Integration of PNPLA3 and TM6SF2 genotypes provides incremental improvement in advanced fibrosis prediction among MASLD patients with type 2 diabetes mellitus

Our research demonstrates that incorporating <i>PNPLA3</i> and <i>TM6SF2</i> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus - a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiring closer monitoring. In practice, genetic information could be integrated into routine risk stratification, especially in settings where elastography is unavailable, allowing serum-based tests to more accurately identify high-risk patients who warrant referral for biopsy or specialist evaluation. However, given the modest absolute improvements and tertiary care derivation, further validation in diverse populations is essential before routine clinical implementation can be recommended.