores., (©2018 American Association for Cancer Research.)

Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m 2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m 2 ; 18.5% vs. 31%). BMI appeared to modify the effect of calcium supplementation on adenomas and especially on high risk-findings: in the VCPPS, there was a 44% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.56, 95% CI = 0.26-1.23), but not among overweight (RR = 1.09, 95% CI = 0.62-1.91) or obese (RR = 1.54, 95% CI = 0.92-2.57) individuals (p interaction = 0.03). Similarly, in the CPPS, there was a 56% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.44, 95% CI = 0.26-0.74), but not among overweight (RR = 0.87, 95% CI = 0.55-1.39) or obese (RR = 1.02, 95% CI = 0.57-1.82) individuals (p interaction = 0.02). Standardization of each trial's findings to the BMI distribution in the other attenuated calcium's protective effect on adenomas in the CPPS but enhanced it in the VCPPS. In conclusion, 1,200 mg/day calcium supplementation may reduce risk of colorectal adenomas among those with normal BMI but not in overweight or obese individuals; and differences in BMI distribution partially account for the apparent difference in calcium efficacy between the two trials., (© 2018 UICC.)

Calcium and, to a lesser extent, dairy products are consistently modestly inversely associated with colorectal cancer (CRC). Dairy products may contain components other than calcium and fat, such as insulin-like growth factor-1, that may affect CRC risk. In the prospective Iowa Women's Health Study, calcium, dairy product, and vitamin D intakes were assessed using a semiquantitative food frequency questionnaire. To investigate dairy products independent of their calcium components, we estimated residuals from linear regression models of their associations with dietary calcium. Of the 35,221 55-69-year-old cancer-free women at baseline in 1986, 1,731 developed CRC during follow-up through 2012. For those in the highest relative to the lowest intake quintiles, the adjusted hazards ratios and 95% confidence intervals from multivariable Cox proportional hazards regression models for overall and distal CRC were 0.81 (0.67-0.98; P trend = 0.004) and 0.59 (0.44-0.80; P trend = 0.003), respectively, for total calcium; and 0.79 (0.66-0.94; P trend = 0.01) and 0.69 (0.53-0.90; P trend = 0.003) for total dairy products, respectively. The various dairy product residuals were not associated with CRC. These results support that, among women, calcium and dairy products may be inversely associated with CRC-perhaps primarily distal CRC-but suggest that the non-calcium, non-fat component of dairy products may not be associated with CRC.

Introduction: Consumption of nuts, which contain multiple anti-carcinogenic components, has been inversely associated with colorectal cancer (CRC), particularly among women, but has not been investigated in relation to colorectal adenoma, the immediate precursor to most CRCs., Methods: We pooled data from three case-control studies of incident, sporadic colorectal adenoma (n = 785 cases, 2107 controls) in which dietary intakes were assessed using food frequency questionnaires, and analyzed the data using multivariable unconditional logistic regression., Results: Among men and women combined, the multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of total nut product (all nuts and peanut butter combined) intakes, for those who consumed 0.5-1.5, 2.0-5.5, and ≥6 servings/week relative to no nut consumption were 0.81 (0.58, 1.12), 0.86 (0.61, 1.23), and 0.93 (0.65, 1.31), respectively. However, among women, the corresponding ORs and 95% CIs were 0.62 (0.40, 0.97), 0.57 (0.35, 0.94), and 0.78 (0.48, 1.25), respectively., Conclusions: These results suggest that moderate nut consumption may be associated with lower risk for colorectal adenoma, primarily among women.

Various individual diet and lifestyle factors are associated with mortality. Investigating these factors collectively may help clarify whether dietary and lifestyle patterns contribute to life expectancy. We investigated the association of previously described evolutionary-concordance and Mediterranean diet pattern scores and a novel evolutionary-concordance lifestyle pattern score with all-cause and cause-specific mortality in the prospective Iowa Women's Health Study (1986-2012). We created the diet pattern scores from Willett FFQ responses, and the lifestyle pattern score from self-reported physical activity, BMI and smoking status, and assessed their associations with mortality, using multivariable Cox proportional hazards regression. Of the 35 221 55- to 69-year-old cancer-free women at baseline, 18 687 died during follow-up. The adjusted hazard ratios (HR) and 95 % CI for all-cause, all CVD, and all-cancer mortality among participants in the highest relative to the lowest quintile of the evolutionary-concordance lifestyle score were, respectively, 0·52 (95 % CI 0·50, 0·55), 0·53 (95 % CI 0·49, 0·57) and 0·51 (95 % CI 0·46, 0·57). The corresponding findings for the Mediterranean diet score were HR 0·85 (95 % CI 0·82, 0·90), 0·83 (95 % CI 0·76, 0·90) and 0·93 (95 % CI 0·84, 1·03), and for the evolutionary-concordance diet score they were close to null and not statistically significant. The lowest estimated risk was among those in the highest joint quintile of the lifestyle score and either diet score (both Pinteraction &lt;0·01). Our findings suggest that (1) a more Mediterranean-like diet pattern and (2) a more evolutionary-concordant lifestyle pattern, alone and in interaction with a more evolutionary-concordant or Mediterranean diet pattern, may be inversely associated with mortality.

To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop "treatable", pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 μg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential "treatable", pre-neoplastic, biomarkers of risk for colorectal neoplasms., Competing Interests: The authors have declared that no competing interests exist.

Objective: Because multiple observational studies and large, randomized controlled trials indicate that NSAIDs strongly reduce the risk of colorectal neoplasms, we investigated whether NSAID use masks associations of various other risk factors with colorectal neoplasms., Materials and Methods: Using pooled data from three case-control studies of incident, sporadic colorectal adenoma (pooled n=789 cases, 2035 polyp-free controls), using multivariable logistic regression, we investigated various risk factor-colorectal adenoma associations stratified by NSAID use., Results: Example multivariable-adjusted odds ratios [95% confidence intervals (CI)] for those in the highest relative to the lowest quartiles of exposure, by regular nonaspirin NSAID nonuse/use, respectively, were 1.57 (95% CI: 0.96-2.55) versus 1.14 (95% CI: 0.37, 3.49) for total fat, 1.37 (95% CI: 0.86-2.18) versus 0.70 (95% CI: 0.23-2.25) for saturated fat, 0.93 (95% CI: 0.68-1.28) versus 1.30 (95% CI: 0.61-2.75) for calcium, 0.89 (95% CI: 0.64-1.23) versus 1.38 (95% CI: 0.65-2.94) for total fruits and vegetables, and 0.85 (95% CI: 0.65-1.11) versus 0.94 (95% CI: 0.52-1.71) for physical activity. For current versus never smokers, the odds ratios (95% CIs) among regular non-NSAID users/nonusers were 2.91 (95% CI: 2.22-3.82) versus 1.75 (95% CI: 0.90-3.41), respectively, and for those who were obese versus those who were normal weight, they were 1.67 (95% CI: 1.28-2.17) versus 1.19 (95% CI: 0.69-2.04), respectively., Conclusion: Our findings suggest that regular nonaspirin NSAID use may mask, beyond simple confounding, associations of major risk factors with colorectal adenoma, and support routinely assessing such associations stratified by regular nonaspirin NSAID use.

Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D 3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/β (pIKKα/β), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/β expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/β. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/β expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Whereas diet and lifestyle are strongly implicated in the etiology of colorectal cancer, single exposures generally are weakly and inconsistently associated with the disease. Exposure patterns may be more helpful for investigating diet and lifestyle-colorectal cancer associations. Evolutionary-concordance diet and Mediterranean diet pattern scores were previously found to be inversely associated with colorectal adenoma. Methods: To investigate associations of these diet scores and an evolutionary-concordance lifestyle score (comprising smoking status, physical activity, and body mass index) with incident colorectal cancer, we analyzed data from the prospective Iowa Women's Health Study. Diet and lifestyle scores were calculated for each participant and categorized into quintiles, and associations estimated using Cox proportional hazards models. Results: Of the 35,221 55- to 69-year-old cancer-free women at baseline, 1,731 developed colorectal cancer during follow-up. The multivariable-adjusted HR comparing persons in the highest relative to the lowest quintile of the lifestyle score was 0.66 (95% confidence interval, 0.56-0.78; P trend < 0.01). Although the estimated associations of the evolutionary-concordance diet and Mediterranean diet scores alone with colorectal cancer were null, relative to those in the lowest tertiles of both the evolutionary-concordance diet and lifestyle scores, those in the highest tertiles of both scores were at the lowest risk ( P interaction < 0.01). Conclusions: Our findings suggest that a more evolutionary-concordant lifestyle, alone and in interaction with a more evolutionary-concordant diet pattern, may be inversely associated with colorectal cancer risk. Impact: These results support further investigation of colorectal cancer etiology using evolutionary-concordance dietary and lifestyle pattern scores. Cancer Epidemiol Biomarkers Prev; 27(10); 1195-202. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Although α- and γ-tocopherol are co-consumed antioxidants, circulating γ-tocopherol concentrations were paradoxically found to be inversely associated with total vitamin E intake and circulating α-tocopherol concentrations. There are limited data on this apparent paradox or on determinants of circulating γ-tocopherol concentrations., Objective: To help clarify possible determinants of circulating γ-tocopherol concentrations, we investigated associations of circulating γ-tocopherol concentrations with various dietary and lifestyle factors and biomarkers of oxidative stress and inflammation., Methods: We pooled cross-sectional data from 2 outpatient, adult, elective colonoscopy populations (pooled n = 419) on whom extensive dietary, lifestyle, and medical information was collected, and the following plasma concentrations were measured: α- and γ-tocopherol (via HPLC), F2-isoprostanes (FiPs; via gas chromatography-mass spectrometry), and high-sensitivity C-reactive protein (hsCRP; via latex-enhanced immunonephelometry). Multivariable general linear models were used to assess mean γ-tocopherol differences across quantiles of plasma antioxidant micronutrients, FiPs, and hsCRP; an oxidative balance score [OBS; a composite of anti- and pro-oxidant dietary and lifestyle exposures (a higher score indicates higher antioxidant relative to pro-oxidant exposures)]; and multiple dietary and lifestyle factors., Results: Adjusted for serum total cholesterol, mean γ-tocopherol concentrations among those in the highest relative to the lowest tertiles of circulating α-tocopherol and β-carotene, the OBS, and total calcium and dietary fiber intakes were 31.0% (P < 0.0001), 29.0% (P < 0.0001), 27.6% (P = 0.0001), 29.7% (P < 0.0001), and 18.6% (P = 0.008) lower, respectively. For those in the highest relative to the lowest tertiles of circulating FiPs and hsCRP, mean γ-tocopherol concentrations were 50% (P < 0.0001) and 39.0% (P < 0.0001) higher, respectively., Conclusions: These findings support the conclusion that circulating γ-tocopherol concentrations are inversely associated with antioxidant exposures and directly associated with systemic oxidative stress and inflammation in adults. Additional research on possible mechanisms underlying these findings and on whether circulating γ-tocopherol may serve as a biomarker of oxidative stress, inflammation, or both is needed.

Concentration of 25-hydroxyvitamin D3 (25(OH)D3), the main circulating form of vitamin D, is inversely associated with incident, sporadic colorectal adenoma risk. We investigated whether this association differs by 2 functional variants in the vitamin D-binding protein (DBP) gene, group-specific component (GC), that encode for common protein isoforms Gc1s, Gc1f, and Gc2 linked to differences in vitamin D metabolism. We pooled data (418 patients with adenoma and 524 polyp-free control subjects) from 3 colonoscopy-based case-control studies (Minnesota, 1991-1994; North Carolina, 1994-1997; South Carolina, 2002). We estimated 25(OH)D3-adenoma associations, stratified by DBP isoforms, using multivariable logistic regression. Higher 25(OH)D3 concentrations were inversely associated with colorectal adenoma risk among those with the Gc2 isoform (per 10-ng/mL increase in 25(OH)D3, odds ratio = 0.71, 95% confidence interval: 0.56, 0.90), but not among those with only Gc1 isoforms (odds ratio = 1.07, 95% confidence interval: 0.87, 1.32; P for interaction = 0.03). Thus, the vitamin D-incident, sporadic colorectal adenoma association may differ by common DBP isoforms, and patients with the Gc2 isoform may particularly benefit from maintaining higher circulating 25(OH)D3 concentrations for adenoma prevention.

Background: Recent data suggest that adenoma size and number are more important predictors of metachronous colorectal neoplasia than advanced histology. Furthermore, there is poor reproducibility in diagnosing advanced histology; high-grade dysplasia and villous histology. Therefore we developed a new metric, adenoma bulk, the sum of diameters of all baseline adenomas, regardless of advanced features., Goal: Compare the predictive value for metachronous advanced neoplasia of adenoma bulk to conventional paradigm., Study: Data were collected prospectively in a multicenter adenoma-chemoprevention trial (2004 to 2013). For the conventional paradigm, high-risk baseline findings were defined as ≥3 adenomas, large adenomas (≥1 cm) or adenomas with villous components or high-grade dysplasia. Adenoma bulk was examined across quartiles and as a continuous variable. Predictive characteristics (sensitivities, specificities, c-statistics) for metachronous advanced neoplasia using conventional criteria and adenoma bulk were calculated. receiver operator characteristic curves were computed using logistic regression., Results: In total, 1948 adults had index and follow-up colonoscopies (mean follow-up, 45.2 mo). Those with an adenoma bulk ≥10 mm (4th quartile) had a higher metachronous advanced neoplasia risk (14.4% vs. 6.9-8.2% in lower 3 quartiles; P=0.0002). The c-statistics and sensitivities (specificity fixed at 0.73) for the adenoma bulk and conventional models were 0.587 and 0.563 (P=0.17) and 0.396 and 0.390, respectively., Conclusions: Categorizing sporadic adenoma patients as high versus low risk for metachronous advanced neoplasia by adenoma bulk of

Somatic mutations in mitochondrial DNA have been reported in colorectal adenomatous polyps (adenomas), the precursors to most colorectal cancers. However, there are no reports of associations of germline variation in mitochondrial DNA with adenoma risk. We investigated associations of germline polymorphisms in the displacement loop (D-loop) and non-D-loop region of the mitochondrial genome with incident, sporadic colorectal adenoma in three pooled colonoscopy-based case-control studies (n = 327 adenoma cases, 420 controls) that used identical methods for case and risk factor ascertainment. We sequenced a 1124 bp fragment to identify all genetic variation in the mitochondrial D-loop region, and used the Sequenom platform to genotype 64 tagSNPs in the non-D-loop region. We used multivariable unconditional logistic regression to estimate associations of the polymorphisms with adenoma. The odds ratios (OR) for associations of four polymorphisms in the HV1 region (mt16294, mt16296, mt16278, mt16069) with adenoma were 2.30, 2.63, 3.34, and 0.56, respectively; all 95% confidence intervals (CI) excluded 1.0, however, after correction for multiple comparisons, none of the findings remained statistically significant. Similar results were found for six polymorphisms in the non-D-loop region. In the HV1 region poly C tract, relative to those with 5 repeats, the ORs for those with fewer or more repeats were, respectively, 2.29 (95%CI 1.07-4.89) and 0.63 (95%CI 0.36-1.08), but repeat numbers in the HV2 region were not associated with adenoma. These findings suggest that mitochondrial D-loop HV1 region polymorphisms may be associated with colorectal adenoma risk and support further investigation., (© 2018 Wiley Periodicals, Inc.)