Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study.

BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed. CONCLUSIONS: Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.

Prevalence and Determinants of Sex-Specific Dietary Supplement Use in a Greek Cohort.

We describe the profile of dietary supplement use and its correlates in the Epirus Health Study cohort, which consists of 1237 adults (60.5% women) residing in urban north-west Greece. The association between dietary supplement use and demographic characteristics, lifestyle behaviors, personal medical history and clinical measurements was assessed using logistic regression models, separately for women and men. The overall prevalence of dietary supplement use was 31.4%, and it was higher in women (37.3%) compared to men (22.4%; p-value = 4.2-08). Based on multivariable logistic regression models, dietary supplement use in women was associated with age (positively until middle-age and slightly negatively afterwards), the presence of a chronic health condition (OR = 1.71; 95% CI, 1.18-2.46), lost/removed teeth (OR = 0.52; 95% CI, 0.35-0.78) and diastolic blood pressure (OR per 5 mmHg increase =0.84; 95% CI, 0.73-0.96); body mass index and worse general health status were borderline inversely associated. In men, dietary supplement use was positively associated with being employed (OR = 2.53; 95% CI, 1.21-5.29). A considerable proportion of our sample used dietary supplements, and the associated factors differed between women and men.

Genetically predicted circulating concentrations of micronutrients and risk of breast cancer: A Mendelian randomization study.

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6 , vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10-7 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10-6 ) higher risk of overall and ER+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER-ve breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.

Metabolites, Nutrients, and Lifestyle Factors in Relation to Coffee Consumption: An Environment-Wide Association Study.

Coffee consumption has been inversely associated with various diseases; however, the underlying mechanisms are not entirely clear. We used data of 17,752 Third National Health and Nutrition Examination Survey participants to investigate the association of 245 metabolites, nutrients, and lifestyle factors with coffee consumption. We used data from the first phase (n = 8825) to identify factors with a false discovery rate of <5%. We then replicated our results using data from the second phase (n = 8927). Regular coffee consumption was positively associated with active and passive smoking, serum lead and urinary cadmium concentrations, dietary intake of potassium and magnesium, and aspirin intake. In contrast, regular coffee consumption was inversely associated with serum folate and red blood cell folate levels, serum vitamin E and C, and beta-cryptoxanthin concentrations, Healthy Eating Index score, and total serum bilirubin. Most of the aforementioned associations were also observed for caffeinated beverage intake. In our assessment of the association between coffee consumption and selected metabolites, nutrients, and lifestyle factors, we observed that regular coffee and caffeinated beverage consumption was strongly associated with smoking, serum lead levels, and poorer dietary habits.

Coffee and tea consumption and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

The epidemiological evidence regarding the association of coffee and tea consumption with prostate cancer risk is inconclusive, and few cohort studies have assessed these associations by disease stage and grade. We examined the associations of coffee (total, caffeinated and decaffeinated) and tea intake with prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 142,196 men, 7,036 incident prostate cancer cases were diagnosed over 14 years of follow-up. Data on coffee and tea consumption were collected through validated country-specific food questionnaires at baseline. We used Cox proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (CI). Models were stratified by center and age, and adjusted for anthropometric, lifestyle and dietary factors. Median coffee and tea intake were 375 and 106 mL/day, respectively, but large variations existed by country. Comparing the highest (median of 855 mL/day) versus lowest (median of 103 mL/day) consumers of coffee and tea (450 vs. 12 mL/day) the HRs were 1.02 (95% CI, 0.94-1.09) and 0.98 (95% CI, 0.90-1.07) for risk of total prostate cancer and 0.97 (95% CI, 0.79-1.21) and 0.89 (95% CI, 0.70-1.13) for risk of fatal disease, respectively. No evidence of association was seen for consumption of total, caffeinated or decaffeinated coffee or tea and risk of total prostate cancer or cancer by stage, grade or fatality in this large cohort. Further investigations are needed to clarify whether an association exists by different preparations or by concentrations and constituents of these beverages.

Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials.

OBJECTIVE: To evaluate the breadth, validity, and presence of biases of the associations of vitamin D with diverse outcomes. DESIGN: Umbrella review of the evidence across systematic reviews and meta-analyses of observational studies of plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D concentrations and randomised controlled trials of vitamin D supplementation. DATA SOURCES: Medline, Embase, and screening of citations and references. ELIGIBILITY CRITERIA: Three types of studies were eligible for the umbrella review: systematic reviews and meta-analyses that examined observational associations between circulating vitamin D concentrations and any clinical outcome; and meta-analyses of randomised controlled trials assessing supplementation with vitamin D or active compounds (both established and newer compounds of vitamin D). RESULTS: 107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people. CONCLUSIONS: Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.

A nutrient-wide association study on blood pressure.

BACKGROUND: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

Low total and nonheme iron intakes are associated with a greater risk of hypertension.

The relationship between iron intake and blood pressure (BP) status has not been well established. Only 1 cross-sectional study has suggested an inverse association of dietary total iron intake and nonheme iron intake with BP. We investigated the relationship between total, heme, and nonheme iron intakes, markers of iron status, 5.4-y changes in BP, and the incidence of hypertension. A total of 2895 participants included in the Supplémentation en Vitamines et Minéraux Antioxydants cohort were followed up for 5.4 y. At least 3 repeated 24-h dietary records were performed at baseline and 5.4 y later. Hemoglobin and serum ferritin concentrations were assessed at baseline. Low nonheme iron intake at baseline was associated with a greater increase in systolic BP (SBP) and pulse pressure over time after adjustment for multiple possible confounding factors (P-trend = 0.002 and 0.0005, respectively). Conversely, participants in the 3rd tertile of nonheme iron intake at baseline had a 37% lower risk of hypertension after 5.4 y of follow-up compared with those in the first tertile (P-trend = 0.04). Heme iron intake was not associated with BP changes or risk of hypertension. Meat intake was positively associated with an increase in SBP (P-trend = 0.04). However, that relation became nonsignificant after adjusting for dietary pattern scores. Baseline hemoglobin and ferritin concentrations were not associated with changes in BP or incidental hypertension. Our data support a possible role of low nonheme iron intake, independent of heme iron intake, in the development of hypertension.

Relation of iron and red meat intake to blood pressure: cross sectional epidemiological study.

OBJECTIVE: To investigate associations of dietary iron (total, haem, and non-haem), supplemental iron, and red meat with blood pressure. DESIGN: Cross sectional epidemiological study. SETTING: 17 population samples from Japan, China, the United Kingdom, and the United States participating in the international collaborative study on macro-/micronutrients and blood pressure (INTERMAP). PARTICIPANTS: 4680 adults aged 40-59. MAIN OUTCOME MEASURE: Average of eight blood pressure readings. RESULTS: In multiple linear regression analyses dietary total iron and non-haem iron were consistently inversely associated with blood pressure. With adjustment for potential non-dietary and dietary confounders, dietary total iron intake higher by 4.20 mg/4.2 MJ (2 SD) was associated with -1.39 mm Hg (P<0.01) lower systolic blood pressure. Dietary non-haem iron intake higher by 4.13 mg/4.2 MJ (2 SD) was associated with -1.45 mm Hg (P<0.001) lower systolic blood pressure. Differences were smaller for diastolic blood pressure. In most models haem iron intake from food was positively, non-significantly associated with blood pressure. Iron intake from combined diet and supplements yielded smaller associations than dietary iron alone. Red meat intake was directly associated with blood pressure; 102.6 g/24 h (2 SD) higher intake was associated with 1.25 mm Hg higher systolic blood pressure. Associations between red meat and blood pressure persisted after adjustment for multiple confounders. CONCLUSION: Non-haem iron has a possible role in the prevention and control of adverse blood pressure levels. An unfavourable effect of red meat on blood pressure was observed. These results need confirmation including in prospective studies, clinical trials, and from experimental evidence on possible mechanisms.

Relationship of dietary linoleic acid to blood pressure. The International Study of Macro-Micronutrients and Blood Pressure Study [corrected].

Findings from observational and interventional studies on the relationship of dietary linoleic acid, the main dietary polyunsaturated fatty acid, with blood pressure have been inconsistent. The International Study of Macro-Micronutrients and Blood Pressure is an international cross-sectional epidemiological study of 4680 men and women ages 40 to 59 years from 17 population samples in China, Japan, United Kingdom, and United States. We report associations of linoleic acid intake of individuals with their blood pressure. Nutrient intake data were based on 4 in-depth multipass 24-hour dietary recalls per person and 2 timed 24-hour urine collections per person. Systolic and diastolic blood pressures were measured 8 times at 4 visits. With several models to control for possible confounders (dietary or other), linear regression analyses showed a nonsignificant inverse relationship of linoleic acid intake (percent kilocalories) to systolic and diastolic blood pressure for all of the participants. When analyzed for 2238 "nonintervened" individuals (not on a special diet, not consuming nutritional supplements, no diagnosed cardiovascular disease or diabetes, and not taking medication for high blood pressure, cardiovascular disease, or diabetes), the relationship was stronger. With adjustment for 14 variables, estimated systolic/diastolic blood pressure differences with 2-SD higher linoleic acid intake (3.77% kcal) were -1.42/-0.91 mm Hg (P<0.05 for both) for nonintervened participants. For total polyunsaturated fatty acid intake, blood pressure differences were -1.42/-0.98 mm Hg (P<0.05 for both) with 2 SD higher intake (4.04% kcal). Dietary linoleic acid intake may contribute to prevention and control of adverse blood pressure levels in general populations.