Despite the importance of healthy diet, adherence to dietary recommendations remains low. This may reflect individual differences in dietary intake that arise from environmental and genetic factors, including hormonal regulation, sex differences, and biological drivers of food preference. Genome-wide association studies (GWAS) have identified hundreds of loci associated with dietary intake, but the X-chromosome, a major source of sex-linked genetic variation, has largely been excluded. We applied multiple X-chromosome-wide association study (X-WAS) models to dietary intake phenotypes to identify novel loci and sex-specific effects. We performed X-WAS of 46 dietary intake traits from food frequency questionnaires in European-ancestry UK Biobank (UKB) participants (N = 424,758). Phenotypes included quantitative measures (e.g., fruit intake), binary traits (e.g., decaffeinated vs. caffeinated coffee), and principal component-derived food groups. We tested five X-WAS models: a traditional sex-combined additive model, sex-stratified additive models, a joint model that accounts for sex-interactions, and a model for non-additive genetic effects. We assessed generalizability across six ancestry groups, conducted a multi-ancestry meta-analysis (N = 445,773), and sought replication of female-specific findings in Women’s Genome Health Study (WGHS; N = 23,129). To characterize the biological context of associated loci, we performed phenome-wide association studies and covariate sensitivity analysis of known confounders of diet. We identified 18 loci associated with 20 dietary traits (P<5 × 10− 8), including two with prior evidence of biological mechanisms related to dietary behavior (GPR173 and HTR2C). Five loci had stronger associations in models accounting for sex-specific effects, including one locus with a significant SNP-by-sex interaction (rs191475305 associated with meat intake), highlighting the importance of considering unique X-chromosome biology. Eight of nine tested loci demonstrated consistent effects across ancestry groups in UKB (heterogeneity P > 0.05), and two of six loci replicated in WGHS (P < 0.05). Our study uncovers novel loci associated with dietary intake and provides evidence that sex-linked genetic variation contributes to individual differences in dietary intake. While most associations were detectable using conventional sex-combined analyses, models accounting for sex-specific and non-additive effects produced the strongest associations on several occasions. These findings establish the X-chromosome as an important component of dietary intake genetic architecture and demonstrate the value of robust X-chromosome models for genetic discovery.
Cichorium intybus L. (chicory) is a globally utilized medicinal plant whose root contains bioactive compounds such as inulin, fructose, chlorogenic acids (CGA), and sesquiterpene lactones (STL). These metabolites are central to its health-promoting properties. This study employed an integrated transcriptomic analysis to elucidate the genetic and molecular mechanisms underlying the effects of these compounds in mice. Microarray datasets (GSE150218 and GSE190056) were analyzed to identify differentially expressed genes (DEGs), hub genes, and associated microRNAs (miRNAs). Gene ontology (GO) enrichment, KEGG pathway analysis, and protein–protein interaction (PPI) networks were applied to characterize functional relevance. Distinct hub genes were identified: Rps28 and Rps2 (inulin), Rplp0, Cct2, and Rps20 (fructose), Mki67, Egfr, and Pparg (STL), and Socs2, Six2, Smtnl2, and Gcsh (CGA). Pathway enrichment revealed significant associations with mRNA surveillance, PPAR signaling, AMPK signaling, ribosome, and coronavirus-related pathways. Furthermore, miRNA analysis highlighted strong predicted regulatory interactions between miRNAs and hub genes, including mmu-miR-204-3p (inulin), mmu-miR-17-5p (fructose), mmu-miR-15a-5p (STL), and mmu-miR-142a-5p (CGA). Collectively, these findings identify molecular pathways and regulatory interactions associated with major chicory root bioactive compounds and provide a basis for future mechanistic studies. Experimental validation is required to confirm these predicted regulatory networks.
Cancer remains one of the leading causes of mortality worldwide, with its progression intimately linked to complex intercellular communication networks within the tumor microenvironment. Exosomes are nanoscale extracellular vesicles (EVs) of endosomal origin acting as active mediators of intercellular communication. Importantly, exosomes have emerged as critical mediators of intracellular communication that can influence microenvironmental homeostasis by transferring their bioactive cargo including proteins, lipids, and nucleic acids between cells. Although exosomes are the best-characterized miRNA carriers, other EV subclasses, including plasma membrane-derived microvesicles, apoptotic bodies, large oncosomes and migrasomes, also convey miRNAs and modify recipient cell behavior, and are therefore considered here alongside exosomes. We further examine mitochondria-derived vesicles (MDVs), a distinct vesicular pathway that connects mitochondrial quality control to the endosomal compartment and that may act upstream of exosomal miRNA loading. Among their cargo, exosome-derived microRNAs (exomiRs) have attracted considerable attention for their ability to negatively regulate gene expression in recipient cells, modulating key oncogenic processes such as angiogenesis, invasion, immune evasion, epithelial-to-mesenchymal transition, drug resistance, and cancer-related stem cell activity. This review aims to synthesize current knowledge on the biogenesis and function of EVs, including exosomes and MDVs, and of exomiRs linked with carcinogenesis and specifically addresses emerging evidence supporting pharmacological and nutraceutical interventions to modulate exomiR profiles as a novel chemopreventive strategy. We further discuss how diet-derived nutraceuticals, including plant polyphenols and isoflavones, can alter the microRNA expression landscape in cancer cells and their secreted exosomes, and we provide a global, cross-study overview of the miRNAs reported to respond to phytochemical exposure. In addition, we discuss the potential consequences of these modulations in several key carcinogenesis-associated processes such as angiogenesis, inflammation, oxidative stress, and stem cell mobilization. While direct targeting of exomiRs remains technically challenging, recent reports support the hypothesis that intracellular miRNA modulation may propagate to the exosomal compartment, thereby influencing intercellular communication. Collectively, this evidence highlights microRNA modulation as an indirect yet promising strategy to influence exosome-mediated intercellular communication in cancer and provides a conceptual framework for understanding exomiRs as a programmable layer of tumor-associated signaling. MicroRNA modulation by nutraceuticals and drugs may extend to the exosomal compartment. Exosome-associated miRNAs (exomiRs) are proposed as a dynamic interface of intercellular signaling. Emerging evidence suggests that intracellular microRNA levels alter the exosomal cargo composition, and that EV subclasses other than exosomes also convey miRNAs. Mitochondria-derived vesicles (MDVs) and mitochondrial stress may act as upstream regulators of exosomal signaling. Modulating miRNAs affects multiple signaling pathways that, in turn, indirectly reshape tumor microenvironment communication.
An Arctic-specific loss-of-function variant in the gene encoding sucrase-isomaltase (SI) results in the inability to digest sucrose in homozygous carriers, and also a healthier cardiometabolic phenotype. Importantly, the specific impact of the SI variant on food intake and preferences has not been studied in detail. We compared 18 homozygous SI-carriers with 20 non-carriers from Greenland matched on sex, age, BMI, and Inuit genetic ancestry. We assessed food intake using a semi-quantitative food frequency questionnaire and an ad libitum free-choice test meal. We assessed food reward using the Leeds Food Preference Questionnaire as well as participants’ ability to discriminate between sucrose and other sugars and sweetness/liking ratings in a sensory test. In the sensory test, carriers rated liking of sucrose and fructose significantly lower than non-carriers on a 100 mm visual analogue scale (−26 mm, p = 0.001 and −13 mm, p = 0.04, respectively). When comparing sucrose with fructose+glucose for most sweet and most liked sample, choice of sample was not associated with genotype. In the Leeds Food Preference Questionnaire, carriers expressed higher explicit liking and wanting for low-fat savoury foods than non-carriers (p = 0.04 and p = 0.01, respectively) as well as a lower explicit liking for high-fat foods relative to low-fat foods compared to non-carriers (p = 0.01). No significant differences were observed for the remaining food reward outcomes. Nutrient composition of the habitual diet and of the ad libitum test meal was overall similar in the two genotype groups. However, half of the carriers reported avoiding foods high in sugar compared to none of the non-carriers and habitual energy intake from high-fat sweet foods was 66
Hyperuricemia(HUA) is associated with metabolic and cardiovascular comorbidities. Genetic factors, particularly the ABCG2 rs2231142 polymorphism, and dietary habits such as vegetarianism, significantly influence hyperuricemia risk. However, the interplay between these factors remains unclear in the Taiwanese population. To investigate the association of the ABCG2 rs2231142 polymorphism and vegetarian diet on the risk of hyperuricemia in a Taiwanese cohort. This population-based case-control study utilized data from 11,113 participants in the Taiwan Biobank. Participants carrying the ABCG2 rs2231142 polymorphism (GG and GT/TT genotypes) were analyzed alongside dietary habits (vegetarian vs. non-vegetarian) and various clinical confounders. Logistic regression was used to calculate odds ratios (ORs) and identify gene–diet interactions. Among 11,113 participants, the overall prevalence of HUA was 11.1
