To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses’ Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28–0.37 between the signature and MEDAS; P = 3 × 10⁻³⁵ to 4 × 10⁻¹¹⁸). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001). We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

As the global population ages, it is critical to identify diets that, beyond preventing noncommunicable diseases, optimally promote healthy aging. Here, using longitudinal questionnaire data from the Nurses’ Health Study (1986–2016) and the Health Professionals Follow-Up Study (1986–2016), we examined the association of long-term adherence to eight dietary patterns and ultraprocessed food consumption with healthy aging, as assessed according to measures of cognitive, physical and mental health, as well as living to 70 years of age free of chronic diseases. After up to 30 years of follow-up, 9,771 (9.3%) of 105,015 participants (66% women, mean age = 53 years (s.d. = 8)) achieved healthy aging. For each dietary pattern, higher adherence was associated with greater odds of healthy aging and its domains. The odds ratios for the highest quintile versus the lowest ranged from 1.45 (95% confidence interval (CI) = 1.35–1.57; healthful plant-based diet) to 1.86 (95% CI = 1.71–2.01; Alternative Healthy Eating Index). When the age threshold for healthy aging was shifted to 75 years, the Alternative Healthy Eating Index diet showed the strongest association with healthy aging, with an odds ratio of 2.24 (95% CI = 2.01–2.50). Higher intakes of fruits, vegetables, whole grains, unsaturated fats, nuts, legumes and low-fat dairy products were linked to greater odds of healthy aging, whereas higher intakes of trans fats, sodium, sugary beverages and red or processed meats (or both) were inversely associated. Our findings suggest that dietary patterns rich in plant-based foods, with moderate inclusion of healthy animal-based foods, may enhance overall healthy aging, guiding future dietary guidelines.

Clinical and epidemiological data suggest that asthma and allergic diseases are associated and may share a common genetic etiology. We analyzed genome-wide SNP data for asthma and allergic diseases in 33,593 cases and 76,768 controls of European ancestry from UK Biobank. Two publicly available independent genome-wide association studies were used for replication. We have found a strong genome-wide genetic correlation between asthma and allergic diseases (r_g = 0.75, P = 6.84 × 10⁻⁶²). Cross-trait analysis identified 38 genome-wide significant loci, including 7 novel shared loci. Computational analysis showed that shared genetic loci are enriched in immune/inflammatory systems and tissues with epithelium cells. Our work identifies common genetic architectures shared between asthma and allergy and will help to advance understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases.

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.