The Journal of Nutrition

Identification of 102 Correlations between Serum Metabolites and Habitual Diet in a Metabolomics Study of the Prostate, Lung, Colorectal, and Ovarian Cancer Trial

Metabolomics has proven useful for detecting objective biomarkers of diet that may help to improve dietary measurement. Studies to date, however, have focused on a relatively narrow set of lipid classes. The aim of this study was to uncover candidate dietary biomarkers by identifying serum metabolites correlated with self-reported diet, particularly metabolites in underinvestigated lipid classes, e.g. triglycerides and plasmalogens. We assessed dietary questionnaire data and serum metabolite correlations from 491 male and female participants aged 55-75 y in an exploratory cross-sectional study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Self-reported intake was categorized into 50 foods, food groups, beverages, and supplements. We examined 522 identified metabolites using 2 metabolomics platforms (Broad Institute and Massachusetts General Hospital). Correlations were identified using partial Pearson's correlations adjusted for age, sex, BMI, smoking status, study site, and total energy intake [Bonferroni-corrected level of 0.05/(50 × 522) = 1.9 × 10-6]. We assessed prediction of dietary intake by multiple-metabolite linear models with the use of 10-fold crossvalidation least absolute shrinkage and selection operator (LASSO) regression. Eighteen foods, beverages, and supplements were correlated with ≥1 serum metabolite at the Bonferroni-corrected significance threshold, for a total of 102 correlations. Of these, only 5 have been reported previously, to our knowledge. Our strongest correlations were between citrus and proline betaine (r = 0.55), supplements and pantothenic acid (r = 0.46), and fish and C40:9 phosphatidylcholine (PC) (r = 0.35). The multivariate analysis similarly found reasonably large correlations between metabolite profiles and citrus (r = 0.59), supplements (r = 0.57), and fish (r = 0.44). Our study of PLCO participants identified many novel food-metabolite associations and replicated 5 previous associations. These candidate biomarkers of diet may help to complement measures of self-reported diet in nutritional epidemiology studies, though further validation work is still needed.

Glycemic Index, Glycemic Load, and Risk of Ovarian Cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cohort

Ovarian cancer is the fifth most common cause of cancer death among women in the US, yet few modifiable risk factors have been established. Diets high in glycemic index (GI) and glycemic load (GL) have been linked to several cancers, but epidemiologic studies of ovarian cancer have yielded inconsistent results. In this study, we aimed to examine associations between GI or GL and ovarian cancer. We used prospective data from the Prostate, Lung, Colorectal, and Ovarian cohort. GI and GL were calculated from validated FFQs. Participants were women who were aged 60 to 74 y, did not have a history of cancer, and had both ovaries. Cox proportional hazard models were used to calculate HRs and 95% CIs for risk of ovarian cancer associated with quartiles of GI and GL. Analyses were performed separately for those who completed the dietary questionnaire at baseline (DQX) or later in the study (DHQ). From the DQX sample set, 181 cases were identified among 24,633 women with median follow-up of 12.1 y; there were 211 cases among 42,410 women in the DHQ set, with median follow-up of 8.9 y. After adjusting for age at dietary questionnaire completion, year of randomization, year of questionnaire, study center, and oral contraceptive use, the risk of ovarian cancer decreased by 43% (HR: 0.57; 95% CI: 0.37, 0.88) among those in the highest compared with those in the lowest quartile of GL (DQX). Those in the highest compared with those in the lowest quartile of GI (DHQ), had a 38% lower risk (HR: 0.62; 95% CI: 0.42, 1.00). We observed lower risk of ovarian cancer associated with higher GI and GL. Results should be interpreted with caution as they may have been influenced by limitations including lack of variability in dietary intake. Additional studies are needed to better understand what is driving these associations.

Associations of RBC and Serum Folate Concentrations with Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Genotypes in Female Chinese Adults

Although folate status is associated with cervical carcinogenesis, it is not clear whether folate deficiency is associated with risk of cervical intraepithelial neoplasia (CIN) progression and infection with high-risk human-papillomavirus (hrHPV). To evaluate the associations of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection, their interactions with prevalence of CIN grades, and RBC folate with the risk of CIN1 progressing to CIN2. Using data from the Shanxi CIN cohort of 2304 female Chinese adults, we used logistic-regression model to estimate ORs and prevalence ratios (PRs) of RBC and serum folate concentrations with prevalence of CIN grades and hrHPV infection. Categoric and spline analyses were used to evaluate the dose-response relations. We estimated the association of RBC folate with risk of CIN1 progressing to CIN2 in the nested case-control cohort. An inverse association was observed between increased RBC folate concentration and the odds of all CIN grades [quartile 1 (Q1) compared with Q4: OR: 2.28; 95% CI: 1.77, 2.93; Ptrend < 0.001]. Significant interaction of RBC folate and hrHPV infection was observed for prevalence of CIN2 or above (Pinteraction < 0.01). No associations were found between RBC and serum folate with PRs of hrHPV in each CIN grade. Over a median follow-up of 21.0 mo, RBC folate was associated with increased risk of CIN1 progressing to CIN2 (Q1 compared with Q4: OR: 3.86; 95% CI: 1.01, 14.76). Our study indicates that RBC folate concentration is associated with prevalence of CIN grades and CIN1 progression in female Chinese adults. Maintenance of normal folate status is important for reducing the risk of CIN and its progression in women with or without hrHPV infection.

Dietary Quality and Circulating Lipidomic Profiles in 2 Cohorts of Middle-Aged and Older Male Finnish Smokers and American Populations

Higher dietary quality is associated with lower disease risks and has not been examined extensively with lipidomic profiles. Our goal was to examine associations of the Healthy Eating Index (HEI)-2015, Alternate HEI-2010 (AHEI-2010), and alternate Mediterranean Diet Index (aMED) diet quality indices with serum lipidomic profiles. We conducted a cross-sectional analysis of HEI-2015, AHEI-2010, and aMED with lipidomic profiles from 2 nested case-control studies within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 627) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 711). We used multivariable linear regression to determine associations of the indices, derived from baseline food-frequency questionnaires (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: 1993-2001, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: 1985-1988) with serum concentrations of 904 lipid species and 252 fatty acids (FAs) across 15 lipid classes and 28 total FAs, within each cohort and meta-analyzed results using fixed-effect models for lipids significant at Bonferroni-corrected threshold in common in both cohorts. Adherence to HEI-2015, AHEI-2010, or aMED was associated positively with 31, 41, and 54 lipid species and 8, 6, and 10 class-specific FAs and inversely with 2, 8, and 34 lipid species and 1, 3, and 5 class-specific FAs, respectively. Twenty-five lipid species and 5 class-specific FAs were common to all indices, predominantly triacylglycerols, FA22:6 [docosahexaenoic acid (DHA)]-containing species, and DHA. All indices were positively associated with total FA22:6. AHEI-2010 and aMED were inversely associated with total FA18:1 (oleic acid) and total FA17:0 (margaric acid), respectively. The identified lipids were most associated with components of seafood and plant proteins and unsaturated:saturated fat ratio in HEI-2015; eicosapentaenoic acid plus DHA in AHEI-2010; and fish and monounsaturated:saturated fat ratio in aMED. Adherence to HEI-2015, AHEI-2010, and aMED is associated with serum lipidomic profiles, mostly triacylglycerols or FA22:6-containing species, which are related to seafood and plant proteins, eicosapentaenoic acid-DHA, fish, or fat ratio index components.

Association between Serum Folate and Vaginal High-Risk Human Papillomavirus Infections in United States Women

Serum concentration of folate was inversely associated with cervical intraepithelial neoplasia and cervical cancer in some studies. The association between folate and human papillomavirus (HPV) infection, a necessary cause of cervical cancer, has not been well elucidated. We evaluated whether serum folate concentrations were associated with high-risk HPV (hrHPV) infection. The study population was 11,801 females, aged 18-59 y, enrolled in the National Health and Nutrition Examination Survey (NHANES), from 2003 to 2016, in the United States. In this cross-sectional study, prevalence ratios (PRs) of vaginal hrHPV were calculated using logistic regression models, by quintiles of serum folate. Females in the lowest quintile had <21.3 nmol/L of folate. Approximately 23% of the females (2733/11,801) were hrHPV positive. In age-adjusted models, folate was significantly associated with hrHPV infection. The PRs and 95% confidence intervals (CIs) were (PR: 1.52; 95% CI: 1.37, 1.70) for the first, (PR: 1.29; 95% CI: 1.15, 1.44) for the second, (PR: 1.19; 95% CI: 1.06, 1.34) for the third, and (PR: 1.09; 95% CI: 0.96, 1.23) for the fourth quintiles, compared with the females in the highest quintile, with a significant P value for trend, <0.0001. The association remained statistically significant after the models were further adjusted for lifestyle and sexual risk factors for hrHPV infection; the females in the lowest quintile were more likely to have hrHPV infection than those in the highest quintile (PR: 1.40; 95% CI: 1.11, 1.53). Results from this sample of females in the United States suggest that serum folate concentration is inversely associated with hrHPV infection.