Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2021; 27(25): 3863-3876
Published online Jul 7, 2021. doi: 10.3748/wjg.v27.i25.3863
PPARGC1A rs8192678 G>A polymorphism affects the severity of hepatic histological features and nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease
Rui-Nan Zhang, Feng Shen, Qin Pan, Hai-Xia Cao, Guang-Yu Chen, Jian-Gao Fan
Rui-Nan Zhang, Feng Shen, Qin Pan, Hai-Xia Cao, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Guang-Yu Chen, Clinical Epidemiology Research Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Jian-Gao Fan, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
Author contributions: Zhang RN and Shen F contributed equally to this work; Zhang RN, Pan Q, Shen F, Chen GY, and Cao HX enrolled the cohorts and collected blood samples; Zhang RN, Pan Q, and Shen F performed genotyping; Zhang RN, Pan Q interpreted the data and were involved in the manuscript preparation; Fan JG designed and supervised the study; Zhang RN and Fan JG wrote the manuscript.
Supported by National Key R&D Program of China, No. 2017YFC0908903; National Natural Science Foundation of China, No. 81700503, No. 81873565, and No. 81470840; WBE Liver Fibrosis Foundation, No. CFHPC2020061; and Hospital Funded Clinical Research, Clinical Research Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 17CSK04.
Institutional review board statement: This study was approved by the institutional review board of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian-Gao Fan, MD, PhD, Director, Professor, Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, No. 1665 Kongjiang Road, Yangpu District, Shanghai 200092, China. fanjiangao@xinhuamed.com.cn
Received: February 8, 2021
Peer-review started: February 8, 2021
First decision: March 28, 2021
Revised: April 8, 2021
Accepted: April 20, 2021
Article in press: April 20, 2021
Published online: July 7, 2021
Processing time: 147 Days and 13.3 Hours
ARTICLE HIGHLIGHTS
Research background

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is a significant global burden worldwide. It is also common in obese and nonobese populations. Although the mechanism of NAFLD is unclear, genetic susceptibility plays a vital role in NAFLD. The association between PPARGC1A rs8192678 polymorphism and NAFLD has been reported in several studies, but it is controversial in the Asian population. Whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population is unknown.

Research motivation

The association between PPARGC1A rs8192678 polymorphism and NAFLD requires further investigation, and the association with hepatic histological features and nonobese NAFLD in the Chinese population is unknown.

Research objectives

The aim was to investigate the association between PPARGC1A rs8192678 polymorphism and nonalcoholic steatohepatitis (NASH) and to determine whether PPARGC1A rs8192678 is associated with the hepatic histological features of NASH.

Research methods

Patients with NAFLD and healthy controls were recruited to a cohort representing the Chinese Han population. Patients with NAFLD were proven by liver biopsy. The SAF (Steatosis, activity, and fibrosis) scoring system was used for histopathological evaluation. The polymorphisms of PPARGC1A rs8192678 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 were genotyped. The intrahepatic mRNA expression of PPARGC1A was evaluated by real-time polymerase chain reaction.

Research results

In NAFLD patients, 37 patients had NASH, of which 12 were nonobese NASH. The PPARGC1A rs8192678 risk A allele (carrying GA and AA genotypes) increased the risk of NAFLD in the dominant model. The PPARGC1A rs8192678 A allele was also found to be a risk factor for NAFLD after adjusting for age, sex, and PNPLA3 rs738409 polymorphism. In the hepatic histological features of NAFLD patients, moderate-to-severe steatosis (S2-3), and Activity 2-4 (A ≥ 2) were more likely to carry PPARGC1A rs8192678 risk A allele. After adjusting for age, sex, body mass index, and PNPLA3 rs738409 risk G allele, the PPARGC1A rs8192678 risk A allele was also independently associated with S2-3, A ≥ 2, and NASH. The results also showed that this polymorphism was associated with nonobese NASH. In the group of patients who carried A allele (GA or AA genotypes), the intrahepatic expression of PPARGC1A mRNA was significantly lower than that in patients with GG genotype.

Research conclusions

The PPARGC1A rs8192678 A allele is a risk factor for NAFLD, and is associated with the severity of hepatic histological features (S2-3 and A ≥ 2) and NASH in NAFLD patients, independent of PNPLA3 rs738409, and might be associated with nonobese NASH.

Research perspectives

The result that PPARGC1A rs8192678 was associated with liver biopsy-proven NASH and had an additive effect on the severity of hepatic histological features was further confirmed in the Chinese Han adult population. PPARGC1A rs8192678 might contribute to the etiology of NAFLD. PPARGC1A rs8192678 might be a useful tool for diagnosing NASH and predicting the severity of the hepatic histological features of NAFLD.