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Background/Objectives: Whether an increased genetic risk of steatotic liver disease (SLD) can be offset by maintaining a healthy weight remains unknown. We aimed to clarify the associations among the body mass index (BMI) and its change patterns with SLD and assess whether genetic susceptibility can modify these associations in Chinese people. Methods: A total of 10,091 and 6124 participants from the Health Omics Preventive Examination (HOPE) Program were enrolled in cross-sectional and follow-up analyses, respectively. BMI change patterns were defined according to the BMI at baseline and the last follow-up visit. Genetic risk was estimated using the polygenic risk score (PRS) derived from variants in PNPLA3, TM6SF2, MBOAT7, and GCKR. Data were analyzed using logistic regression models and Cox proportional-hazards models. Results: The analyses of the BMI and genetic risk simultaneously showed a dose–response association with the risk of SLD (p-trend < 0.001). Significant interactions between BMI and PRS were found for alanine aminotransferase (ALT) elevation (p = 0.007) and aspartate aminotransferase (AST) elevation (p < 0.001). Weight loss led to a 71%, 60%, and 67% lower risk of SLD, ALT elevation, and AST elevation, compared with stable overweight/obesity. A significant interaction between the genetic risk and BMI change patterns in ALT elevation was observed (p = 0.008). The absolute risk reductions associated with weight loss were greater for participants at a high genetic risk (26.60, 12.29, and 9.31 per 100 person years for SLD, ALT elevation, and AST elevation, respectively). Conclusions: Maintaining a healthy weight reduces the liver injury risk among all individuals, and the risk reduction is greater among the subset with a high genetic risk of SLD. [ABSTRACT FROM AUTHOR]

Background & Aims: Physical activity, sedentary behaviour, and genetic variants have been associated with the nonalcoholic fatty liver disease (NAFLD). However, whether and how the degree of healthy activity patterns may modify the impact of genetic susceptibility on NAFLD remains unknown. Methods: Behaviour activity factors were determined according to total physical activity (TPA) and sedentary time. The polygenic risk score (PRS) was calculated by variants in PNPLA3, TM6SF2, MBOAT7, and GCKR. Cox regression was used to analyse the associations of genetic and behaviour activity factors with incident NAFLD in the UK Biobank (N = 338 087). Results: During a median follow‐up of 12.4 years, 3201 incident NAFLD cases were ascertained. Analyses of TPA and sedentary time simultaneously showed a dose–response association with the risk of NAFLD (ptrend <.001). The association of behaviour activity patterns with NAFLD varied by genetic variants. Of the subjects with high genetic risk, we observed a null protective effect of moderate or high TPA on NAFLD risk, while sitting less than three hours a day significantly decreased the risk of NAFLD (p = 3.50 × 10−4). The high genetic risk of NAFLD can also be offset by the combination of moderate physical activity and shorter sedentary time. Moreover, the high genetic risk group has the greatest reduction of 10‐year absolute risk (6.95 per 1000 person‐years) if reaching both healthy activities. Conclusions: Moderate‐to‐high physical activity and favourable sedentary behaviour may be lifestyle modifications in preventing NAFLD, which could offset the harmful effect of predisposing genetic factors. [ABSTRACT FROM AUTHOR]