• October 24, 2023
  • Alejandro Soto-Gutierrez, MD, PhD
  • Lans Taylor, PhD
  • Jaideep Behari, MD, PhD

Alex Soto-Gutierrez, MD, PhD director of the HSLBC Core along with co-director Lans Taylor, PhD and PLRC associate Director Jai Behari, MD, PhD, and a team of other scientists including PLRC members, Rodrigo Florentino, PhD, Alina Ostrowska,PhD, Lanuza Faccioli, PhD published an article in Gastro Hep Advances entitled, “Polymorphisms Associated with Metabolic Dysfunction-Associated Steatotic Liver Disease Influence the Progression of End-Stage Liver Disease“

Open AccessPublished:October 05, 2023DOI:https://doi.org/10.1016/j.gastha.2023.09.011
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ABSTRACT

BACKGROUND AND AIMS

Chronic liver injury that results in cirrhosis and end-stage liver disease (ESLD) causes more than 1 million deaths annually worldwide. Although the impact of genetic factors on the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) has been previously studied, their contribution to the development of ESLD remains largely unexplored.

METHODS

We genotyped six MASLD-associated polymorphisms in healthy (n=123), metabolic dysfunction-associated steatohepatitis (MASH) (n=145), MASLD-associated ESLD (n=72), and ALD-associated ESLD (n=57) cohorts and performed multinomial logistic regression to determine the combined contribution of genetic, demographic, and clinical factors to the progression of ESLD.

RESULTS

Distinct sets of factors are associated with the progression to ESLD. The PNPLA3rs738409:G and TM6SF2 rs58542926:T alleles, body mass index (BMI), age, and female sex were positively associated with progression from a healthy state to MASH. The PNPLA3 rs738409:G allele, age, male sex, and having type 2 diabetes mellitus were positively associated, while BMI was negatively associated with progression from MASH to MASLD-associated ESLD. The PNPLA3 rs738409:G and GCKR rs780094:T alleles, age, and male sex were positively associated, while BMI was negatively associated with progression from a healthy state to ALD-associated ESLD. The findings indicate that the PNPLA3 rs738409:G allele increases susceptibility to ESLD regardless of etiology, the TM6SF2 rs58542926:T allele increases susceptibility to MASH, and the GCKR rs780094:T allele increases susceptibility to ALD-associated ESLD.

CONCLUSION

The PNPLA3, TM6SF2, and GCKR minor alleles influence the progression of MASLD- or ALD-associated ESLD. Genotyping for these variants in MASLD and ALD patients can enhance risk assessment, prompting early interventions to prevent ESLD.