<p><em>FTO</em> Polymorphisms are Associated with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Susceptibility in the Older Chinese Han Population</p>

Background: As fat and obesity play a vital role in the pathophysiology of metabolic dysfunction-associated fatty liver disease (MAFLD), this study aims to investigate the association between the fat mass and obesity-associated gene ( FTO ) and MAFLD. Methods: Six SNPs (rs6499640, rs1421085, rs8050136, rs3751812, rs9939609 and rs9930506) within FTO were genotyped for 741 MAFLD patients (median age, 69.98; interquartile range, 66.55– 75.93) and 825 healthy people (median age, 69.94; interquartile range, 66.39– 75.64). Allele and genotype frequencies, pairwise linkage disequilibrium (LD) and haplotype analysis were calculated. Results: BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, triglyceride, alanine transaminase, glutamyl transpeptidase and the prevalence of diabetes were found to be higher in the MAFLD individuals comparing to the control ones ( P < 0.05). For rs1421085, the C allele frequency was remarkably higher in MAFLD after Bonferroni correction (OR [95% CI] =1.353 [1.095– 1.671]; P corr =0.030), and a significantly different genotype result was observed in log-additive model (OR [95% CI] =1.369 [1.108– 1.691]; P corr =0.024). For rs8050136, significantly increased A allele frequency was observed in MAFLD (OR [95% CI] =1.371 [1.109– 1.695]; P corr =0.024), and A-allele carriers showed increased MAFLD risk (OR [95% CI] =1.393 [1.103– 1.759]; P corr =0.030). For rs3751812, the T allele frequency was remarkably higher in MAFLD (OR [95% CI] =1.369 [1.108– 1.691]; P corr =0.024), and T-allele carriers demonstrated high MAFLD risk (OR [95% CI] =1.392 [1.103– 1.756]; P corr =0.030). For rs9939609, A allele frequency was also remarkably high in MAFLD (OR [95% CI] =1.369 [1.108– 1.691]; P corr =0.024), and A-allele carriers were more susceptible to MAFLD (OR [95% CI] =[1.103– 1.756]; P corr =0.030). A strong LD was found among rs1421085, rs8050136, rs3751812 and rs9939609 (r 2 > 0.8), and individuals with C-A-T-A haplotype had an elevated MAFLD risk (P =0.005). Conclusion: The case-control study indicated that C variant of rs1421085, A variant of rs8050136, T variant of rs3751812 and A variant of rs9939609 are associated with elevated MAFLD risk in the older Chinese Han population. Keywords: MAFLD, FTO , polymorphism, genetic association, susceptibility