AIMS: The study aimed to investigate the association between domestic water hardness and the incidence of AF and the interaction effects between water hardness and genetic susceptibility to incident AF risk. As a secondary objective, its associations with incident heart failure (HF), coronary heart disease (CHD), and stroke were measured. METHODS: The UK Biobank is a prospective cohort study comprising over 500,000 participants recruited in the United Kingdom between 2006 and 2010, aged 37 to 73 years. A total of 447,950 participants did not have prevalent AF, and 423,946 participants who were free of HF, CHD, and stroke at baseline were included. Water hardness was assessed by CaCO RESULTS: During a median follow-up of 13.74 years, 30,726 (6.86%) individuals were diagnosed with AF for the first time. Compared with those with water hardness ≤ 60 mg/L, individuals with domestic water hardness 121-180 mg/L had a 17% lower risk of developing AF (HR 0.83, 95% CI 0.79-0.87), but water hardness of 61-120 mg/L and >
180 mg/L was associated with a higher risk of incident AF (both 1.04, 1.01-1.07). A non-linear relationship between water hardness and incident AF (P for non-linear = 0.001) was found. Individuals with water hardness 121-180 mg/L were also significantly associated with a lower risk of incident HF (HR 0.82, 95% CI 0.75-0.89), CHD (HR 0.80, 95% CI 0.76-0.84) and stroke (HR 0.88, 95% CI 0.81-0.95). There were no significant interaction effects between water hardness level and genetic susceptibility to AF, HF, CHD, and stroke risk (all P for interaction >
0.05). CONCLUSION: Potential U-shaped associations between domestic water hardness and incident AF across varying levels of genetic risk were found. Hard water (121-180 mg/L) may offer the most benefits compared to soft water when considering overall cardiovascular health, including AF, HF, CHD, and stroke.