Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women.

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.

Association between consumption of nonessential energy-dense food and body mass index among Mexican school-aged children: a prospective cohort study.

BACKGROUND/OBJECTIVES: Obesity prevalence in Mexican children has increased rapidly and is among the highest in the world. We aimed to estimate the longitudinal association between nonessential energy-dense food (NEDF) consumption and body mass index (BMI) in school-aged children 5 to 11 years, using a cohort study with 6 years of follow-up. SUBJECTS/METHODS: We studied the offspring of women in the Prenatal omega-3 fatty acid supplementation, child growth, and development (POSGRAD) cohort study. NEDF was classified into four main groups: chips and popcorn, sweet bakery products, non-cereal based sweets, and ready-to-eat cereals. We fitted fixed effects models to assess the association between change in NEDF consumption and changes in BMI. RESULTS: Between 5 and 11 years, children increased their consumption of NEDF by 225 kJ/day (53.9 kcal/day). In fully adjusted models, we found that change in total NEDF was not associated with change in children's BMI (0.033 kg/m2, [p = 0.246]). However, BMI increased 0.078 kg/m2 for every 418.6 kJ/day (100 kcal/day) of sweet bakery products (p = 0.035) in fully adjusted models. For chips and popcorn, BMI increased 0.208 kg/m2 (p = 0.035), yet, the association was attenuated after adjustment (p = 0.303). CONCLUSIONS: Changes in total NEDF consumption were not associated with changes in BMI in children. However, increases in the consumption of sweet bakery products were associated with BMI gain. NEDF are widely recognized as providing poor nutrition yet, their impact in Mexican children BMI seems to be heterogeneous.

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies.

BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Circulating inflammatory biomarkers, adipokines and breast cancer risk-a case-control study nested within the EPIC cohort.

BACKGROUND: Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status. METHODS: Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration. RESULTS: Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77-1.03), OR= 0.88 (0.76-1.01) and OR= 0.87 (0.75-1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05-1.29), OR= 1.11 (1.01-1.23), OR= 1.10 (0.99-1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68-1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66-0.97), CRP: OR = 0.85 (0.72-1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96-1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89-1.16), CRP: OR = 1.04 (0.92-1.16)]. CONCLUSIONS: Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation.

Modification of the association by sex between the prenatal exposure to di(2-ethylhexyl) phthalate and fat percentage in a cohort of Mexicans schoolchildren.

INTRODUCTION: Children's overweight and obesity are global public health problems, children with obesity have grater obesity risk as adults, thus leading to develop cardiometabolic diseases. Previous studies have found positive and significant associations between the exposure to phthalates and body mass index and body composition. OBJECTIVE: To evaluate the modification of the association by sex between DEHP exposure during pregnancy and the percentage of body fat in a cohort of Mexican schoolchildren. MATERIAL AND METHODS: The sample was comprised by children which had previously participated in a POSGRAD longitudinal study. A subsample of 190 mother-children binomials were included. Mothers' DEHP concentrations and its metabolites had been measured in the second trimester of pregnancy: Mono-2-ethylhexyl phthalate (MEHP), Mono-2-ethyl-5-carboxypentyl phthalate (MECPP), Mono-2-ethyl-5-hidroxyhexyl phthalate (MEHHP), and Mono-2-ethyl-5-oxohexyl phthalate (MEOHP). The children's adipose mass was measured at age 8, 9, and 10. Longitudinal data were analyzed using the mixed effects linear regression model, with intercept and random slope, adjusted by important confounders and stratified by sex. RESULTS: We found a differentiated effect by sex, the exposure to DEHP during pregnancy significantly increases the adipose mass in boys. The average increase was 0.058% (p = 0.02) for every 1% variation in MECPP; 0.047% (p = 0.04) in MEHHP; 0.051% (p = 0.03) in MEOHP, and 0.066% (p = 0.007) in MECPP. CONCLUSIONS: The results suggest an effect differentiated by sex; with boys being the main ones affected by the prenatal exposure to phthalates. However, we cannot rule out effects in girls.

Inflammatory biomarkers and risk of breast cancer among young women in Latin America: a case-control study.

BACKGROUND: Breast cancer incidence is increasing rapidly in Latin America, with a higher proportion of cases among young women than in developed countries. Studies have linked inflammation to breast cancer development, but data is limited in premenopausal women, especially in Latin America. METHODS: We investigated the associations between serum biomarkers of chronic inflammation (interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), leptin, adiponectin) and risk of premenopausal breast cancer among 453 cases and 453 matched, population-based controls from Chile, Colombia, Costa Rica, and Mexico. Odds ratios (OR) were estimated using conditional logistic regression models. Analyses were stratified by size and hormonal receptor status of the tumors. RESULTS: IL-6 (ORper standard deviation (SD) = 1.33 (1.11-1.60)) and TNF-α (ORper SD = 1.32 (1.11-1.58)) were positively associated with breast cancer risk in fully adjusted models. Evidence of heterogeneity by estrogen receptor (ER) status was observed for IL-8 (P-homogeneity = 0.05), with a positive association in ER-negative tumors only. IL-8 (P-homogeneity = 0.06) and TNF-α (P-homogeneity = 0.003) were positively associated with risk in the largest tumors, while for leptin (P-homogeneity = 0.003) a positive association was observed for the smallest tumors only. CONCLUSIONS: The results of this study support the implication of chronic inflammation in breast cancer risk in young women in Latin America. Largest studies of prospective design are needed to confirm these findings in premenopausal women.

Degree of food processing and breast cancer risk in black urban women from Soweto, South African: the South African Breast Cancer study.

This study aimed to investigate the association between consumption of ultra-processed foods, whole foods and breast cancer risk in black women from Soweto, South Africa. A population-based case (n 396)-control (n 396) study matched on age and residence, using data from the South African Breast Cancer study. Dietary intake was assessed using a validated quantified FFQ. Food items were categorised using the NOVA system ((1) unprocessed/minimally processed foods, (2) culinary ingredients, (3) processed foods and (4) ultra-processed foods). Conditional logistic regression models were used to estimate OR and 95 % CI of dietary contributions from each NOVA food group (as a percentage of total energy intake (EI)) and adjusting for potential confounders. Considering contributions to total EI per day, ultra-processed food consumption contributed to 44·8 % in cases and 47·9 % in controls, while unprocessed/minimally processed foods contributed to 38·8 % in cases and 35·2 % in controls. Unprocessed/minimally processed food consumption showed an inverse association with breast cancer risk overall (OR = 0·52, 95 % CI 0·35, 0·78), as well as in pre- and postmenopausal women separately (OR = 0·52, 95 % CI 0·27, 0·95 and OR = 0·55, 95 % CI 0·35, 0·89, respectively) and in women with progesterone positive breast cancer (OR = 0·23, 95 % CI 0·06, 0·86). There was no heterogeneity in association with breast cancer when analyses were stratified according to BMI. No significant associations were observed for the consumption of other NOVA food groups. Intake of unprocessed/minimally processed foods may reduce the risk of developing breast cancer in black women from Soweto, South Africa.

Adherence to cancer prevention recommendations is associated with a lower breast cancer risk in black urban South African women.

Breast cancer prevention is of great importance to reduce high incidence in South Africa. This study aimed to investigate adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Cancer Prevention Recommendations and the association with breast cancer risk in black urban women from Soweto, South Africa. A total of 396 breast cancer cases and 396 population-based controls from the South African Breast Cancer study (SABC) matched on age and demographic settings were included. Validated questionnaires were used to collect dietary and epidemiological data. To assess adherence to these recommendations, an eight-point adherence score was developed, using tertiles among controls for scoring each recommendation (0, 0·5 and 1) with zero indicating the lowest adherence to the recommendations. OR and 95 % CI were estimated using multivariate logistic regression models to analyse associations between the WCRF/AICR score and breast cancer risk. Greater adherence (>4·5 v. <3·25) to the 2018 WCRF/AICR Cancer Prevention Recommendations was associated with a significant inverse association with breast cancer risk overall (OR = 0·54, 95 % CI 0·35, 0·91) and specifically in postmenopausal women (OR = 0·55, 95 % CI 0·34, 0·95), in cases with oestrogen positive and progesterone positive breast cancer subtypes (OR = 0·54, 95 % CI 0·39, 0·89 and OR = 0·68, 95 % CI 0·43, 0·89, respectively) and in obese women (OR = 0·52, 95 % CI 0·35, 0·81). No significant association with breast cancer risk was observed in premenopausal women. Greater adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations may reduce breast cancer risk in this black urban population of Soweto. Adherence thereof should be encouraged and form a part of cost-effective breast cancer prevention guidelines.

Validity and reliability of the International Physical Activity Questionnaire (IPAQ) long-form in a subsample of female Mexican teachers.

OBJECTIVE: To evaluate the test-retest reliability and validity of the long-form International Physical Activity Questionnaire (IPAQ-long form). MATERIALS AND METHODS: A subsample of 86 teachers underwent telephone interviews and clinic visits in Mexico City. Through 22 months, physical activity (PA) levels were obtained from accelerometers (months 6 and 22) and IPAQ long-form (months 1, 3, 6, 9 and 12). Minutes per week of moderate (MPA), walking (WPA), vigorous (VPA) and moderate-to-vigorous physical activity (MVPA) were calculated for each intensity and domain. Variables were loga-rithmically transformed. Intra-class and Pearson correlations were used to determine the relationship between instru-ments. RESULTS: Test-retest reliability of the average IPAQs long-form varied across intensities and domains (ranged from r= 0.24 to r= 0.65). Minutes per week of VPA and MVPA ac-celerometer 1 (AC1) were fairly associated to International Physical Activity Questionnaire-long form 3 (IPAQ3) (r= 0.60 and r= 0.31, respectively) one week apart. CONCLUSIONS: IPAQ long-form is fairly reliable for MVPA and valid for as-sessing MVPA and VPA in a subsample of Mexican teachers.

Prevalent diabetes and risk of total, colorectal, prostate and breast cancers in an ageing population: meta-analysis of individual participant data from cohorts of the CHANCES consortium.

BACKGROUND: We investigated whether associations between prevalent diabetes and cancer risk are pertinent to older adults and whether associations differ across subgroups of age, body weight status or levels of physical activity. METHODS: We harmonised data from seven prospective cohort studies of older individuals in Europe and the United States participating in the CHANCES consortium. Cox proportional hazard regression was used to estimate the associations of prevalent diabetes with cancer risk (all cancers combined, and for colorectum, prostate and breast). We calculated summary risk estimates across cohorts using pooled analysis and random-effects meta-analysis. RESULTS: A total of 667,916 individuals were included with an overall median (P25-P75) age at recruitment of 62.3 (57-67) years. During a median follow-up time of 10.5 years, 114,404 total cancer cases were ascertained. Diabetes was not associated with the risk of all cancers combined (hazard ratio (HR) = 0.94; 95% confidence interval (CI): 0.86-1.04; I2 = 63.3%). Diabetes was positively associated with colorectal cancer risk in men (HR = 1.17; 95% CI: 1.08-1.26; I2 = 0%) and a similar HR in women (1.13; 95% CI: 0.82-1.56; I2 = 46%), but with a confidence interval including the null. Diabetes was inversely associated with prostate cancer risk (HR = 0.81; 95% CI: 0.77-0.85; I2 = 0%), but not with postmenopausal breast cancer (HR = 0.96; 95% CI: 0.89-1.03; I2 = 0%). In exploratory subgroup analyses, diabetes was inversely associated with prostate cancer risk only in men with overweight or obesity. CONCLUSIONS: Prevalent diabetes was positively associated with colorectal cancer risk and inversely associated with prostate cancer risk in older Europeans and Americans.

Body mass index and waist circumference in relation to the risk of 26 types of cancer: a prospective cohort study of 3.5 million adults in Spain.

BACKGROUND: A high body mass index (BMI) has been associated with increased risk of several cancers; however, whether BMI is related to a larger number of cancers than currently recognized is unclear. Moreover, whether waist circumference (WC) is more strongly associated with specific cancers than BMI is not well established. We aimed to investigate the associations between BMI and 26 cancers accounting for non-linearity and residual confounding by smoking status as well as to compare cancer risk estimates between BMI and WC. METHODS: Prospective cohort study with population-based electronic health records from Catalonia, Spain. We included 3,658,417 adults aged ≥ 18 years and free of cancer at baseline between 2006 and 2017. Our main outcome measures were cause-specific hazard ratios (HRs) with 99% confidence intervals (CIs) for incident cancer at 26 anatomical sites. RESULTS: After a median follow-up time of 8.3 years, 202,837 participants were diagnosed with cancer. A higher BMI was positively associated with risk of nine cancers (corpus uteri, kidney, gallbladder, thyroid, colorectal, breast post-menopausal, multiple myeloma, leukemia, non-Hodgkin lymphoma) and was positively associated with three additional cancers among never smokers (head and neck, brain and central nervous system, Hodgkin lymphoma). The respective HRs (per 5 kg/m2 increment) ranged from 1.04 (99%CI 1.01 to 1.08) for non-Hodgkin lymphoma to 1.49 (1.45 to 1.53) for corpus uteri cancer. While BMI was negatively associated to five cancer types in the linear analyses of the overall population, accounting for non-linearity revealed that BMI was associated to prostate cancer in a U-shaped manner and to head and neck, esophagus, larynx, and trachea, bronchus and lung cancers in an L-shaped fashion, suggesting that low BMIs are an approximation of heavy smoking. Of the 291,305 participants with a WC measurement, 27,837 were diagnosed with cancer. The 99%CIs of the BMI and WC point estimates (per 1 standard deviation increment) overlapped for all cancers. CONCLUSIONS: In this large Southern European study, a higher BMI was associated with increased risk of twelve cancers, including four hematological and head and neck (only among never smokers) cancers. Furthermore, BMI and WC showed comparable estimates of cancer risk associated with adiposity.

Reproductive factors and risk of breast cancer in black South African women.

PURPOSE: Breast cancer (BC) is increasing in black South African women, but few studies have investigated its risk factors. METHODS: We conducted an analysis of reproductive factors and BC risk in the South African Breast Cancer (SABC) study-a population-based case-control study of black South African women from Soweto that included 399 cases and 399 matched controls. Information on lifestyle and reproductive history was obtained by interviews. Conditional logistic regression was used to determine the association of reproductive factors with BC, adjusting for potential confounding factors. RESULTS: Seventy-five percent of all BC cases were ER+, 66% PR+, 30% HER2+, and 16% TN. None of the reproductive variables were associated with BC overall or by subtype in the overall population, nor in pre- (n = 135 cases) or in post-menopausal women separately. In HIV-negative pre-menopausal women (n = 97 cases), later age at first pregnancy and longer time between menarche and first full-time pregnancy were inversely related to BC risk (OR 0.89 (95% CI 0.82-0.97; and 0.93 95% CI 0.86-1.01, respectively). CONCLUSION: In this population of black South African women, reproductive factors were not associated with BC risk.

Infant Metabolome in Relation to Prenatal DHA Supplementation and Maternal Single-Nucleotide Polymorphism rs174602: Secondary Analysis of a Randomized Controlled Trial in Mexico.

BACKGROUND: Although DHA (22:6n-3) is critical for fetal development, results from randomized controlled trials (RCTs) of prenatal DHA supplementation report inconsistent effects on offspring health. Variants in fatty acid desaturase (FADS) genes that regulate the conversion of n-3 and n-6 essential fatty acids into their biologically active derivatives may explain this heterogeneity. OBJECTIVES: We investigated the effect of prenatal DHA supplementation on the offspring metabolome at age 3 mo and explored differences by maternal FADS single-nucleotide polymorphism (SNP) rs174602. METHODS: Data were obtained from a double-blind RCT in Mexico [POSGRAD (Prenatal Omega-3 Fatty Acid Supplementation and Child Growth and Development)] in which women (18-35 y old) received DHA (400 mg/d) or placebo from mid-gestation until delivery. Using high-resolution MS with LC, untargeted metabolomics was performed on 112 offspring plasma samples. Discriminatory metabolic features were selected via linear regression (P < 0.05) with false discovery rate (FDR) correction (q = 0.2). Interaction by SNP rs174602 was assessed using 2-factor ANOVA. Stratified analyses were performed, where the study population was grouped into carriers (TT, TC; n = 70) and noncarriers (CC; n = 42) of the minor allele. Pathway enrichment analysis was performed with Mummichog (P < 0.05). RESULTS: After FDR correction, there were no differences in metabolic features between infants whose mothers received prenatal DHA (n = 58) and those whose mothers received placebo (n = 54). However, we identified 343 differentially expressed features in the interaction analysis after FDR correction. DHA supplementation positively enriched amino acid and aminosugars metabolism pathways and decreased fatty acid metabolism pathways among offspring of minor allele carriers and decreased metabolites within the tricarboxylic acid cycle and galactose metabolism pathways among offspring of noncarriers. CONCLUSIONS: Our findings demonstrate differences in infant metabolism in response to prenatal DHA supplementation by maternal SNP rs174602 and further support the need to incorporate genetic analysis of FADS polymorphisms into DHA supplementation trials.This trial was registered at clinicaltrials.gov as NCT00646360.

Adherence to the South African food based dietary guidelines may reduce breast cancer risk in black South African women: the South African Breast Cancer (SABC) study.

OBJECTIVE: To determine the level of adherence and to assess the association between higher adherence to the South African food based dietary guidelines (SAFBDG) and breast cancer risk. DESIGN: Population-based, case-control study (the South African Breast Cancer study) matched on age and demographic settings. Validated questionnaires were used to collect dietary and epidemiological data. To assess adherence to the SAFBDG, a nine-point adherence score (out of eleven guidelines) was developed, using suggested adherence cut-points for scoring each recommendation (0 and 1). When the association between higher adherence to the SAFBDG and breast cancer risk was assessed, data-driven tertiles among controls were used as cut-points for scoring each recommendation (0, 0·5 and 1). OR and 95 % CI were estimated using multivariate logistic regression models. SETTING: Soweto, South Africa. PARTICIPANTS: Black urban women, 396 breast cancer cases and 396 controls. RESULTS: After adjusting for potential confounders, higher adherence (>5·0) to the SAFBDG v. lower adherence (<3·5) was statistically significantly inversely associated with breast cancer risk overall (OR = 0·56, 95 % CI 0·38, 0·85), among postmenopausal women (OR = 0·64, 95 % CI 0·40, 0·97) as well as for oestrogen-positive breast cancers (OR = 0·51, 95 % CI 0·32, 0·89). Only 32·3 % of cases and 39·1 % of controls adhered to at least half (a score >4·5) of the SAFBDG. CONCLUSIONS: Higher adherence to the SAFBDG may reduce breast cancer risk in this population. The concerning low levels of adherence to the SAFBDG emphasise the need for education campaigns and to create healthy food environments in South Africa to increase adherence to the SAFBDG.

Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study.

BACKGROUND: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. METHODS: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. RESULTS: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. CONCLUSION: Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.

Serum Phospholipid Fatty Acids and Mammographic Density in Premenopausal Women.

BACKGROUND: The role of fatty acids (FAs) on mammographic density (MD) is unclear, and available studies are based on self-reported dietary intake. OBJECTIVES: This study assessed the association between specific serum phospholipid fatty acids (PLFAs) and MD in premenopausal women. METHODS: The cross-sectional study DDM-Madrid recruited 1392 Spanish premenopausal women, aged 39-50 y, who attended a screening in a breast radiodiagnosis unit of Madrid City Council. Women completed lifestyle questionnaires and FFQs. Percentage MD was estimated using a validated computer tool (DM-Scan), and serum PLFA percentages were measured by GC-MS. Multivariable linear regression models were used to quantify the association of FA tertiles with MD. Models were adjusted for age, education, BMI, waist circumference, parity, oral contraceptive use, previous breast biopsies, and energy intake, and they were corrected for multiple testing. RESULTS: Women in the third tertile of SFAs showed significantly higher MD compared with those in the first tertile (ßT3vsT1 = 7.53; 95% CI: 5.44, 9.61). Elevated relative concentrations of palmitoleic (ßT3vsT1 = 3.12; 95% CI: 0.99, 5.25) and gondoic (ßT3vsT1 = 2.67; 95% CI: 0.57, 4.77) MUFAs, as well as high relative concentrations of palmitelaidic (ßT3vsT1 = 5.22; 95% CI: 3.15, 7.29) and elaidic (ßT3vsT1 = 2.69; 95% CI: 0.59, 4.79) trans FAs, were also associated with higher MD. On the contrary, women with elevated relative concentrations of n-6 (ω-6) linoleic (ßT3vsT1 = -5.49; 95% CI; -7.62, -3.35) and arachidonic (ßT3vsT1 = -4.68; 95% CI: -6.79, -2.58) PUFAs showed lower MD. Regarding desaturation indices, an elevated palmitoleic to palmitic ratio and a low ratio of oleic to steric and arachidonic to dihomo-γ-linolenic acids were associated with higher MD. CONCLUSIONS: Spanish premenopausal women with high relative concentrations of most SFAs and some MUFAs and trans FAs showed an increased MD, whereas those with high relative concentrations of some n-6 PUFAs presented lower density. These results, which should be confirmed in further studies, underscore the importance of analyzing serum FAs individually.

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos.

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies.

BACKGROUND: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. METHODS: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. RESULTS: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). CONCLUSIONS: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

Prospective analysis of circulating metabolites and breast cancer in EPIC.

BACKGROUND: Metabolomics is a promising molecular tool to identify novel etiologic pathways leading to cancer. Using a targeted approach, we prospectively investigated the associations between metabolite concentrations in plasma and breast cancer risk. METHODS: A nested case-control study was established within the European Prospective Investigation into Cancer cohort, which included 1624 first primary incident invasive breast cancer cases (with known estrogen and progesterone receptor and HER2 status) and 1624 matched controls. Metabolites (n = 127, acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, sphingolipids) were measured by mass spectrometry in pre-diagnostic plasma samples and tested for associations with breast cancer incidence using multivariable conditional logistic regression. RESULTS: Among women not using hormones at baseline (n = 2248), and after control for multiple tests, concentrations of arginine (odds ratio [OR] per SD = 0.79, 95% confidence interval [CI] = 0.70-0.90), asparagine (OR = 0.83 (0.74-0.92)), and phosphatidylcholines (PCs) ae C36:3 (OR = 0.83 (0.76-0.90)), aa C36:3 (OR = 0.84 (0.77-0.93)), ae C34:2 (OR = 0.85 (0.78-0.94)), ae C36:2 (OR = 0.85 (0.78-0.88)), and ae C38:2 (OR = 0.84 (0.76-0.93)) were inversely associated with breast cancer risk, while the acylcarnitine C2 (OR = 1.23 (1.11-1.35)) was positively associated with disease risk. In the overall population, C2 (OR = 1.15 (1.06-1.24)) and PC ae C36:3 (OR = 0.88 (0.82-0.95)) were associated with risk of breast cancer, and these relationships did not differ by breast cancer subtype, age at diagnosis, fasting status, menopausal status, or adiposity. CONCLUSIONS: These findings point to potentially novel pathways and biomarkers of breast cancer development. Results warrant replication in other epidemiological studies.

Maternal obesity leads to long-term altered levels of plasma ceramides in the offspring as revealed by a longitudinal lipidomic study in children.

BACKGROUND/OBJECTIVES: Maternal obesity is associated with increased risk of obesity and other symptoms of the metabolic syndrome in the offspring. Nevertheless, the molecular mechanisms and cellular factors underlying this enhanced disease susceptibility remain to be determined. Here, we aimed at identifying changes in plasma lipids in offspring of obese mothers that might underpin, and serve as early biomarkers of, their enhanced metabolic disease risk. SUBJECTS/METHODS: We performed a longitudinal lipidomic profiling in plasma samples from normal weight, overweight, and obese pregnant women and their children that participated in the Prenatal Omega-3 Fatty Acid Supplementation, Growth, and Development trial conducted in Mexico. At recruitment women were aged between 18 and 35 years and in week 18-22 of pregnancy. Blood samples were collected at term delivery by venipuncture from mothers and from the umbilical cord of their newborns and from the same infants at 4 years old under non-fasting conditions. Lipidomic profiling was done using ultra-performance liquid chromatography high-resolution mass spectrometry. RESULTS: Analysis of the lipidomic data showed that overweight and obese mothers exhibited a significant reduction in the total abundance of ceramides (Cer) in plasma, mainly of Cer (d18:1/20:0), Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), compared with mothers of normal body weight. This reduction was confirmed by the direct quantification of these and other ceramide species. Similar quantitative differences in the plasma concentration of Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), were also found between 4-year-old children of overweight and obese mothers compared with children of mothers of normal body weight. Noteworthy, children exhibited equal daily amounts of energy and food intake independently of the BMI of their mothers. CONCLUSIONS: Maternal obesity results in long-lasting changes in plasma ceramides in the offspring suggesting that these lipids might be used as early predictors of metabolic disease risk due to maternal obesity.