Repositório Científico do Instituto Nacional de Saúde
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The Genetics of Iron Metabolism on Biochemical and Hematological Phenotypes of Heart Failure
Publication . Barbosa, Mário; Aguiar, Laura; Matias, Ana; Ferreira, Joana; Caldeira, João; Melício, Ana; Faustino, Paula; Menezes Falcão, Luiz; Bicho, Manuel; Inácio, Ângela
Heart failure (HF) is frequently associated with iron deficiency and anemia, negatively impacting patient outcomes. This study aimed to investigate the contribution of genetic variation in iron metabolism-related genes to biochemical and hematological phenotypes in HF. An HF population of 182 patients with functional iron deficiency (ID) and anemia was stratified by sex and heart failure subtype, including HF with reduced ejection fraction (HFrEF) and HF with non-reduced ejection fraction (HFnrEF). Genetic variants in HFE (rs1799945), SLC40A1 (rs1439816, rs2304704), and TMPRSS6 (rs855791) were evaluated. Variants in HFE and SLC40A1 were associated with differences in serum iron, ferritin, transferrin saturation, hemoglobin, and RDW. The phenotypic impact of these variants was modulated by sex and heart failure subtype, highlighting the influence of iron availability, inflammatory burden, and erythropoietic demand. In contrast, no significant associations were observed for the TMPRSS6 variant. In conclusion, genetic variation in key regulators of iron metabolism contributes to the heterogeneity of iron-related biochemical and hematological phenotypes in HF. These findings emphasize the interplay between genetic background, sex, and heart failure physiology and support the relevance of personalized approaches to iron assessment and management in heart failure.
Hepatitis C Virus: An Overview of Its Chronic Impact on Liver Function, Metabolic Dysregulation, Inflammatory–Oxidative Pathogenesis and Epigenetic Memory
Publication . Ferreira, Joana; Caldeira, João; Bicho, Manuel; Faustino, Paula; Serejo, Fátima
Hepatitis C virus (HCV) infection is a global health concern, chronically affecting over 71 million people. It primarily targets the liver but also causes systemic complications through inflammation, oxidative stress, and metabolic dysregulation. HCV is a highly variable RNA virus with six major genotypes that are mainly transmitted via blood. Often asymptomatic, the infection progresses silently to chronic hepatitis C (CHC), which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have revolutionized treatment, achieving cure rates above 95%, improving liver function, reversing fibrosis, and normalizing metabolism. HCV disrupts iron metabolism by suppressing hepcidin, causing iron overload and oxidative stress. It also alters lipid metabolism, inducing steatosis, and affects glucose metabolism, contributing to insulin resistance and type 2 diabetes. DAAs improve these metabolic outcomes. HCV promotes oxidative stress via viral proteins, damaging liver cells and DNA and triggering inflammation and fibrogenesis. Even post-cure, oxidative stress and iron overload may continue to drive disease progression. Genetic and epigenetic factors influence fibrosis progression and HCC risk. Despite a sustained virologic response (SVR), patients with advanced liver damage remain at risk for HCC and metabolic diseases, highlighting the need for continued monitoring and personalized post-treatment care.
A strategic research and innovation Agenda for personalized prevention: towards a European implementation roadmap
Publication . Boccia, Stefania; Pastorino, Roberta; PROPHET Consortium
No abstract available
Ancestry-stratified variant classification in monogenic diabetes genes: Annotation coverage and differential curation burden
Publication . Dario, Paulo
Background: Variant databases ClinVar and gnomAD underpin clinical variant interpretation, but their composition is skewed toward European ancestry. Whether this produces systematic disadvantages for non-European patients with monogenic diabetes has not been examined at the database level with mutually exclusive ancestry groups.
Objective: To quantify ClinVar annotation coverage and ancestry-stratified classification outcomes across monogenic diabetes genes, using mutually exclusive population-private variant groups.
Methods: gnomAD v4.0 (genomes and exomes; 807,162 individuals) was cross-referenced with the ClinVar GRCh38 record (accessed June 29, 2026) for 16 monogenic diabetes (maturity-onset diabetes of the young [MODY]) genes, and variants were classified as population-private to European or non-European ancestry from ancestry-specific allele counts.
Results: Across 54,865 gnomAD variants, 86.7% carried no ClinVar classification. The annotation gap was near-universal rather than ancestry-specific (unannotated fraction 89.4% European-private, 87.5% non-European-private). Among classified population-private variants, however, the pathogenic or likely pathogenic rate was 19.8% for European-private but only 8.6% for non-European-private variants (Fisher exact OR 2.6, 95% CI 2.1-3.3, p = 1 × 10- 1 8), with a higher uncertain-significance rate in non-European-private variants (52.1% vs. 45.8%).
Conclusion: The dominant problem is therefore an annotation deficit affecting all ancestries; the ancestry inequity the data support is one of actionability, not of raw uncertain-significance rates. Closing it requires ClinVar submissions and population-specific sequencing from underrepresented populations.
Variation in reporting of heatstroke mortality: evidence from a multi-country study
Publication . Tobias, Aurelio; Honda, Yasushi; Madaniyazi, Lina; Alhamad, Barrak; Lavigne, Erik; Roye, Dominic; Tong, Shilu; de Sousa Zanotti Stagliorio Coelho, Micheline; Huber, Veronica; Urban, Ales; das Neves Pereira da Silva, Susana; Achilleos, Souzana; Parks, Robbie M.; Iñiguez, Carmen; Masselot, Pierre; Vicedo-Cabrera, Ana M.; Armstrong, Ben; Gasparrini, Antonio; Hashizume, Masahiro; Multi-City Multi-Country Collaborative Research Network
Background: Heatstroke represents the most severe manifestation of heat exposure. Heatstroke is rare and under-reported, resulting in limited empirical data on its global incidence and burden. This study aimed to examine geographical variations and temporal trends in reported heatstroke mortality across multiple countries.
Methods: We collected annual heatstroke mortality data from 34 countries participating in the Multi-Country Multi-City Collaborative Research Network between 2000 and 2022, using the ICD-10 code X30. Country-specific mortality rates were estimated using Poisson regression, alongside analyses of annual trends and associations with mean warm-season temperature. We also assessed the proportion of heatstroke deaths relative to both overall heat and extreme heat-attributable all-cause mortality.
Findings: Heatstroke mortality rates varied widely across countries, with Japan reporting the highest rate (5·81 per 1 million population; 95% CI 4·43-7·62), followed by Cyprus (2·51; 1·36-4·61), and China (2·42; 1·21-4·85). By contrast, most countries in Europe, South America, and southeast Asia reported rates of less than one death per 1 million population. Heatstroke mortality increased over time in several countries and was associated with warm-season temperatures in most regions. The proportion of heatstroke deaths relative to overall heat-attributable mortality ranged from less than 1% in many countries to as close to 24% in Japan. When analyses were restricted to deaths attributable to extreme heat, the proportion of heatstroke deaths increased substantially.
Interpretation: Our broad international assessment of heatstroke mortality highlights its distinct patterns compared with overall heat-attributable mortality. The observed variability likely reflects differences in recognition, reporting, and diagnostic practices, while climate exposure and health system capacity influence whether heat-related deaths are identified and recorded as heatstroke.