Association of TM6SF2 rs58542926 with MASLD, clinical phenotypes, and longitudinal outcomes: a systematic review and meta-analysis

Background The rs58542926 variant in transmembrane 6 superfamily member 2 (TM6SF2) has been linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but its associations with disease risk, histological severity, metabolic traits, and outcomes remain unclear. We evaluated these associations in adults. Methods PubMed, Embase, Web of Science, and the Cochrane Library were searched for observational studies published up to 11 November 2025. Pooled estimates were calculated for MASLD susceptibility, histological features, metabolic and liver injury markers, and long-term outcomes. The protocol was registered in PROSPERO (CRD420251273179). Results Data from 368,852 participants across 55 studies were included in the meta-analysis. Under a dominant genetic model, rs58542926 was associated with higher MASLD susceptibility (odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.27–1.55), including in ultrasound-, biopsy-, and elastography-based subgroups. The T allele was associated with moderate-to-severe steatosis (OR = 1.42, 95% CI: 1.11–1.80) and significant fibrosis (OR = 1.34, 95% CI: 1.07–1.68). Carriers showed lower triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, slightly higher high-density lipoprotein cholesterol levels, and modestly higher fasting glucose, insulin, AST, and ALT levels. For long-term outcomes, the dominant model showed a potential association with increased liver-related event risk (HR = 2.20, 95% CI 1.22–3.95), and CT vs. CC was associated with lower cardiovascular mortality in one study (HR = 0.35, 95% CI 0.13–0.97). Conclusion TM6SF2 rs58542926 is associated with increased MASLD susceptibility, greater steatosis and fibrosis severity, a lipid-lowering phenotype accompanied by modest alterations in liver injury markers, and a potential increase in liver-related events. These findings support its potential value in genetic risk stratification, although clinical utility requires validation.