Placental efflux transporters and antiseizure or antidepressant medication use impact birth weight in MoBa cohort.

Low birth weight raises neonatal risks and lifelong health issues and is linked to maternal medication use during pregnancy. We examined data from the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, including 69,828 offspring with genotype data and 81,189 with maternal genotype data. We identified genetic risk variants in placental efflux transporters, calculated genetic scores based on alleles related to transporter activity, and assessed their interaction with prenatal use of antiseizure or antidepressant medication on offspring birth weight. Our study uncovered possible genetic variants in both offspring (rs3740066) and mothers (rs10248420; rs2235015) in placental efflux transporters (MRP2-ABCC2 and MDR1-ABCB1) that modulated the association between prenatal exposure to antiseizure medication and low birth weight in the offspring. Antidepressant exposure was associated with low birth weight, but there were no gene-drug interactions. The interplay between MRP2-ABCC2 and MDR1-ABCB1 variants and antiseizure medication may impact neonatal birth weight.

Parental infertility and offspring cardiometabolic trajectories: a pooled analysis of three European cohorts.

OBJECTIVE: To assess whether parental infertility is associated with differences in cardiometabolic trajectories in offspring. DESIGN: Pooled observational analysis in three prospective cohorts. SETTING: Three nationwide pregnancy cohorts. PATIENTS: A total of 14,609 singletons from the UK Avon Longitudinal Study of Parents and Children, the Portuguese Geraçao 21, and the Amsterdam Born Children and Their Development study. Each cohort contributed data up to ages 26, 12, and 13 years, respectively. INTERVENTION: Parental infertility is defined as time-to-pregnancy of ≥12 months (n = 1,392, 9.5%). MAIN OUTCOME MEASURES: Trajectories of body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol (LDL-C) level, high-density lipoprotein cholesterol (HDL-C) level, triglycerides level, and glucose level were compared in the offspring of couples with and without infertility. Trajectories were modeled using mixed-effects models with natural cubic splines adjusting for cohort, sex of the offspring, and maternal factors (age, BMI, smoking, educational level, parity, and ethnicity). Predicted levels of cardiometabolic traits up to 25 years of age were compared with parental infertility. RESULTS: Offspring of couples with infertility had increasingly higher BMI (difference in mean predicted levels by age 25 years: 1.09 kg/m2, 95% confidence interval [0.68-1.50]) and suggestively higher diastolic blood pressure at age 25 years (1.21 mmHg [-0.003 to 2.43]). Their LDL-C tended to be higher, and their HDL-C values tended to be lower over time (age: 25 years, LDL-C: 4.07% [-0.79 to 8.93]; HDL-C: -2.78% [-6.99 to 1.43]). At age 17 years, offspring of couples with infertility had higher waist circumference (1.05 cm [0.11-1.99]) and systolic blood pressure (age: 17 years; 0.93 mmHg [0.044-1.81]), but these differences attenuated at later ages. No intergroup differences in triglyceride and glucose level trajectories were observed. Further adjustment for paternal age, BMI, smoking, and educational level, and both parents' histories of diabetes and hypertension in the cohort with this information available (Avon Longitudinal Study of Parents and Children) did not attenuate intergroup differences. CONCLUSION: Offspring of couples with infertility relative to those of fertile couples have increasingly higher BMI over the years, suggestively higher blood pressure levels, and tend to have greater values of LDL-C and lower values of HDL-C with age.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

STUDY QUESTION: Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? SUMMARY ANSWER: Genetic instruments suggest that higher fasting insulin may increase infertility in women. WHAT IS KNOWN ALREADY: Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. STUDY DESIGN, SIZE, DURATION: This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). MAIN RESULTS AND THE ROLE OF CHANCE: In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. LIMITATIONS, REASONS FOR CAUTION: We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. WIDER IMPLICATIONS OF THE FINDINGS: Treatments for lower fasting insulin levels may reduce the risk of infertility in women. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Blood DNA methylation signature of diet quality and association with cardiometabolic traits.

AIMS: Diet quality might influence cardiometabolic health through epigenetic changes, but this has been little investigated in adults. Our aims were to identify cytosine-phosphate-guanine (CpG) dinucleotides associated with diet quality by conducting an epigenome-wide association study (EWAS) based on blood DNA methylation (DNAm) and to assess how diet-related CpGs associate with inherited susceptibility to cardiometabolic traits: body mass index (BMI), systolic blood pressure (SBP), triglycerides, type 2 diabetes (T2D), and coronary heart disease (CHD). METHODS AND RESULTS: Meta-EWAS including 5274 participants in four cohorts from Spain, the USA, and the UK. We derived three dietary scores (exposures) to measure adherence to a Mediterranean diet, to a healthy plant-based diet, and to the Dietary Approaches to Stop Hypertension. Blood DNAm (outcome) was assessed with the Infinium arrays Human Methylation 450K BeadChip and MethylationEPIC BeadChip. For each diet score, we performed linear EWAS adjusted for age, sex, blood cells, smoking and technical variables, and BMI in a second set of models. We also conducted Mendelian randomization analyses to assess the potential causal relationship between diet-related CpGs and cardiometabolic traits. We found 18 differentially methylated CpGs associated with dietary scores (P < 1.08 × 10-7; Bonferroni correction), of which 12 were previously associated with cardiometabolic traits. Enrichment analysis revealed overrepresentation of diet-associated genes in pathways involved in inflammation and cardiovascular disease. Mendelian randomization analyses suggested that genetically determined methylation levels corresponding to lower diet quality at cg02079413 (SNORA54), cg02107842 (MAST4), and cg23761815 (SLC29A3) were causally associated with higher BMI and at cg05399785 (WDR8) with greater SBP, and methylation levels associated with higher diet quality at cg00711496 (PRMT1) with lower BMI, T2D risk, and CHD risk and at cg0557921 (AHRR) with lower CHD risk. CONCLUSION: Diet quality in adults was related to differential methylation in blood at 18 CpGs, some of which related to cardiometabolic health.

We conducted a study to investigate the connection between diet quality, epigenetic changes, and cardiovascular health in adults. The study included 5274 participants from Spain, the USA, and the UK, combining data from four different cohorts. We assessed adherence to different healthy diets: Mediterranean style diet, plant-based diet, and Dietary Approaches to Stop Hypertension diet. We used advanced technology to analyse blood DNA methylation, which refers to chemical modifications in the DNA that can affect gene activity.We discovered 18 CpGs that showed differential methylation patterns related to the dietary scores. Importantly, 12 of these CpGs had previously been associated with cardiovascular disease or risk factors, suggesting a potential link between diet, epigenetic changes, and heart health. Some of the diet-related CpGs mapped to genes involved in pathways associated with cardiovascular disease. Moreover, using a method called Mendelian randomization, we found that several CpGs may have a causal association with body mass index, systolic blood pressure, and risk of type 2 diabetes and coronary heart disease.

Yearly attained adherence to Mediterranean diet and incidence of diabetes in a large randomized trial.

BACKGROUND: Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet. METHODS: PREDIMED (''PREvención con DIeta MEDiterránea'') was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n = 1147, control group), Mediterranean diet supplemented with extra virgin olive (n = 1154) or Mediterranean diet supplemented with mixed nuts (n = 1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups: < 8, 8-< 10, 10- < 12, and 12-14 points. The outcome was new-onset type 2 diabetes. RESULTS: Multivariable-adjusted hazard ratios from time-varying Cox models were 0.80 (95% confidence interval, 0.70-0.92) per + 2 points in Mediterranean Diet Adherence Screener (linear trend p = .001), and 0.46 (0.25-0.83) for the highest (12-14 points) versus the lowest (< 8) adherence. This inverse association was maintained after additionally adjusting for the randomized arm. Age- and sex-adjusted analysis of a validated plasma metabolomic signature of the Mediterranean Diet Adherence Screener (constituted of 67 metabolites) in a subset of 889 participants also supported these results. CONCLUSIONS: Dietary intervention trials should quantify actual dietary adherence throughout the trial period to enhance the benefits and to assist results interpretation. A rapid dietary assessment tool, yearly repeated as a screener, was able to capture a strong inverse linear relationship between Mediterranean diet and type 2 diabetes. Trial registration ISRCTN35739639.

Asociación de la actividad física con la funcionalidad de las lipoproteínas de alta densidad en una cohorte de base poblacional: el estudio REGICOR / Association of physical activity with high-density lipoprotein functionality in a population-based cohort: the REGICOR study

Introducción y objetivos Determinar la relación dosis-respuesta entre la actividad física en el tiempo libre (AFTL) actual y pasada, total y según su intensidad, y la funcionalidad de las lipoproteínas de alta densidad (HDL). Métodos Se seleccionó a 642 participantes de un estudio poblacional: la edad media era de 63,2 años y el 51,1% eran mujeres. Se incluyeron datos de la visita inicial y de un seguimiento a 4 años. La AFTL se evaluó mediante cuestionarios validados. Se determinó la capacidad de eflujo de colesterol y antioxidante en el seguimiento. Se utilizaron modelos de regresión lineal y aditivos para evaluar la relación dosis-respuesta. Resultados Se observó una relación inversa y lineal entre la AFTL total actual (entre 0-400 MET x min/día) y la capacidad antioxidante de HDL (coeficiente de regresión [beta]: -0,022; IC95%, -0,030; -0,013), con una meseta por encima de este umbral. Se observaron resultados similares para la AFTL de intensidad moderada (beta: -0,028; IC95%, -0,049; -0,007) y vigorosa (beta: -0,025; IC95%, -0,043; -0,007), pero no para AFTL de intensidad ligera. La AFTL en el seguimiento no se asoció con la capacidad de eflujo de colesterol. La AFTL basal no se asoció con la funcionalidad de HDL. Conclusiones La AFTL de intensidad moderada-vigorosa actual se asocia de forma no lineal con una mayor capacidad antioxidante de las partículas de HDL. Se observa un beneficio máximo con dosis intermedias-bajas de AFTL (0-400 MET x min/día). Nuestros resultados concuerdan con las recomendaciones de práctica de AFTL y sugieren una asociación con la funcionalidad de HDL (AU)

Introduction and objectives To determine the dose-response association between current and past leisure-time physical activity (LTPA), total and at different intensities, and high-density lipoprotein (HDL) functionality parameters. Methods Study participants (n=642) were randomly drawn from a large population-based survey. Mean age of the participants was 63.2 years and 51.1% were women. The analysis included data from a baseline and a follow-up visit (median follow-up, 4 years). LTPA was assessed using validated questionnaires at both visits. Two main HDL functions were assessed: cholesterol efflux capacity and HDL antioxidant capacity, at the follow-up visit. Linear regression and linear additive models were used to assess the linear and nonlinear association between LTPA and HDL functionality. Results Total LTPA at follow-up showed an inverse and linear relationship between 0 and 400 METs x min/d with HDL antioxidant capacity (regression coefficient [beta]: −0.022; 95%CI, −0.030, −0.013), with a plateau above this threshold. The results were similar for moderate (beta: −0.028; 95%CI, −0.049, −0.007) and vigorous (beta: −0.025; 95%CI, −0.043, −0.007), but not for light-intensity LTPA. LTPA at follow-up was not associated with cholesterol efflux capacity. Baseline LTPA was not associated with any of the HDL functionality parameters analyzed. Conclusions Current moderate and vigorous LTPA showed a nonlinear association with higher HDL antioxidant capacity. Maximal benefit was observed with low-intermediate doses of total LTPA (up to 400 METs x min/d). Our results agree with current recommendations for moderate-vigorous LTPA practice and suggest an association between PA and HDL functionality in the general population (AU)

Association of physical activity with high-density lipoprotein functionality in a population-based cohort: the REGICOR study.

INTRODUCTION AND OBJECTIVES: To determine the dose-response association between current and past leisure-time physical activity (LTPA), total and at different intensities, and high-density lipoprotein (HDL) functionality parameters. METHODS: Study participants (n=642) were randomly drawn from a large population-based survey. Mean age of the participants was 63.2 years and 51.1% were women. The analysis included data from a baseline and a follow-up visit (median follow-up, 4 years). LTPA was assessed using validated questionnaires at both visits. Two main HDL functions were assessed: cholesterol efflux capacity and HDL antioxidant capacity, at the follow-up visit. Linear regression and linear additive models were used to assess the linear and nonlinear association between LTPA and HDL functionality. RESULTS: Total LTPA at follow-up showed an inverse and linear relationship between 0 and 400 METs x min/d with HDL antioxidant capacity (regression coefficient [beta]: -0.022; 95%CI, -0.030, -0.013), with a plateau above this threshold. The results were similar for moderate (beta: -0.028; 95%CI, -0.049, -0.007) and vigorous (beta: -0.025; 95%CI, -0.043, -0.007), but not for light-intensity LTPA. LTPA at follow-up was not associated with cholesterol efflux capacity. Baseline LTPA was not associated with any of the HDL functionality parameters analyzed. CONCLUSIONS: Current moderate and vigorous LTPA showed a nonlinear association with higher HDL antioxidant capacity. Maximal benefit was observed with low-intermediate doses of total LTPA (up to 400 METs x min/d). Our results agree with current recommendations for moderate-vigorous LTPA practice and suggest an association between PA and HDL functionality in the general population.

Mediterranean Diet, Energy Restriction, Physical Activity, and Atherogenicity of Very-Low Density Lipoproteins: Findings from Two Randomized Controlled Trials.

SCOPE: Some very-low density lipoprotein (VLDL) properties may render them more pro-atherogenic. We aimed to assess whether a Mediterranean diet (MedDiet) or an energy-reduced MedDiet with increased physical activity improves them. METHODS AND RESULTS: In a sample of the PREvención con DIeta MEDiterránea (PREDIMED) study, a 1-year intervention with MedDiet with extra-virgin olive oil (n = 89) or nuts (MedDiet-Nuts; n = 79) is compared with a low-fat diet (n = 90). In the PREDIMED-Plus study, a 1-year intervention with energy-reduced MedDiet and physical activity (n = 103) is compared with an ad libitum MedDiet (n = 101). VLDL levels of apolipoprotein C-I, C-III, triglycerides, and cholesterol; the apolipoprotein E-/C-I ratio; and VLDL ex-vivo triglyceride transfer are measured. In PREDIMED participants in both MedDiet groups combined, VLDL apolipoprotein C-III levels are nominally reduced (-0.023 SD units, 95% CI -0.44 to -0.014, p = 0.037). VLDL triglyceride transfer is nominally increased in the MedDiet-Nuts group (+0.39 SD units, 95% CI 0.012-0.78, p = 0.045). In PREDIMED-Plus, no inter-group differences are detected. CONCLUSIONS: In older adults at high cardiovascular risk, MedDiet is associated with lower VLDL atherogenicity versus a low-fat diet. No differences are seen after an energy-reduced MedDiet with physical activity.

Association Among Polyphenol Intake, Uric Acid, and Hyperuricemia: A Cross-Sectional Analysis in a Population at High Cardiovascular Risk.

Background Dietary polyphenol intake has been associated with a decreased risk of hyperuricemia, but most of this knowledge comes from preclinical studies. The aim of the present study was to assess the association of the intake of different classes of polyphenols with serum uric acid and hyperuricemia. Methods and Results This cross-sectional analysis involved baseline data of 6332 participants. Food polyphenol content was estimated by a validated semiquantitative food frequency questionnaire and from the Phenol-Explorer database. Multivariable-adjusted linear regression models with serum uric acid (milligrams per deciliter) as the outcome and polyphenol intake (quintiles) as the main independent variable were fitted. Cox regression models with constant follow-up time (t=1) were performed to estimate the prevalence ratios (PRs) of hyperuricemia (≥7 mg/dL in men and ≥6 mg/dL in women). An inverse association between the intake of the phenolic acid class (ß coefficient, -0.17 mg/dL for quintile 5 versus quintile 1 [95% CI, -0.27 to -0.06]) and hydroxycinnamic acids (ß coefficient, -0.19 [95% CI, -0.3 to -0.09]), alkylmethoxyphenols (ß coefficient, -0.2 [95% CI, -0.31 to -0.1]), and methoxyphenols (ß coefficient, -0.24 [95% CI, -0.34 to -0.13]) subclasses with serum uric acid levels and hyperuricemia (PR, 0.82 [95% CI, 0.71-0.95]; PR, 0.82 [95% CI, 0.71-0.95]; PR, 0.80 [95% CI, 0.70-0.92]; and PR, 0.79 [95% CI, 0.69-0.91]; respectively) was found. The intake of hydroxybenzoic acids was directly and significantly associated with mean serum uric acid levels (ß coefficient, 0.14 for quintile 5 versus quintile 1 [95% CI, 0.02-0.26]) but not with hyperuricemia. Conclusions In individuals with metabolic syndrome, a higher intake of some polyphenol subclasses (hydroxycinnamic acids, alkylmethoxyphenol, and methoxyphenol) was inversely associated with serum uric acid levels and hyperuricemia. Nevertheless, our findings warrant further research.

Risk of cardiovascular disease in women and men with subfertility: the Trøndelag Health Study.

OBJECTIVE: To investigate the association between subfertility and risk of cardiovascular disease (CVD) outcomes. DESIGN: Prospective study. SETTING: Population-based cohort. PATIENT(S): We studied 31,629 women and 17,630 men participating in the Trøndelag Health Study. INTERVENTION(S): Self-reported subfertility. As men were not directly asked about fertility, male partners of female participants were identified through linkage to the Medical Birth Registry of Norway and assigned the fertility information obtained from their partners. MAIN OUTCOME MEASURE(S): The primary outcomes were stroke and coronary heart disease in women and men with and without a history of subfertility. The secondary outcomes were myocardial infarction and angina (subgroups of coronary heart disease) and any CVD (stroke or coronary heart disease). Information on CVD was available by linkage to hospital records. We used Cox proportional hazards models adjusted for age at participation in the Trøndelag Health Study (linear + squared), birth year, smoking history, cohabitation, and education. Cardiometabolic factors were assessed in separate models. RESULT(S): A total of 17% of women and 15% of men reported subfertility. In women, subfertility was modestly associated with an increased risk of stroke (age-adjusted hazard ratio [aaHR], 1.19; 95% confidence interval [CI], 1.02-1.39; adjusted hazard ratio [aHR]; 1.18; 95% CI, 1.01-1.37) and coronary heart disease (aaHR, 1.19; 95% CI, 1.06-1.33; aHR, 1.16; 95% CI, 1.03-1.30) compared with fertile women. In men, we observed a weak positive association for stroke (aaHR, 1.11; 95% CI, 0.91-1.34; aHR, 1.10; 95% CI, 0.91-1.33) and a weak inverse association for coronary heart disease (aaHR, 0.92; 95% CI, 0.81-1.05; aHR, 0.93; 95% CI, 0.81-1.06). CONCLUSION(S): We observed modestly increased risks of CVD outcomes in women and some weak associations in men, although with no strong statistical evidence on sex differences. We acknowledge that we were only able to include men linked to pregnancies ending at 12 completed gestational weeks or later, potentially resulting in selection bias and misclassification of history of subfertility in analyses of male partners. Despite the large sample size, our results indicate the need for larger studies to obtain precise results in both sexes and determine whether there are true sex differences.

Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

OBJECTIVE: To investigate the association between smoking and infertility. DESIGN: Prospective study. SETTING: Nationwide cohort. PATIENTS: 28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study. INTERVENTION: Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization. MAIN OUTCOME MEASURE: Infertility (time-to-pregnancy ≥12 months). RESULTS: Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11-1.28; ORadjusted 1.12; 95% CI, 1.03-1.21), also after adjusting for the partner's tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88-0.99; ORadjusted 0.89; 95% CI, 0.84-0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75-0.91; ORadjusted, 0.83; 95% CI, 0.75-0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization. CONCLUSIONS: We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.

Emotional eating and cognitive restraint mediate the association between sleep quality and BMI in young adults.

This cross-sectional study was designed to investigate whether diet quality and eating behaviors could mediate the association between sleep quality and body mass index (BMI) in young adults. For all participants (n = 925; aged 21.4 ± 2.5 years; 77.8% women) we evaluated: BMI, sleep quality, diet quality, and eating behavior dimensions (emotional eating, cognitive restraint, and uncontrolled eating). Linear regression models were used to test associations between exposure and outcome variables. Path analysis was conducted with all potential mediators and covariates entered at the same time. Results showed that emotional eating (ß = 0.04 [95% CI: 0.03; 0.06]), cognitive restraint (ß = 0.03 [95% CI: 0.01; 0.04]), uncontrolled eating (ß = 0.02 [95% CI: 0.01; 0.04]) and diet quality (ß = -0.14 [95% CI: 0.19;-0.08]) were significantly associated with sleep quality. Additionally, BMI was significantly associated with PSQI score (ß = 0.09 [95% CI: 0.01; 0.17]), emotional eating (ß = 0.89 [95% CI: 0.60; 1.18]), and cognitive restraint (ß = 1.37 [95% CI: 1.02; 1.71]). After testing for mediation, results revealed that emotional eating and cognitive restraint evidenced a significant mediating effect on the association between sleep quality and BMI. Additionally, diet quality was significantly associated with emotional eating (ß = -0.35 [95% CI: 0.56;-0.13]), cognitive restraint (ß = 0.53 [95% CI: 0.27; 0.79]), and uncontrolled eating (ß = -0.49 [95% CI: 0.74;-0.25]). In conclusion, young adults with poor sleep quality are more likely to deal with negative emotions with food, which, in turn, could be associated with higher cognitive restraint, becoming a vicious cycle that has a negative impact on body weight. Our results also emphasize the role of eating behaviors as determinants of diet quality, highlighting the importance of considering sleep quality and eating behaviors when designing obesity prevention strategies in this population.

Transcriptional response to a Mediterranean diet intervention exerts a modulatory effect on neuroinflammation signaling pathway.

Background: The Traditional Mediterranean Diet (TMD) is known to have beneficial effects on several chronic diseases. However, data concerning the whole transcriptome modulation of the TMD are scarce.Objective: We aimed to explore the effects of the TMD on the whole transcriptome of individuals at high cardiovascular risk.Methods: Thirty-four participants at high cardiovascular risk were randomly assigned to a TMD enriched with extra-virgin olive oil (TMD + VOO), mixed nuts (TMD + Nuts), or a control diet based on low-fat diet recommendations. A microarray analysis in circulating peripheral blood mononuclear cells of the participants was conducted before and after 3 months of the intervention. The association of changes in gene expression was modeled into canonical pathways by conducting an untargeted functional analysis with the Ingenuity Pathway Analysis® (IPA). Effects were considered significant when the absolute z-score values were ≥2.0 and the logarithm P (adjusted by the Benjamini-Hochberg procedure [BH]) values were ≥1.30.Results: According to IPA, interventions with TMD + Nuts, TMD + VOO, and control diet downregulated neuroinflammation, triggering receptor expressed on myeloid cells 1 , and cholecystokinin/gastrin-mediated signaling pathways, respectively. The gene expression among these pathways included cytokines, T-cell activation receptors, nuclear factor kappa ß/inflammasome components, pro-inflammatory enzymes and cell cycle regulators.Conclusion: The current findings suggest that the TMD enriched with mixed nuts or VOO downregulate transcriptomic pathways, including those related to neuroinflammation, which could influence development of neurodegenerative diseases. Our data should be corroborated in other tissue cells, such as neurons and glial cells. The PREDIMED trial was registered at https://www.controlled-trials.com (ISRCTN35739639).

Polyphenol intake and cardiovascular risk in the PREDIMED-Plus trial. A comparison of different risk equations.

INTRODUCTION AND OBJECTIVES: Quantification of cardiovascular risk has been based on scores such as Framingham, Framingham-REGICOR, SCORE or Life's Simple 7 (LS7). In vitro, animal, and randomized clinical studies have shown that polyphenols may provide benefits to the vascular system and reduce the inflammatory response. However, some clinical-epidemiological studies have yielded inconsistent results. Our aim was to assess the possible association between intake of the various polyphenol classes and established cardiovascular scores. METHODS: This cross-sectional analysis involved 6633 PREDIMED-Plus study participants. Food polyphenol content was estimated by a semiquantitative food frequency questionnaire, adjusted for total energy intake according to the residual method. The association between polyphenol intake and cardiovascular risk was tested using linear regression analyses. RESULTS: Total polyphenol and flavonoid intake were directly and significantly associated only with the LS7 scale. Intake of lignans was directly and significantly associated with SCORE and LS7 scales, stilbene intake with SCORE, and phenolic acid intake with Framingham and Framingham-REGICOR scores. Other polyphenol classes were associated in a protective and significant manner in Framingham, SCORE and LS7 scores. In women, intake of all the polyphenol classes, except phenolic acids, showed a protective trend in the results of the Framingham, Framingham-REGICOR scores and LS7 scale. CONCLUSIONS: An inverse association was found between consumption of the 'other polyphenols' class and, especially among women, with estimated cardiovascular risk. The results were similar to those of Framingham, Framingham-REGICOR and LS7 (after eliminating the diet component) and differed from those of SCORE, but the predictors included were limited in the latter case.

Modification of High-Density Lipoprotein Functions by Diet and Other Lifestyle Changes: A Systematic Review of Randomized Controlled Trials.

High-density lipoprotein (HDL) functional traits have emerged as relevant elements that may explain HDL antiatherogenic capacity better than HDL cholesterol levels. These properties have been improved in several lifestyle intervention trials. The aim of this systematic review is to summarize the results of such trials of the most commonly used dietary modifications (fatty acids, cholesterol, antioxidants, alcohol, and calorie restriction) and physical activity. Articles were screened from the Medline database until March 2021, and 118 randomized controlled trials were selected. Results from HDL functions and associated functional components were extracted, including cholesterol efflux capacity, cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, HDL antioxidant capacity, HDL oxidation status, paraoxonase-1 activity, HDL anti-inflammatory and endothelial protection capacity, HDL-associated phospholipase A2, HDL-associated serum amyloid A, and HDL-alpha-1-antitrypsin. In mainly short-term clinical trials, the consumption of monounsaturated and polyunsaturated fatty acids (particularly omega-3 in fish), and dietary antioxidants showed benefits to HDL functionality, especially in subjects with cardiovascular risk factors. In this regard, antioxidant-rich dietary patterns were able to improve HDL function in both healthy individuals and subjects at high cardiovascular risk. In addition, in randomized trial assays performed mainly in healthy individuals, reverse cholesterol transport with ethanol in moderate quantities enhanced HDL function. Nevertheless, the evidence summarized was of unclear quality and short-term nature and presented heterogeneity in lifestyle modifications, trial designs, and biochemical techniques for the assessment of HDL functions. Such findings should therefore be interpreted with caution. Large-scale, long-term, randomized, controlled trials in different populations and individuals with diverse pathologies are warranted.

Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: What is the association between BMI and subfertility? SUMMARY ANSWER: We observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis. WHAT IS KNOWN ALREADY: High BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Cohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months). MAIN RESULTS AND THE ROLE OF CHANCE: Our findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI <20.0 kg/m2. A 1 kg/m2 higher genetically predicted BMI was linked to 26% greater odds of subfertility (8-48%) among obese men. Low genetically predicted BMI values were also related to greater subfertility risk in men at the lower end of the BMI distribution. A genetically predicted BMI of 23 and 25 kg/m2 was linked to the lowest subfertility risk in women and men, respectively. LIMITATIONS, REASONS FOR CAUTION: The main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values <20.0 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: Our results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values <20 kg/m2 may have an increased risk of subfertility. These results suggest that BMI values between 20 and 25 kg/m2 are optimal for a minimal risk of subfertility. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.