Approximately 10% of breast cancer (BC) cases are hereditary (HBC), with HBC most commonly encountered in the context of hereditary breast and ovarian cancer syndrome (HBOC). Although thousands of loss-of-function (LoF) alleles in over 20 genes have been associated with HBC susceptibility, the genetic etiology of approximately 70% of cases remains unexplained. We focused on one of the least-studied European populations and applied whole exome sequencing (WES) to 52 individuals from 17 Greek HBOC families, in which at least one patient was negative for known HBC risk mutations. Initial screening revealed mutations in known cancer genes, including BARD1:p.Trp91* detected in a cancer-free individual, and MEN1:p.Glu260Lys detected in a BC patient. Gene and variant-based approaches were applied to exome data to identify candidate risk variants outside of known risk genes. Findings were verified in a collection of Canadian HBOC patients of European ancestry (FBRCAX), in an independent group of Canadian BC patients and controls, as well as in individuals from The Cancer Genome Atlas (TCGA) and the UK Biobank (UKB). Rare LoF variants were uncovered in MDM1 and NBEAL1 in Greek and Canadian HBOC patients. We also report prioritized missense variants SETBP1:c.4129G>C and C7orf34:c.248C>T. These variants comprise promising candidates whose role in cancer pathogenicity needs to be explored further.

The microbiome is emerging as a major player in tissue homeostasis in health and disease. Gut microbiome dysbiosis correlates with several autoimmune and metabolic diseases, while high-fat diets and ensuing obesity are known to affect the complexity and diversity of the microbiome, thus modulating pathophysiology. Moreover, the existence of a gut-liver microbial axis has been proposed, which may extend to the lung. In this context, we systematically compared the microbiomes of the gut, liver, and lung of mice fed a high-fat diet to those of littermates fed a matched control diet. We carried out deep sequencing of seven hypervariable regions of the 16S rRNA microbial gene to examine microbial diversity in the tissues of interest. Comparison of the local microbiomes indicated that lung tissue has the least diverse microbiome under healthy conditions, while microbial diversity in the healthy liver clustered closer to the gut. Obesity increased microbial complexity in all three tissues, with lung microbial diversity being the most modified. Obesity promoted the expansion of Firmicutes along the gut-liver-lung axis, highlighting staphylococcus as a possible pathologic link between obesity and systemic pathophysiology, especially in the lungs.

Dietary interventions constitute powerful approaches for disease prevention and treatment. However, the molecular mechanisms through which diet affects health remain underexplored in humans. Here, we compare plasma metabolomic and proteomic profiles between dietary states for a unique group of individuals who alternate between omnivory and restriction of animal products for religious reasons. We find that short-term restriction drives reductions in levels of lipid classes and of branched-chain amino acids, not detected in a control group of individuals, and results in metabolic profiles associated with decreased risk for all-cause mortality. We show that 23% of proteins whose levels are affected by dietary restriction are druggable targets and reveal that pro-longevity hormone FGF21 and seven additional proteins (FOLR2, SUMF2, HAVCR1, PLA2G1B, OXT, SPP1, HPGDS) display the greatest magnitude of change. Through Mendelian randomization we demonstrate potentially causal effects of FGF21 and HAVCR1 on risk for type 2 diabetes, of HPGDS on BMI, and of OXT on risk for lacunar stroke. Collectively, we find that restriction-associated reprogramming improves metabolic health and emphasise high-value targets for pharmacological intervention.

Emerging evidence suggests a potential role of gut dysbiosis in neurodegenerative disorders and, in particular, Alzheimer’s disease (AD) pathology and cognitive decline. However, the role of gut microbiome in the early prodromal stages of AD and particularly in mild cognitive impairment (MCI) remains understudied and has been mostly explored in Asian populations with no representation of European populations. To address this research gap in the literature and to suggest novel microbiome features associated with MCI, we conducted a cross-sectional study in a European population sample and profiled gut microbiota in 99 individuals without dementia through 16s ribosomal RNA (rRNA) sequencing. Individuals were categorized by cognitive status based on standard clinical criteria to cognitively normal (n = 49) or individuals with MCI (n = 50). Differential abundance through Microbiome Multivariable Associations with Linear model (MaAsLin2) and elastic net logistic regression analyses were used to identify gut microbiome features associated with MCI. MCI group was older than the CN group and age was used as covariate in the differential abundance analysis. No differences in alpha and beta diversity were found between the two groups (p > 0.05). At false discovery rate (FDR) < 0.05, we identified specific genera associated with MCI, mostly linked to short chain fatty acids (SCFAs) production (e.g., Candidatus_Soleaferrea q = 0.027, MaAsLin2 coefficient = 1.65, Sellimonas q = 0.017, MaAsLin2 coefficient = −4.45), while we highlight nominal (p < 0.05, q > 0.05) correlations of genera (e.g., Hydrogenoanaerobacterium, Subdoligranulum) with metrics of cognitive assessment. Microbiota was shown to have a fairly good discriminative capacity for MCI status (area under the curve AUC = 0.77), with Rothia genus found as the top predictor for MCI (beta coefficient [95% confidence intervals] = 0.224 [0.216–0.233]). Overall, our findings add to current knowledge reporting gut microbiome alterations in MCI by suggesting novel associated microbiome features; however, larger scale longitudinal studies are needed to further elucidate the underlying biological pathways linked to the disease.

Background: Expression quantitative trait loci (eQTL) studies provide insights into regulatory mechanisms underlying disease risk. Expanding studies of gene regulation to underexplored populations and to medically relevant tissues offers potential to reveal yet unknown regulatory variants and to better understand disease mechanisms. Here, we performed eQTL mapping in subcutaneous (S) and visceral (V) adipose tissue from 106 Greek individuals (Greek Metabolic study, GM) and compared our findings to those from the Genotype-Tissue Expression (GTEx) resource. Results: We identified 1,930 and 1,515 eGenes in S and V respectively, over 13% of which are not observed in GTEx adipose tissue, and that do not arise due to different ancestry. We report additional context-specific regulatory effects in genes of clinical interest (e.g. oncogene ST7) and in genes regulating responses to environmental stimuli (e.g. MIR21, SNX33). We suggest that a fraction of the reported differences across populations is due to environmental effects on gene expression, driving context-specific eQTLs, and suggest that environmental effects can determine the penetrance of disease variants thus shaping disease risk. We report that over half of GM eQTLs colocalize with GWAS SNPs and of these colocalizations 41% are not detected in GTEx. We also highlight the clinical relevance of S adipose tissue by revealing that inflammatory processes are upregulated in individuals with obesity, not only in V, but also in S tissue. Conclusions: By focusing on an understudied population, our results provide further candidate genes for investigation regarding their role in adipose tissue biology and their contribution to disease risk and pathogenesis.

Background: Dietary interventions are powerful tools for disease prevention and health promotion, yet the molecular mechanisms by which diet influences health remain incompletely understood. Investigating the effects of diet in healthy individuals enables characterization of molecular and physiological responses in the absence of disease-related confounders and facilitates the identification of diet-responsive pathways underlying physiological regulation. Methods: We investigated the metabolic and immune effects of short-term dietary restriction of animal products in a unique group of apparently healthy individuals (N = 200) who alternate between omnivory and animal product restriction for religious reasons. We profiled clinical biomarkers and immune parameters during both dietary states, alongside a control group of continuously omnivorous individuals (N = 211). Results: Short-term restriction is associated with reductions in total and non-high-density lipoprotein cholesterol, urea, creatinine, alanine aminotransferase, and gamma-glutamyltransferase, and a concurrent 73% reduction of normal-range C-reactive protein levels. Immune profiling reveals reductions in frequencies of non-classical monocytes, CD56⁺ natural killer cells, and CD8⁺ memory T cells, accompanied by an increased response of cytokine IL-10, suggesting enhanced immune regulation against inflammation. Although most changes are in a direction suggesting beneficial health effects, levels of alkaline phosphatase increase upon restriction, implying possible negative effects on bone turnover or liver function. Conclusions: Short-term animal product restriction mostly improves systemic metabolic and immune health markers and may lower chronic inflammatory disease risk. Our findings highlight the value of studying diet in the absence of disease to reveal adaptive molecular changes and emphasize the translational potential of short-term dietary interventions in altering health-related risks.