Lifestyle and genetic risk for chronic liver disease in metabolically healthy and unhealthy individuals from a general population

Background & Aims It is unclear to what extent lifestyle and genetic factors affect incidence of chronic liver disease (CLD) in a general population and if lifestyle affects CLD independently of underlying cardiometabolic perturbations and genetic predisposition. Methods We examined 27,991 men and women aged 44-73 years from the Malmö Diet and Cancer Study recruited between 1991-1996 and followed until end of 2020 using registry-linkage (median follow-up time 25.1 years; 382 incident first-time CLD events). Associations between cardiometabolic factors, polygenic risk scores (PRSs), and lifestyle factors in relation to CLD were examined using multivariable Cox proportional hazards regression models. Results Incidence of CLD increased with number of cardiometabolic risk factors (the hazard ratio (HR) per each additional cardiometabolic risk factor was 1.33 (95% CI: 1.21-1.45; p= 5.1 x 10-10). Two novel polygenic risk scores (PRS) for metabolic dysfunction-associated steatotic liver disease (MASLD) and a PRS for liver cirrhosis associated with higher risk of CLD but provided marginal predictive utility on top of other risk factors and compared to the PNPLA3 rs738409 genetic variant. An unhealthy lifestyle (high alcohol intake, current smoking, physical inactivity and unhealthy diet) markedly increased risk of CLD (HR=3.97, 95% CI: 2.59-6.10). Observed associations between examined lifestyle factors and CLD were largely independent of cardiometabolic perturbations and polygenic risk. Conclusions We confirmed the importance of cardiometabolic dysfunction in relation to risk of CLD in a general population. Lifestyle risk factors were shown to independently associate with CLD and added predictive information on top of cardiometabolic risk factors. Information on the polygenic risk of liver disease does not currently add to prediction of CLD in a general population. Lay summary In this large longitudinal study of a general population, we found that cardiometabolic, genetic and lifestyle risk factors all contribute to the development of chronic liver disease (CLD). Our results suggest that an unhealthy lifestyle, including alcohol consumption, smoking, physical inactivity, and an unhealthy diet, substantially increase risk of CLD independently of underlying genetic risk or cardiometabolic health. This suggest that a large proportion of CLD cases are potentially preventable through adoption of healthy lifestyle changes. Impact and implications This large population-based prospective study suggests largely independent roles of cardiometabolic, lifestyle, and genetic risk factors in the development of chronic liver disease. Findings strengthen the evidence base for a beneficial effect of modification of high-risk lifestyle behaviors in the primary prevention of chronic liver disease in the general population.