The Role Of SNPs Associated With Liver Disease In The Development And Progression Of Metabolic-associated Fatty Liver Disease

BackgroundMetabolic associated fatty liver disease(MAFLD)is now the leading liver disease in the world.The prevalence of MAFLD in China is 29.2%,and the prevalence of MAFLD in overweight and obese adults is more than 50%.MAFLD is a chronic liver disease characterized by excessive accumulation of fat in liver cells,which not only leads to liver inflammation,fibrosis,cirrhosis,liver cancer and extrahepatic malignant tumors,but also is often associated with a variety of metabolic disorders,causing chronic kidney disease and cardiovascular disease,etc.The main risk factors for MAFLD include obesity,type 2 diabetes mellitus,various inflammation,hypertension,dyslipidemia,intestinal flora disorders,metabolic syndrome,and genetic factors.The researchers found that PNPLA3,TM6SF2,GCKR,MBOAT7,and HSD17B13,which were previously identified as susceptibility genes of nonalcoholic fatty liver disease(NAFLD)were also associated with the risk of MAFLD.However,several new NAFLD susceptibility genes which have recently been identified,and whether the susceptibility gene loci related to liver diseases,such as cirrhosis and liver cancer,are also associated with the risk of MAFLD is unknown at present.In addition,it is not clear whether these liver disease-related genetic factors are associated with MAFLD promoting the risk of cirrhosis,liver cancer,other liver diseases,cardiovascular disease,kidney disease,and extrahepatic cancers.ObjectivesIn this study,based on the UKBiobank database of 500,000 people with rich phenotypic information and comprehensive genetic data,we analyzed whether the genetic factors related to liver disease identified so far are related to the development of MAFLD,and whether they are related to the risk of liver cirrhosis or liver cancer in patients with MAFLD.At the same time,a risk prediction model integrating MAFLD and genetic risk score(GRS)was constructed to evaluate its role in predicting the risk of liver cirrhosis,liver cancer and other diseases.Methods1.Apply for and download all phenotypic data and genome-wide genotyping data of 500,000 subjects from the UKBiobank database,and conduct sample screening according to preset data quality control procedures.2.According to the definition criteria of MAFLD,the MAFLD population and Non-MAFLD population were identified from the UKBiobank samples,while the patients with cirrhosis,liver cancer and other diseases were screened according to the International Classification of Diseases Code.3.A Pubmed literature search was conducted to tease out all NAFLD-susceptible single nucleotide polymorphisms(SNPs),SNPs associated with cirrhosis and SNPs associated with liver cancer.4.Based on the SNPs associated with liver disease,the population standardized weighted GRS was constructed by the method of odds ratio(OR).Including the construction of GRSclassic_NaFLD,GRSnew_NAFLD,GRStotal NAFLD,GRScirrhosis and GRSlivercancer based on various liver diseases-related SNPs,and GRScombined based on all liver diseases-related SNPs.5.Logistic regression was used to analyze the correlation between the above liver diseases-related SNPs and the constructed GRS and the occurrence of MAFLD,cirrhosis,liver cancer,other liver diseases,cardiovascular diseases,kidney diseases and extrahepatic cancers.Cox regression was used to analyze the effect of GRS on MAFLD’s promotion of the risk and cumulative risk of liver eirrhosis,liver cancer,other liver diseases,cardiovascular diseases,kidney diseases,extrahepatic cancers,etc.area under the curve(AUC)analysis was used to evaluate the combined modeling efficiency of MAFLD and GRS in predicting the risk of liver cirrhosis,liver cancer,other liver diseases,cardiovascular diseases,kidney diseases,extrahepatic cancers,etc.Results1.Multiple liver disease-related SNPS and GRS constructed based on liver disease-related SNPS were significantly associated with the risk of developing MAFLD.2.MAFLD can promote the risk of cirrhosis,liver cancer,other liver diseases,cardiovascular diseases,kidney diseases,and extrahepatic cancers(hazard ratio,HR>1),and when multiple groups of GRS are distinguished according to High and Low,the ORs of liver cirrhosis,liver cancer and other liver diseases were significantly greater in the GRS-High group than in the GRS-Low group,but this effect did not exist in cardiovascular disease,kidney disease and extrahepatic cancers.3.MAFLD can increase the cumulative risk of liver cirrhosis,liver cancer,other liver diseases,cardiovascular diseases,kidney diseases,extrahepatic cancers,etc.,and when grouped according to the High and Low GRS of multiple groups,The cumulative risk of cirrhosis,liver cancer,and other liver diseases was greater in the group with both MAFLD and GRS-High than in the group with both MAFLD and GRS-Low,and this effect was not seen in cardiovascular disease,kidney disease,or extrahepatic cancers.4.The AUC of MAFLD alone in the prediction of cirrhosis was 0.672,and the AUC of all combined models constructed by MAFLD and GRS was greater than that of MAFLD alone in the prediction of cirrhosis.Among them,the AUC of MAFLD combined with GRStotal_NAFLD was 0.705.The risk prediction of liver cancer and other liver diseases was similar to that of liver cirrhosis.But for cardiovascular disease,kidney disease,and extrahepatic cancers,all jointly modeled AUCs were very close to those of MAFLD alone.Conclusions1.MAFLD can promote the occurrence of liver cirrhosis,liver cancer,other liver diseases,cardiovascular diseases,kidney diseases and extrahepatic cancers,and GRS constructed by liver diseases-related SNPs can amplify the promoting effect of MAFLD on the occurrence risk of liver cirrhosis,liver cancer and other liver diseases,but there is no correlation with the promoting effect of MAFLD on the occurrence risk of cardiovascular diseases,kidney diseases and extrahepatic cancers.2.All types of GRS constructed with liver diseases-related SNPs amplified the promoting effect of MAFLD on the cumulative risk of liver cirrhosis,liver cancer and other liver diseases,but GRS had little effect on the promoting cumulative risk of cardiovascular disease,kidney disease and extrahepatic cancers.3.MAFLD can predict the risk of liver cirrhosis,liver cancer and other liver diseases,and GRS constructed with SNPs related to liver disease can enhance the predictive effect of MAFLD on the risk of liver cirrhosis,liver cancer and other liver diseases,but have little effect on the predietive effect of MAFLD on the risk of cardiovascular disease,kidney disease and extrahepatic cancers.