Associations of dietary and lifestyle inflammation scores with mortality due to CVD, cancer, and all causes among Black and White American men and women.

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); Pfor trend < 0·01) and 1·25 (95 % CI (1·12, 1·38); Pfor 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) (Pfor 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 Inflammation Scores Are Inversely Associated with Metabolic-Associated Fatty Liver Disease among Iranian Adults: A Nested Case-Control Study.

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.

Associations of Evolutionary-Concordance Diet and Lifestyle Pattern Scores with Incident, Sporadic Colorectal Adenoma in a Pooled Case-Control Study.

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; Ptrend:0.03) and 0.41 (95% CI 0.29, 0.59; Ptrend:<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 .

Associations of Novel Lifestyle- and Whole Foods-Based Inflammation Scores with Incident Colorectal Cancer Among Women.

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; Ptrend < 0.01) and 1.07 (0.91, 1.25; Ptrend = 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.

Association of an evolutionary-concordance lifestyle pattern score with incident CVD among Black and White 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; Ptrend < 0·001), 0·72 (0·59, 0·89; Ptrend < 0·001) and 0·76 (0·59, 0·98; Ptrend = 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.

Associations of dietary, lifestyle, other participant characteristics, and oxidative balance scores with plasma F2-isoprostanes concentrations in a pooled cross-sectional study.

PURPOSE: Plasma F2-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.

Novel Dietary and Lifestyle Inflammation Scores Directly Associated with All-Cause, All-Cancer, and All-Cardiovascular Disease Mortality Risks Among Women.

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.

Dietary and Lifestyle Oxidative Balance Scores and Incident Colorectal Cancer Risk among Older Women; the Iowa Women's Health Study.

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) (Ptrend=0.02) and 0.61 (0.52, 0.71) (Ptrend<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.

Associations of dietary and lifestyle oxidative balance scores with mortality risk among older women: the Iowa Women's Health Study.

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 Ptrend < 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.

A novel evolutionary-concordance lifestyle score is inversely associated with all-cause, all-cancer, and all-cardiovascular disease mortality risk.

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.

Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common, inherited vitamin D-binding protein isoforms.

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 (Pinteraction = .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 (Pinteraction = .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.

Body mass index, calcium supplementation and risk of colorectal adenomas.

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/m2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m2 ; 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 (pinteraction = 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 (pinteraction = 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.

Effects of supplemental calcium and vitamin D on tight-junction proteins and mucin-12 expression in the normal rectal mucosa of colorectal adenoma patients.

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 D3 (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 D3 alone group; however, modest increases were found in the combined calcium/vitamin D3 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.

Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (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 D3 (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 D3 and vitamin D3 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), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 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 D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 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, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Development and Validation of Novel Dietary and Lifestyle Inflammation Scores.

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.

Associations of Nut Intakes with Incident Sporadic Colorectal Adenoma: A Pooled Case-Control Study.

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.

Associations of Calcium, Vitamin D, and Dairy Product Intakes with Colorectal Cancer Risk among Older Women: The Iowa Women's Health Study.

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; Ptrend = 0.004) and 0.59 (0.44-0.80; Ptrend = 0.003), respectively, for total calcium; and 0.79 (0.66-0.94; Ptrend = 0.01) and 0.69 (0.53-0.90; Ptrend = 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.

Associations of calcium and dairy product intakes with all-cause, all-cancer, colorectal cancer and CHD mortality among older women in the Iowa Women's Health Study.

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 <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.

Associations of Circulating 25-Hydroxyvitamin D3 Concentrations With Incident, Sporadic Colorectal Adenoma Risk According to Common Vitamin D-Binding Protein Isoforms.

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.

A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas.

BACKGROUND: Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS: We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS: Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).