Differential association of platelet indices in NAFLD/NASH: a Mendelian randomized study

Platelets play important roles in thrombosis, immunity, and inflammation. Recent studies have shown a relationship between platelet indices and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this causal relationship remain controversial. This study used two-sample Mendelian randomization (MR) to elucidate the potential causal relationships.

Genetic associations of platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) were obtained from the summary statistics of a genome-wide association study from the UK Biobank, those of NAFLD/NASH were sourced from the FinnGen database, and two different genome-wide association meta-analyses. Inverse variance weighting was conducted, with weighted median, Mendelian randomisation-Egger, and Mendelian randomisation Pleiotropy Residual Sum and Outlier methods used as sensitivity analyses. Estimates from the inverse variance weighting method were meta-analyzed. Reverse MR Analysis was conducted using NAFLD data.

Increased genetically predicted PDW levels were consistently associated with increased NAFLD risk from all three sources (OR = 1.08, 95% CI = 1.01-1.15; P  = 0.020). Genetically predicted NAFLD was associated with increased MPV (OR = 1.008, 95% CI: 1.005-1.032; P  = 0.008). Increased levels of genetically predicted PDW were associated with an increased risk of NASH (OR = 1.603, 95% CI: 1.154-2.228; P  = 0.005). Decreased levels of genetically predicted PLT and PCT were associated with an increased risk of NASH (OR = 0.679, 95% CI: 0.487-0.947, P  = 0.023; OR = 0.587, 95% CI: 0.408-0.843; P  = 0.004).

Our results suggest that fluctuations in platelet indices are important in predicting the onset and progression of NAFLD/NASH.