Case Control Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Sep 18, 2017; 9(26): 1101-1107
Published online Sep 18, 2017. doi: 10.4254/wjh.v9.i26.1101
Regional differences in genetic susceptibility to non-alcoholic liver disease in two distinct Indian ethnicities
Govardhan Bale, Avanthi Urmila Steffie, Vishnubhotla Venkata Ravi Kanth, Padaki Nagaraja Rao, Mithun Sharma, Mitnala Sasikala, Duvvur Nageshwar Reddy
Govardhan Bale, Avanthi Urmila Steffie, Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, Hyderabad 500082, Telangana, India
Padaki Nagaraja Rao, Mithun Sharma, Duvvur Nageshwar Reddy, Asian Institute of Gastroenterology, Hyderabad 500082, India
Author contributions: Bale G and Steffie AU performed research; Rao PN, Sharma M and Reddy DN recruited patients; Ravi Kanth VV, Sasikala M and Rao PN designed the research; Ravi Kanth VV monitored the study, performed statistical analyses, and drafted the manuscript.
Institutional review board statement: The study was reviewed and approved by Institutional review (Scientific) board (AIG/AHF IRB: 16/2014) of Asian Institute of Gastroenterology.
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: None to declare.
Data sharing statement: No additional data available.
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:
Correspondence to: Dr. Vishnubhotla Venkata Ravi Kanth, Group Leader-Genetics, Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
Telephone: +91-40-23378888 Fax: +91-40-23324255
Received: April 27, 2017
Peer-review started: April 28, 2017
First decision: May 23, 2017
Revised: June 29, 2017
Accepted: July 7, 2017
Article in press: July 10, 2017
Published online: September 18, 2017

To validate the association of variants in PNPLA3 (rs2281135) and TM6SF2 (rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease (NAFLD).


A total of 503 individuals with and without fatty infiltration were recruited. Fatty infiltration was confirmed based on ultrasound findings. Anthropometric data and blood samples were collected from the study group. DNA was isolated from peripheral blood, quality and quantity was assessed by gel electrophoresis and spectrophotometer respectively. Genotyping of the variants in PNPLA3 and TM6SF2 genes was carried out by employing taqman probes (C_15875080_10 for PNPLA3 and C_8946351_10 for TM6SF2 SNP) on real time PCR (Stepone-Lifetechnologies). Genotype data was tested for deviations from Hardy-Weinberg equilibrium. χ2 test was used to analyze the statistical significance of the difference in genotype distribution of the studied variants in patients and controls and the strength of association was expressed as odds ratio (95%CI). A two-tailed P value of ≤ 0.05 was considered statistically significant.


The study group comprised of 503 individuals of which 256 had fatty infiltration and 247 without fatty infiltration and thus formed the patient and control groups respectively. As the patient group could be divided in to two distinct ethnicities (ancestral South Indians-ASI and North-East Indians-NEI), further recruitment of control cohort and association analyses was carried out based on ethnicities. Of the 256 with fatty infiltration 93 were ASI and 163 were NEI and of the 247 controls 138 were ASI and 109 were NEI. As expected, there were significant differences in the anthropometric and other clinical data between the control and the patient groups. However significant differences within the ethnicities were also noted. While rs2281135 in PNPLA3 gene was significantly associated (P = 0.03) with higher risk (odds 1.9, 95%CI: 1.5-3.14, P = 0.03) of NAFLD in NEI ethnicity, rs58542926 in TM6SF2 gene was significantly associated with NAFLD with a 2.7 fold higher risk (odds 2.7, 95%CI: 1.37-5.3, P = 0.0004) of the disease. There were significantly higher proportions of individuals with variants in both the genes in the patient group in both ASI (patients - 14/93 and controls - 7/138; P = 0.009) and NEI ethnicities (patients - 17/163 and controls - 7/109; P = 0.01).


Although the study identified distinct genetic susceptibility in the two ethnicities, transheterozygosity of the variants suggests higher risk of NAFLD in individuals with both the variants.

Keywords: Transmembrane 6 superfamily 2, Patatin-like phospholipase domain-containing protein 3, Fatty infiltration, Genetic susceptibility, Ethnicity, Non-alcoholic fatty liver disease, Cirrhosis, Single nucleotide polymorphism

Core tip: Non-alcoholic fatty liver disease has become the leading cause of liver damage contributing to considerable mortality. The spectrum spans from simple steatosis, through non alcoholic steatohepatitis, fibrosis, cirrhosis and finally to hepatocellular carcinoma. Genetic variants have now been recognized to contribute to a substantial extent to the onset of the disease. Reliable genetic markers that confer susceptibility to the disease have to be identified for better management of the disease. Identification of at risk individuals at a younger age by screening for genetic susceptibility will aid in better management by early interventions and lifestyle changes. This study identified regional differences and ethnicity based genetic susceptibility for non-alcoholic liver disease.