Associations Between Domestic Water Hardness, Genetic Risk and Severe MASLD : A Large‐Scale Cohort Study

ABSTRACT

This study aims to investigate the association between domestic water hardness and the risk of severe metabolic dysfunction‐associated steatotic liver disease (MASLD) and to assess the potential modifying role of genetic susceptibility. The UK Biobank is a prospective cohort study that recruited over 500,000 participants across the United Kingdom between 2006 and 2010. Domestic water hardness was assessed based on calcium carbonate (CaCO ₃ ) concentration. Severe MASLD was defined using ICD‐10 codes and death registry data. A polygenic risk score (PRS) for severe MASLD was constructed using 61 single nucleotide polymorphisms (SNPs) and divided into tertiles (low, intermediate, high risk). Cox proportional hazards regression models and restricted cubic spline analyses were employed. A total of 7039 incident severe MASLD cases (1.5%) were documented during a mean 13.8‐year follow‐up. Compared to water hardness < 100 mg/L, individuals with domestic water hardness of 100–200 mg/L were associated with a 22% lower risk of severe MASLD (HR 0.78, 95% CI 0.72–0.86), while water hardness > 200 mg/L was associated with an 11% higher risk (HR 1.11, 95% CI 1.05–1.16). A non‐linear relationship was observed between water hardness and severe MASLD incidence ( p for non‐linear < 0.001). The association did not significantly differ across strata of genetic susceptibility ( p ‐interaction > 0.05). The study revealed a U ‐shaped relationship between water hardness and severe MASLD, which was robust to genetic risk. An optimal water hardness range (100–200 mg/L) may serve as a modifiable environmental factor for the prevention of severe MASLD.