PNPLA3 rs738409 and risk of fibrosis in NAFLD: Exploring... : Hepatology (original) (raw)

ORIGINAL ARTICLES: STEATOHEPATITIS

PNPLA3 rs738409 and risk of fibrosis in NAFLD: Exploring mediation pathways through intermediate histological features

Vilar‐Gomez, Eduardo1; Pirola, Carlos J.2; Sookoian, Silvia2; Wilson, Laura A.3; Liang, Tiebing1; Chalasani, Naga*,1

112250Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisIndianaUSA

2Molecular Genetics and Biology of Complex Diseases and Department of Clinical and Molecular HepatologyInstitute of Medical ResearchUniversity of Buenos Aires‐National Scientific and Technical Research CouncilCiudad Autonoma de Buenos AiresArgentina

3Johns Hopkins Bloomberg School of Public HealthBaltimoreMarylandUSA

* Correspondence
Naga Chalasani, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN 46202, USA.
Email: [email protected]

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Abstract

Background and Aims

It is unclear whether rs738409 (p.I148M) missense variant in patatin‐like phospholipase domain‐containing 3 rs738409 promotes fibrosis development by triggering specific fibrogenic pathways or by creating an unfavorable microenvironment by promoting steatosis, inflammation, and ultimately fibrosis. We tested the hypothesis that intermediate histologic traits, including steatosis, lobular and portal inflammation, and ballooning may determine the effect of rs738409 on liver fibrosis among individuals with biopsy‐proven NAFLD.

Approach and Results

Causal mediation models including multiple mediators in parallel or sequentially were performed to examine the effect of rs738409, by decomposing its total effect on fibrosis severity into direct and indirect effects, mediated by histology traits in 1153 non‐Hispanic White patients. Total effect of rs738409 on fibrosis was β = 0.19 (95% CI: 0.09–0.29). The direct effect of rs738409 on fibrosis after removing mediators’ effects was β = 0.09 (95% CI: 0.01–0.17) and the indirect effect of rs738409 on fibrosis through all mediators' effects were β = 0.010 (95% CI: 0.04–0.15). Among all mediators, the greatest estimated effect size was displayed by portal inflammation (β = 0.09, 95% CI: 0.05–0.12). Among different sequential combinations of histology traits, the path including lobular inflammation followed by ballooning degeneration displayed the most significant indirect effect (β = 0.023, 95% CI: 0.011–0.037). Mediation analysis in a separate group of 404 individuals with biopsy‐proven NAFLD from other races and ethnicity showed similar results.

Conclusions

In NAFLD, nearly half of the total effect of the rs738409 G allele on fibrosis severity could be explained by a direct pathway, suggesting that rs738409 may promote fibrosis development by activating specific fibrogenic pathways. A large proportion of the indirect effect of rs738409 on fibrosis severity is mediated through portal inflammation.

Half of the total effect of PNPLA3 rs738409 on fibrosis severity could be explained by a direct pathway without the mediation of other histology factors. The other half of the total effect of PNPLA3 rs738409 on fibrosis severity seems to be mediated primarily through portal inflammation.

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