Genetic polymorphisms associated with metabolic dysfunction-associated steatotic liver disease and cardiometabolic risk susceptibility in the Chinese Han population

Genetic insights into metabolic dysfunction-associated steatotic liver disease (MASLD) and its cardiometabolic subphenotypes in Asian populations remain limited. This study aimed to investigate the genetic polymorphisms associated with MASLD and its cardiometabolic subphenotypes susceptibility in a Chinese Han cohort. We genotyped 24 candidate single nucleotide polymorphisms (SNPs) in 870 MASLD patients, previously associated with fatty liver disease or related traits in published literature, and 1165 controls without hepatic steatosis or any cardiometabolic risk factors. Subgroup analyses (obesity, glucose/lipid abnormalities, carotid plaque) were conducted using sex- and age-adjusted logistic regression and haplotype construction. The HSD17B13rs72613567 "T/T" genotype was associated with a significantly reduced susceptibility to MASLD with carotid plaque compared to the "A/A" genotype (OR 0.33, 95% CI 0.16–0.66, P = 0.004). Additionally, the KLB rs12152703 "T/T" genotype demonstrated a protective effect against overall MASLD susceptibility (OR 0.33, 95% CI 0.13–0.81, P = 0.028), with consistent trends observed in subgroups stratified by obesity and glucose metabolism disorders. Meanwhile, GCKR rs1260326 "C/C" decreased MASLD susceptibility (OR 0.75, 95% CI 0.60–0.94, P = 0.012), while KLB rs12639940 elevated risk. Haplotype analyses further supported the roles of KLB and HSD17B13 in MASLD and its cardiometabolic subphenotypes (all P < 0.05). This study demonstrated that rs72613567 in HSD17B13 might reduce the susceptibility to carotid plaque in MASLD. Moreover, KLB rs12152703 may reduce the susceptibility to MASLD and its cardiometabolic subtypes. These findings identify genes such as the HSD17B13 and KLB as key genetic determinants of MASLD and its cardiometabolic complications in Chinese Han individuals.