The impact of genetic risk on the prevalence of advanced fibrosis and cirrhosis in prospectively assessed patients with type 2 diabetes

Aliment Pharmacol Ther. 2024 Aug;60(3):369-377. doi: 10.1111/apt.18099. Epub 2024 Jun 2.


Background: Genetic factors contribute to the risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised.

Aims: To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines.

Methods: We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration-controlled transient elastography to assess for advanced fibrosis and cirrhosis.

Results: Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis-4 index (FIB-4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB-4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk.

Conclusions: Utilising a well-phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at-risk populations may improve risk prediction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases
  • Acyltransferases
  • Aged
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / genetics
  • Elasticity Imaging Techniques*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lipase / genetics
  • Liver Cirrhosis* / epidemiology
  • Liver Cirrhosis* / genetics
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / epidemiology
  • Non-alcoholic Fatty Liver Disease / genetics
  • Phospholipases A2, Calcium-Independent
  • Prevalence
  • Prospective Studies
  • Risk Assessment / methods
  • Risk Factors
  • alpha 1-Antitrypsin


  • Membrane Proteins
  • Lipase
  • TM6SF2 protein, human
  • PNPLA3 protein, human
  • SERPINA1 protein, human
  • HSD17B13 protein, human
  • Acyltransferases
  • alpha 1-Antitrypsin
  • 17-Hydroxysteroid Dehydrogenases
  • Phospholipases A2, Calcium-Independent