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©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B
Qin Pan, Rui-Nan Zhang, Yu-Qin Wang, Rui-Dan Zheng, Yu-Qiang Mi, Wen-Bin Liu, Feng Shen, Guang-Yu Chen, Jia-Fa Lu, Chan-Yan Zhu, Shu-Yi Zhang, Yi-Ming Chen, Wan-Lu Sun, Jian-Gao Fan
Qin Pan, Rui-Nan Zhang, Yu-Qin Wang, Feng Shen, Jia-Fa Lu, Chan-Yan Zhu, Shu-Yi Zhang, Yi-Ming Chen, Wan-Lu Sun, Jian-Gao Fan, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
Rui-Dan Zheng, Diagnosis and Treatment Center for Liver Diseases, Zhengxing Hospital, Zhangzhou 363000, Fujian Province, China
Yu-Qiang Mi, Department of Infectious Diseases, Tianjin Infectious Disease Hospital, Tianjin 300192, China
Wen-Bin Liu, Wu-Jiao-Chang Community Health Center, Shanghai 200433, China
Guang-Yu Chen, Clinical Epidemiology Center, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
Jian-Gao Fan, Shanghai Key Laboratory of Children’s Digestion and Nutrition, Shanghai 200092, China
Author contributions: Pan Q, Zhang RN, Wang YQ, Zheng RD and Mi YQ contributed equally to this work; Pan Q, Zhang RN, Wang YQ, Zheng RD, Mi YQ, Shen F, Liu WB, Chen GY, Lu JF, Zhu CY, Zhang SY, Sun WL, and Chen YM enrolled the cohorts and collected blood samples; Pan Q, Shen F, Liu WB, and Zhang RN performed genotyping; Pan Q interpreted the data and was involved in the manuscript preparation; and Fan JG designed and supervised the study and wrote the manuscript.
Supported by State Key Development Program for Basic Research of China, No. 2012CB517501; National Natural Science Foundation of China, No. 81070322, No. 81270491 and No. 81470840; 100 Talents Program, No. XBR2011007h; and Program of the Shanghai Committee of Science and Technology, No. 09140903500 and No. 13ZR14267.
Institutional review board statement: This paper was approved by the Xinhua Hospital Ethics Committee Affiliated to Shanghai Jiaotong University School of Medicine.
Institutional animal care and use committee statement: No animal has been employed in the experiments relating to manuscript of “Linked polymorphisms of PNPLA3 confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B”.
Conflict-of-interest statement: No conflict of interest is declared for each author of the manuscript.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at fattyliver2004@126.com. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Jian-Gao Fan, MD, PhD, Professor, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. fattyliver2004@126.com
Telephone: +86-21-63846590 Fax: +86-21-25077340
Received: January 23, 2015
Peer-review started: January 24, 2015
First decision: February 10, 2015
Revised: March 5, 2015
Accepted: April 16, 2015
Article in press: April 17, 2015
Published online: July 28, 2015
AIM: To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD).
METHODS: A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA.
RESULTS: After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05).
CONCLUSION: Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients.
Core tip: The association of PNPLA3 polymorphisms with concurrent chronic hepatitis B and nonalcoholic fatty liver disease was determined in Chinese Han patients. The effect of PNPLA3 genotypes on hepatitis B virus load was also evaluated. Four linked single-nucleotide polymorphisms of PNPLA3 (rs738409 G allele, rs3747206 T allele, rs4823173 A allele, and rs2072906 G allele) conferred susceptibility to nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and liver fibrosis in chronic hepatitis B patients. Patients carrying these single-nucleotide polymorphisms showed a significantly lower serum level of hepatitis B virus DNA.
