Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD

doi:10.1016/j.cgh.2023.12.009

. 2024 May;22(5):1024-1036.e2.

doi: 10.1016/j.cgh.2023.12.009. Epub 2023 Dec 23.

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD

Affiliations

¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana.
² Division of Gastroenterology, and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana.
³ Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.
⁴ Division of Gastroenterology, and Hepatology, Saint Louis University, St Louis, Missouri.
⁵ Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Diego School of Medicine, La Jolla, California.
⁶ Division of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
⁷ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California; Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California.
¹⁰ Division of Gastroenterology, and Hepatology, Virginia Commonwealth University, Richmond, Virginia.
¹¹ Department of Biostatistics and Epidemiology, Johns Hopkins University, Baltimore, Maryland.
¹² Division of Gastroenterology, and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana. Electronic address: nchalasa@iu.edu.

PMID: 38145725
PMCID: PMC11045318 (available on 2025-05-01)
DOI: 10.1016/j.cgh.2023.12.009

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD

Chaowapong Jarasvaraparn et al. Clin Gastroenterol Hepatol. 2024 May.

. 2024 May;22(5):1024-1036.e2.

doi: 10.1016/j.cgh.2023.12.009. Epub 2023 Dec 23.

Affiliations

¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana.
² Division of Gastroenterology, and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana.
³ Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.
⁴ Division of Gastroenterology, and Hepatology, Saint Louis University, St Louis, Missouri.
⁵ Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Diego School of Medicine, La Jolla, California.
⁶ Division of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
⁷ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
⁸ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California; Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California.
¹⁰ Division of Gastroenterology, and Hepatology, Virginia Commonwealth University, Richmond, Virginia.
¹¹ Department of Biostatistics and Epidemiology, Johns Hopkins University, Baltimore, Maryland.
¹² Division of Gastroenterology, and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana. Electronic address: nchalasa@iu.edu.

PMID: 38145725
PMCID: PMC11045318 (available on 2025-05-01)
DOI: 10.1016/j.cgh.2023.12.009

Abstract

Background & aims: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD.

Methods: A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG).

Results: PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% CI, 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013-1.026), CG (OR, 1.024; 95% CI, 1.018-1.030), and GG (OR, 1.03; 95% CI, 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m² was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both).

Conclusions: Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD.

Keywords: Advanced Fibrosis; Genotypes; Modifier; PNPLA3.

PubMed Disclaimer

Cited by

Current Status of Genetics and Polygenic Risk Scores in Metabolic Dysfunction-Associated Steatohepatitis.
Chalasani N. Chalasani N. Gastroenterol Hepatol (N Y). 2024 Aug;20(8):460-503. Gastroenterol Hepatol (N Y). 2024. PMID: 39205952 Free PMC article. No abstract available.
Genetics of Metabolic Dysfunction-associated Steatotic Liver Disease: The State of the Art Update.
Sookoian S, Rotman Y, Valenti L. Sookoian S, et al. Clin Gastroenterol Hepatol. 2024 Nov;22(11):2177-2187.e3. doi: 10.1016/j.cgh.2024.05.052. Epub 2024 Jul 31. Clin Gastroenterol Hepatol. 2024. PMID: 39094912 Review.
What Not to Overlook in the Management of Patients with Type 2 Diabetes Mellitus: The Nephrological and Hepatological Perspectives.
Alfieri CM, Molinari P, Cinque F, Vettoretti S, Cespiati A, Bignamini D, Nardelli L, Fracanzani AL, Castellano G, Lombardi R. Alfieri CM, et al. Int J Mol Sci. 2024 Jul 15;25(14):7728. doi: 10.3390/ijms25147728. Int J Mol Sci. 2024. PMID: 39062970 Free PMC article. Review.

References

1. Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease. Obesity (Silver Spring) 2021;29:1950–1960. - PMC - PubMed
1. Hamid O, Eltelbany A, Mohammed A, Alsabbagh Alchirazi K, Trakroo S, Asaad I. The epidemiology of non-alcoholic steatohepatitis (NASH) in the United States between 2010–2020: a population-based study. Annals of Hepatology 2022;27:100727. - PubMed
1. Wang J, Conti DV, Bogumil D, Sheng X, Noureddin M, Wilkens LR, Le Marchand L, et al. Association of genetic risk score with NAFLD in an ethnically diverse cohort. Hepatology Communications 2021;5:1689–1703. - PMC - PubMed
1. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461–1465. - PMC - PubMed
1. Sookoian S, Pirola CJ. Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883–1894. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

[1] Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease. Obesity (Silver Spring) 2021;29:1950–1960. - PMC - PubMed

[2] Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease. Obesity (Silver Spring) 2021;29:1950–1960. - PMC - PubMed

[3] Hamid O, Eltelbany A, Mohammed A, Alsabbagh Alchirazi K, Trakroo S, Asaad I. The epidemiology of non-alcoholic steatohepatitis (NASH) in the United States between 2010–2020: a population-based study. Annals of Hepatology 2022;27:100727. - PubMed

[4] Hamid O, Eltelbany A, Mohammed A, Alsabbagh Alchirazi K, Trakroo S, Asaad I. The epidemiology of non-alcoholic steatohepatitis (NASH) in the United States between 2010–2020: a population-based study. Annals of Hepatology 2022;27:100727. - PubMed

[5] Wang J, Conti DV, Bogumil D, Sheng X, Noureddin M, Wilkens LR, Le Marchand L, et al. Association of genetic risk score with NAFLD in an ethnically diverse cohort. Hepatology Communications 2021;5:1689–1703. - PMC - PubMed

[6] Wang J, Conti DV, Bogumil D, Sheng X, Noureddin M, Wilkens LR, Le Marchand L, et al. Association of genetic risk score with NAFLD in an ethnically diverse cohort. Hepatology Communications 2021;5:1689–1703. - PMC - PubMed

[7] Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461–1465. - PMC - PubMed

[8] Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461–1465. - PMC - PubMed

[9] Sookoian S, Pirola CJ. Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883–1894. - PubMed

[10] Sookoian S, Pirola CJ. Meta‐analysis of the influence of I148M variant of patatin‐like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883–1894. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD

Affiliations

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD

Authors

Affiliations

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical