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

Area of Science:

• Environmental Health
• Hepatology
• Epidemiology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern.
• Environmental factors, such as domestic water composition, may influence MASLD risk.
• The role of water hardness in MASLD pathogenesis, considering genetic predispositions, remains unclear.

Purpose of the Study:

• To investigate the association between domestic water hardness and the risk of developing severe MASLD.
• To evaluate whether genetic susceptibility modifies the relationship between water hardness and severe MASLD.
• To identify potential environmental targets for MASLD prevention strategies.

Main Methods:

• Utilized UK Biobank prospective cohort data (over 500,000 participants).
• Assessed domestic water hardness via calcium carbonate (CaCO3) concentration.
• Defined severe MASLD using ICD-10 codes and death registry data; constructed a polygenic risk score (PRS) for MASLD.

Main Results:

• A U-shaped, non-linear relationship was observed between water hardness and severe MASLD incidence (p < 0.001).
• Water hardness between 100-200 mg/L was associated with a 22% lower risk of severe MASLD compared to <100 mg/L.
• Water hardness >200 mg/L was linked to an 11% increased risk; this association was consistent across genetic risk strata (p-interaction > 0.05).

Conclusions:

• Domestic water hardness exhibits a significant U-shaped association with severe MASLD risk.
• An intermediate range of water hardness (100-200 mg/L) appears protective against severe MASLD.
• This protective effect is independent of an individual's genetic susceptibility to MASLD, suggesting water hardness as a modifiable factor.