Impact of PNPLA3 and TM6SF2 polymorphisms on the prognosis of patients with MASLD and type 2 diabetes mellitus

Longitudinal studies assessing the impact of genetic polymorphisms on outcomes in patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are scarce. This study aimed to evaluate the effect of PNPLA3 and TM6SF2 risk alleles on hepatic and ex...

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Published in:	Liver international Vol. 44; no. 4; pp. 1042 - 1050
Main Authors:	Lavrado, Natália Coelho, Salles, Gil Fernando, Cardoso, Claudia Regina Lopes, de França, Paulo Henrique Condeixa, Melo, Maria Fernanda Di Guimarães Gonçalves, Leite, Nathalie Carvalho, Villela-Nogueira, Cristiane Alves
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-04-2024
Subjects:	Alleles Cirrhosis Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - genetics Fatty Liver Female Fibrosis Gene polymorphism Genetic Predisposition to Disease Genotype Humans Liver cirrhosis Liver Cirrhosis - genetics Liver diseases Longitudinal studies Male Membrane Proteins - genetics Mortality Non-alcoholic Fatty Liver Disease - genetics Polymorphism Polymorphism, Single Nucleotide Prognosis Risk PNPLA3 type 2 diabetes mellitus genetic polymorphisms metabolic dysfunction‐associated steatotic liver disease prognosis TM6SF2
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Summary:	Longitudinal studies assessing the impact of genetic polymorphisms on outcomes in patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) are scarce. This study aimed to evaluate the effect of PNPLA3 and TM6SF2 risk alleles on hepatic and extrahepatic outcomes in T2DM-MASLD individuals. Patients' polymorphisms were analysed as follows: PNPLA3 CC, CG and GG; TM6SF2 CC and CT + TT; combined comparing no mutant allele, one allele G or T or ≥2 alleles G or T. Hierarchical models were built to assess associations between polymorphisms and outcomes, independently of confounding factors. Multivariate logistic regression was used for cirrhosis and its complications and extrahepatic cancer, and Cox regression for cardiovascular events (CVEs) and all-cause mortality. In total, 407 T2DM-MASLD patients (62.1 ± 10.5 years, 67.6% women) were followed for 11 (6-13) years. Having at least one G or T allele independently increased the risk of cirrhosis in the separate analysis of PNPLA3 and TM6SF2. Combined polymorphism analysis demonstrated an even higher risk of cirrhosis if two or more risk alleles were present (OR 18.48; 95% CI 6.15-55.58; p < .001). Regarding cirrhosis complications, the risk was higher in PNPLA3 GG and TM6SF2 CT + TT, also with an even higher risk when two or more risk alleles were present in the combined evaluation (OR 27.20; 95% CI 5.26-140.62; p < .001). There were no associations with CVEs or mortality outcomes. In T2DM, PNPLA3 and TM6SF2 polymorphisms, individually and additively, impact MASLD severity, with an increased risk of cirrhosis and its complications.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1478-3223 1478-3231 1478-3231
DOI:	10.1111/liv.15845