Role of IFNL4 Genotype in Hepatic Inflammation and Fibrosis due to Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND AND AIMS: In patients infected with hepatitis C virus, genetic polymorphisms within or near the interferon lambda 4 gene ( IFNL4 ) predict the risk of hepatic inflammation and fibrosis. Several studies have reported that these polymorphisms are also associated with inflammation and fibrosis in patients with fatty liver disease. To further explore this question, we examined whether the functional IFNL4 -ΔG allele, which generates the IFN-λ4 protein, was associated with decreased severity of hepatic inflammation, fibrosis and related measures across three cohorts of participants with metabolic dysfunction-associated steatotic liver disease (MASLD). APPROACH AND RESULTS: Among 1786 non-Hispanic, white adults with biopsy-confirmed MASLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network cohort (NASH CRN), the IFNL4 -ΔG allele did not associate with histologic measures of disease severity: fibrosis - adjusted odds ratio [aOR] = 0.98, 95% confidence interval [CI] 0.86-1.11, p = 0.74; steatosis - aOR = 0.95, 95% CI 0.83-1.08, p = 0.40; lobular inflammation - aOR = 1.03, 95% CI 0.90-1.19, p = 0.63; NAFLD Activity Score - aOR = 1.00, 95% 0.88-1.13, p = 0.98. Results were similar in 358 Hispanic adults and 897 children enrolled in NASH CRN. In the Indiana University Nonalcoholic Fatty Liver Disease cohort (n = 606), IFNL4 -ΔG was not associated with liver stiffness measurement (LSM). In the HIV NASH CRN cohort (n = 645), the IFNL4 -ΔG allele associated with increased LSM in non-Hispanic, white, but not in non-Hispanic, black individuals. Conclusions In contrast to some previous studies, this investigation of > 4,000 individuals provides no evidence that the IFNL4 -ΔG allele is associated with decreased hepatic inflammation or fibrosis in patients with MASLD.