Rationale and Design of the Atrial Natriuretic Peptide and Regulation of Cardiometabolic Health: A Genotype-Guided Human Physiological Study (GENESIS)

The increase in obesity and cardiometabolic disease prevalence has highlighted the importance of identifying biological pathways that may inform risk stratification and targeted prevention strategies. Atrial natriuretic peptide (ANP) regulates blood pressure, glucose homeostasis, energy expenditure, and lipid metabolism, and lower levels are associated with adverse outcomes. The minor G allele of a common NPPA genetic variant (rs5068) is associated with ∼30% higher ANP levels, likely because microRNA-425 (miR-425), a post-transcriptional negative regulator, is unable to bind to the variant allele. Individuals lacking the minor allele represent a genetically defined low-ANP phenotype. GENESIS (Genotype-Guided Human Physiological Study) is a prospective, genotype-guided physiological study designed to determine whether genetically lower ANP levels alter metabolic responses to standardized oral glucose and exercise challenges. Two hundred adults (50 high-ANP genotype and 150 low-ANP genotype) are recruited from Birmingham, Alabama, and undergo a 5-day salt-standardized diet, a body composition assessment, an exercise challenge, an 8-hour oral glucose challenge, and comprehensive metabolic phenotyping. Participants with diabetes, significant cardiovascular, kidney, or liver disease, or body mass index ≥45 kg/m² are excluded. Primary endpoints include changes in mid-regional pro-atrial natriuretic peptide levels following an oral glucose challenge and differences in exercise energy expenditure between genotype groups. Secondary objectives include evaluating changes in miR-425 expression following glucose and exercise challenges, and changes in natriuretic peptides, glucose, insulin, lipid metabolism, and their relationships with miR-425. GENESIS will provide mechanistic insight into the ANP-miR-425 pathway and may identify a genetically defined cardiometabolic phenotype with implications for precision prevention.