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PNPLA3 genotype and diabetes identify patients with nonalcoholic fatty liver disease at high risk of incident cirrhosis

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Chen, Vincent L., Oliveri, Antonino, Miller, Matthew J., Wijarnpreecha, Karn, Du, Xiaomeng, Chen, Yanhua, Cushing, Kelly C., Lok, Anna S. +1 more·2023·Gastroenterology
DOI 10.1053/j.gastro.2023.01.040PMC PMC10550206
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Abstract

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

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  • Overall evidence suggests that PNPLA3 p.I148M and TM6SF2 p.E167K variants are major risk factors for progressive MASLD, and genotyping helps to noninvasively predict progressive MASH, cirrhosis and HCC when considered alongside clinical factors, but accuracy is suboptimal for prediction of liver disease severity and progression at the individual level.

    “Overall evidence suggests that the PNPLA3 p.I148M and TM6SF2 p.E167K variants are major risk factors for progressive MASLD, and genotyping helps to noninvasively predict progressive MASH, cirrhosis and HCC when considered alongside clinical factors, 194 -196 but accuracy is suboptimal for prediction of liver disease severity and progression at the individual level.”

    From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [194]

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Research works printed but not linked: 2

  1. [2]Alvarez CS, Graubard BI, Thistle JE, Attributable Fractions of NAFLD for Mortality in the United States: Results From NHANES III With 27 Years of Follow-up. Hepatology 2019; n/a. PMC7496113 31733165
  2. [37]Brenner H, Gefeller O. Variation of Sensitivity, Specificity, Likelihood Ratios and Predictive Values with Disease Prevalence. Statistics in Medicine 1997; 16: 981– 991. 9160493

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Authors
Chen, V. L., Oliveri, A., Miller, M. J., Wijarnpreecha, K., Du, X., Chen, Y., Cushing, K. C., Lok, A. S., & Speliotes, E. K.
Affiliations
University of Michigan (US)
Corresponding author
Chen, Vincent L.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2023-05
Volume
164
Issue
6
Pages
966-977.e17
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2023.01.040
PMC
PMC10550206
OpenAlex
W4319442654
Cited by
108
References
54
Citations by year
2026: 28 · 2025: 32 · 2024: 32 · 2023: 15 · 2022: 1
FWCI
21.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, other-oa)
Funders
  • National Institutes of Health
  • NIDDK (K08 DK132312, R01 DK106621, R01 DK107904)
  • American Association for the Study of Liver Diseases
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
non-alcoholic fatty liver disease, liver cirrhosis, PNPLA3, rs738409, genetic risk stratification, diabetes mellitus, FIB-4, liver fibrosis, alanine aminotransferase, obesity, disease progression, outcome prediction
MeSH terms
Acyltransferases, Diabetes Mellitus, Genotype, Humans, Liver Cirrhosis, Obesity, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Phospholipases A2, Calcium-Independent, Non-alcoholic Fatty Liver Disease

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