rs55959738 is Associated with Hepcidin in Metabolic Dysfunction‐Associated Steatotic Liver Disease

In individuals with metabolic dysfunction‐associated steatotic liver disease (MASLD) increased hepatic hepcidin gene expression, is associated with hepatic iron deposition, which is in turn associated with more severe steatohepatitis and fibrosis. We investigated single nucleotide polymorphisms (SNPs) associated with serum hepcidin level in MASLD. A targeted Genome Wide Association Studies (GWAS) was performed in individuals with biopsy‐proven MASLD of European ancestry in the nonalcoholic steatohepatitis‐clinical research network (NASH CRN) database I and PIVENS. Association between SNPs and serum hepcidin level was tested using PLINK2. Linear regression was performed to determine association with SNPs and serum hepcidin level in individuals with MASLD. MASLD cohort included 563 individuals, (65% female, 29% had diabetes‐2, mean age = 49.7 ± 10.8 years, mean BMI = 34.8 ± 6.5 kg/m 2 ). Mean hepcidin level was 71.6 ± 48.2 ng/ml, and mean ferritin level was 239.3 ± 270.1 ng/dl. After adjusting for age, sex, BMI, diabetes‐2, and presence of hepatic iron staining, the SNP rs55959738 (T) on chromosome 6 was associated with lower serum hepcidin level ( β = −0.48, se = 0.09, p = 3.29E‐08) in the cohort. The association even after adjusting for PNPLA3 G allele or common pathogenic HFE variants (C282Y and H63D). The SNP rs55959738 is intergenic in location and is in linkage disequilibrium with SNORD genes. In MASLD, a novel SNP rs55959738 on chromosome 6 is associated with lower serum hepcidin level, independent of common HFE and PNPLA3 variants. Additional studies to explore the role of SNP rs55959738 on hepcidin mediated inflammation in MASLD.