High salt diet causally increases metabolic dysfunction-associated steatotic liver disease risk: A bidirectional mendelian randomization study

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder associated with metabolic and lifestyle factors, affecting approximately 25% of the global population. Although high salt intake has been implicated as a potential dietary risk factor, its causal relationship with MASLD remains uncertain. We hypothesized that genetic liability to higher salt intake causally increases the risk of MASLD. To address this, bidirectional Mendelian Randomization (MR) analysis was performed to evaluate the causal relationship between “salt added to food” and MASLD. Genetic variants were used as instrumental variables across large-scale genome-wide association study datasets from the UK Biobank and multiple MASLD cohorts. The inverse variance weighting method served as the primary analytical approach, with sensitivity analyses, including MR-Egger and MR-PRESSO, to evaluate pleiotropy and heterogeneity. Forward MR analysis demonstrated a significant association between “salt added to food” and increased MASLD risk across three MASLD datasets: odds ratio (OR) = 1.538, 95% confidence interval (CI): 1.145-2.067, P = .004; OR = 1.787, 95% CI: 1.247-2.561, P = .002; and OR = 2.094, 95% CI: 1.274-3.442, P = .004. Sensitivity analyses indicated low heterogeneity and no evidence of pleiotropy. Reverse MR analysis did not demonstrate a causal effect of MASLD on “salt added to food”. These findings provide robust genetic evidence that “salt added to food” is a causal risk factor for MASLD, emphasizing the importance of dietary salt reduction in MASLD prevention strategies. This study supports public health recommendations advocating reduced salt intake to promote liver health and prevent MASLD.