Association Between Alcohol,and SNP Related With Alcohol Metabolism And The Risk Of Fibrosis

Objective: Alcoholic liver disease(ALD)accounts for 50% of cirrhosis cases globally,and the proportion of alcoholic fatty liver disease(AFLD)is more than 50% in the population with excessive drinking,in some areas of China,the prevalence of ALD range from 2.3% to 6.1%(average prevalence at around 4.5%).However,studies related to alcohol intake are mostly focused on community or hospital,and there are few population-based studies,at the same time,evidence related to alcoholic fatty liver disease is also insufficient.Therefore,this study aimed to explore the relationship between the flushing response,alcohol consumption and risk of alcohol-related fatty liver,as well as liver fibrosis,and to investigate the interaction between alcohol metabolism-related genetic polymorphisms the amount of alcohol consumption in the population-based study.Methods: A cross-sectional study was conducted based on the natural population chronic disease prospective cohort in Fuqing City,Fujian Province.A total of 9906 baseline people enrolled from February 2019 to December 2020 were included as potential research subjects.By means of questionnaire,physical examination and clinical examination at baseline,we obtained a series of information including personal health-related behavior and lifestyle,abdominal ultrasonography and blood testing results.On the basis of the blood routine examination and biochemical indicators,we calculated FIB-4,ZJU and ANI index,and then according to abdominal ultrasound results and alcohol consumption,the reliability of ZJU and ANI index were verified.In the first section,5419 subjects who met the conditions were involved in the analysis,and multi-factor Logistic regression model was used to assess alcohol related information(such as alcohol intake,flush reaction,etc.)and the risk of injury of liver fibrosis,strength of association was evaluated by odds ratio(OR)and 95% confidence interval(CI),and we performed sensitivity analysis among baseline population in 2020;In the second section,the baseline population of the chronic hepatitis B sub-cohort,which was established based on the cohort mentioned above,were taken as the research subjects of this part,that is,all 977 hepatitis B surface antigen positive population in 2019 were included.Basing on all the research data such as the questionnaire information collected in the early stage,ASA(Asian Screening Array)technology was adopted for genotyping of genetic susceptibility loci,the Logistic regression model was also used in this section to explore the relationship between two alcohol metabolism-related genetic polymorphisms(ADH1B rs1229984 and ALDH2 rs671),which were the most common in Asian population,and the risk of liver fibrosis.Results: Ex-drinkers,moderate or heavy drinkers(≥20 g/day for men or ≥10 g/day for women)had a 2.14-fold(95%CI:1.05-4.36)and 1.58-fold(95%CI:1.00-2.48)higher risk of alcoholic fatty liver disease with hepatic fibrosis injury compared with non-drinkers,respectively.In the total population(N=5419,mean age: 57.8±11.2 years)and the male(N=3008,mean age: 60.1±10.4 years),the risk of alcoholic fatty liver disease and liver fibrosis in non-flushers was 1.47 times(95%CI: 1.06-2.05)and 1.69 times(95%CI:1.03-2.78)higher,respectively,compared with those who had never drunk.The proportion of moderate or excessive drinking in non-flushers was higher than flushers(that is,alcoholsensitive people).In the interaction,non-flushers with moderate or heavy drinking had an increased risk of alcoholic fatty liver disease with hepatic fibrosis(OR and 95%CI,1.69(1.01-2.82)),and in HBs Ag negative population,the risk of alcoholic fatty liver disease and hepatic fibrosis injury in moderate or excessive drinking group was 1.68 times higher than that in non-drinking group(95%CI:1.03-2.74),similar findings were found in sensitivity analysis,and due to the fact that individuals with alcohol intake were limited in HBs Ag positive group,so this part still needs to be verified.The risk of flushing reaction was 7.94 times higher in individuals with ALDH2 rs671 A allele than those with GG genotype(95%CI: 5.18-12.16).In the interaction between the two loci,among the individuals with ADH1 B rs1229984 T allele,the risk of flushing reaction in individuals with ALDH2 rs671 A allele was 9.67 times higher than those with GG genotype(95%CI: 6.12-15.28).Individuals with ALDH2 rs671 A allele had a reduced risk of alcoholic fatty liver disease with hepatic fibrosis(OR and 95%CI: 0.48(0.25-0.95)).When checking the interaction between ALDH2 rs671 and ADH1 B rs1229984,among individuals with the same wild TT genotype of ADH1 B rs1229984,individuals with ALDH2 rs671 A allele may have a reduced risk of hepatic fibrosis injury compared with those with the GG genotype(OR and 95%CI: 0.36(0.13-0.99)).Compared with those who carried ALDH2 rs671 GG genotype and non-drinking,the risk of liver fibrosis may be increased in those who carried ALDH2 rs671 A allele and drank excessively.However,due to the limited sample size in this group,a larger population with genotyping is required for further verification in the future studies.Conclusion: Non-flushers were more prone to binge drinking and alcoholism,while flushers were more likely to drink little or never drinking.Those carrying ALDH2 rs671 A allele can reduce the risk of hepatic fibrosis injury.Different genotypes of ALDH2 rs671 and ADH1 B rs1229984 can affect the occurrence and development of diseases by influencing whether individuals may experience uncomfortable reactions such as flushing after drinking,which results in reduction of the amount of alcohol intake.There may be an interaction between ALDH2 rs671 and alcohol consumption,which requires further studies with larger sample sizes.