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
Abstract
BACKGROUND

The association between PPARGC1A rs8192678 and nonalcoholic fatty liver disease (NAFLD) requires further confirmation. In addition, it is still unknown whether PPARGC1A rs8192678 is associated with hepatic histological features in NAFLD in the Chinese population.

AIM

To investigate the interaction between PPARGC1A rs8192678 and nonalcoholic steatohepatitis (NASH), and whether this polymorphism is associated with hepatic histological features.

METHODS

Fifty-nine patients with liver biopsy-proven NAFLD and 93 healthy controls were recruited to a cohort representing the Chinese Han population. The SAF (steatosis, activity, and fibrosis) scoring system was used for hepatic 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.

RESULTS

Thirty-seven patients with NAFLD had NASH, of which 12 were nonobese. The PPARGC1A rs8192678 risk A allele (carrying GA and AA genotypes) had the lowest P value in the dominant model; the odds ratio (OR) for NAFLD was 2.321 [95% confidence interval (CI): 1.121-4.806]. After adjusting for age, sex, and the PNPLA3 rs738409 risk G allele, the PPARGC1A rs8192678 A allele was a risk factor for NAFLD (OR 2.202, 95%CI: 1.030-4.705, P = 0.042). The genetic analysis showed that patients with NAFLD, moderate-to-severe steatosis (S2-3), and Activity 2-4 (A ≥ 2) were more likely to carry A in PPARGC1A rs8192678 (OR 5.000, 95%CI: 1.343-18.620, P = 0.012; and OR 4.071, 95%CI: 1.076-15.402, P = 0.031). The multivariate logistic regression analysis showed that PPARGC1A rs8192678 risk A allele was also independently associated with S2-3, A ≥ 2, and NASH (OR 6.190, 95%CI: 1.508-25.410, P = 0.011; OR 4.506, 95%CI 1.070-18.978, P = 0.040; and OR 6.337, 95%CI: 1.135-35.392, P = 0.035, respectively) after adjusting for age, sex, body mass index, and PNPLA3 rs738409 risk G allele. The results also showed that this polymorphism was associated with nonobese NASH (OR 22.000, 95%CI: 1.540-314.292, P = 0.021). The intrahepatic expression of PPARGC1A mRNA was significantly lower in the group of patients who carried the risk A allele (P = 0.014).

CONCLUSION

The PPARGC1A rs8192678 risk A allele is associated with NAFLD, and with S2-3, A ≥ 2 and NASH in NAFLD patients, independent of PNPLA3 rs738409, and may be associated with nonobese NASH.

Keywords: Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, PPARGC1A rs8192678 polymorphism, Steatosis, Activity

Core Tip: The PPARGC1A rs8192678 A allele was found to be a risk factor for liver biopsy-proven nonalcoholic fatty liver disease (NAFLD) after adjusting for age, sex, and patatin-like phospholipase domain-containing protein 3 rs738409 polymorphism. The multivariate logistic regression analysis showed that the PPARGC1A rs8192678 risk A allele was also independently associated with the severity of hepatic histological features (S2-3 and A ≥ 2) and nonalcoholic steatohepatitis (NASH), and might also be associated with nonobese NASH, indicating that the PPARGC1A rs8192678 risk A allele was associated with NAFLD in the Chinese Han adult population. Also, the intrahepatic expression of PPARGC1A mRNA was significantly lower in the patients who carried the risk A allele, implying that it might be a genetic contribution to the pathogenesis of NAFLD.