Review Article Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) Narendra Singh Choudhary1, Ajay Duseja2 1Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India; 2Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Contributions: (I) Conception and design: A Duseja; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: NS Choudhary; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Dr. Ajay Duseja, MD, DM, FAMS, FAASLD, FACG, FSGEI. Professor, Department of Hepatology, Sector 12, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Email: [email protected]. Abstract: Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients. Keywords: Non-alcoholic steatohepatitis (NASH); fatty liver; hepatic steatosis; cirrhosis; hepatocellular carcinoma (HCC) Received: 15 June 2019; Accepted: 04 September 2019; Published: 05 January 2021. doi: 10.21037/tgh.2019.09.06 View this article at: http://dx.doi.org/10.21037/tgh.2019.09.06 Introduction (HCC) (1,2). In some parts of the world, equally common problem is the alcoholic liver disease (ALD) with a similar Non-alcoholic fatty liver disease (NAFLD) has become the spectrum of alcoholic steatosis, alcoholic steatohepatitis, most common liver disease, the world over and encompasses cirrhosis and HCC (3). There are significant inter- a spectrum ranging from simple steatosis (non-alcoholic individual differences in the severity and progression of liver fatty liver or NAFL), non-alcoholic steatohepatitis (NASH), disease in patients with NAFLD sharing similar metabolic NASH related cirrhosis and hepatocellular carcinoma and other environmental risk factors (4). Similarly severity © Translational Gastroenterology and Hepatology. All rights reserved. Transl Gastroenterol Hepatol 2021;6:2 | http://dx.doi.org/10.21037/tgh.2019.09.06 Page 2 of 17 Translational Gastroenterology and Hepatology, 2021 of liver disease differs among patients consuming similar Twin studies type and quantity of alcohol over a similar duration (5). Prevalence studies in twins suggest a stronger genetic basis In addition to inter-individual differences, inter-ethnic of NAFLD in comparison to that evident from familial differences in NAFLD and ALD and familial clustering clustering studies. Several twin studies have shown higher points towards the role of genetic and epigenetic factors prevalence of NAFLD in monozygotic twins as compared in the pathogenesis of these two diseases (6-11). In this to dizygotic twins. Makkonen et al. studied 313 twin pairs review article, we discuss the role of genetic and epigenetic and observed significantly higher intra-pair correlations modifiers in NAFLD and ALD. in monozygotic than the dizygotic twins for both alanine transaminases (ALT) (0.65 and 0.04 respectively) and fasting Genetic basis in the pathogenesis of NAFLD serum insulin (0.58 and 0.34 respectively). Heritability of ALT was 55% and that of fasting serum insulin was 61%. NAFLD is a complex disease with multiple factors involved ALT and fasting serum insulin correlated with liver fat in the pathogenesis that include both environmental and content in 66 subjects (measured by magnetic resonance genetic modifiers. Also, NASH and fibrosis progression spectroscopy) (16). In a study using ultrasonography for varies with some patients being ‘rapid progressors’ (12,13). NAFLD and carotid intima media thickness in 208 (58 men Risk factors for fibrosis progression in patients with and 150 women) Hungarian twins (63 monozygotic and 41 NAFLD include metabolic syndrome, presence of type dizygotic pairs, aged 43.7±16.7 years), heritability was linked 2 diabetes mellitus, high body mass index (BMI)/obesity, to cardiovascular risk, but not to NAFLD (17). However, age, steatosis grade, high insulin resistance, baseline it should be noted that ultrasound with its limitations may biopsy showing inflammation and fibrosis (1,2,13). In a have categorized some patients with mild steatosis as normal meta-analysis of studies including paired biopsies, Singh on ultrasound. Loomba et al. studied 60 pairs of twins (42 et al. showed that rate of fibrosis progression was twice as monozygotic and 18 dizygotic) aged 45.7±22.1 years. Steatosis common in patients with NASH in comparison to patients and fibrosis were measured by MR-PDFF and MR elastography with NAFL (12). (MRE) in the study subjects. Twenty-six (21.7%) had NAFLD, In addition to environmental and metabolic risk factors, which correlated between monozygotic twins (r2=0.70; familial clustering, studies involving the monozygotic P<0.0001) but not in dizygotic twins. The fibrosis also twins and inter-ethnic differences point towards the role of correlated between monozygotic twins (r2=0.48; P<0.002) genetics in the pathogenesis of NAFLD. but not in dizygotic twins (r2=0.12; P=0.7). The heritability of hepatic steatosis was 0.52 and of hepatic fibrosis was Familial clustering in NAFLD 0.5 (18). In a prospective study, Cui et al. studied 65 twin pairs (45 monozygotic, 20 dizygotic twin pairs, aged Several studies have shown the clustering of cases of 47.1±21.9 years) and found that 20% (n=26) had hepatic NAFLD among the families (8,14,15). Brouwers et al. steatosis and 8.2% (n=10) had hepatic fibrosis. Steatosis and compared 157 familial combined hyperlipidemia family fibrosis had a significant shared gene effect of 0.756 (95% members with 20 spouses. Fatty liver was more prevalent in CI, 0.716–1) (19). probands (40%) and relatives (35%) compared to spouses (15%) (8). In a study, siblings and parents of overweight/ Ethnic differences obese children with and without NAFLD were compared with the help of magnetic resonance proton density fat Major evidence for having the genetic basis in NAFLD fraction (MR-PDFF) (15). NAFLD was present in 17% of comes from studies showing the ethnic differences in the siblings and 37% of parents in non-NAFLD overweight/ prevalence and severity of NAFLD. In a study including obese children group in comparison to presence of NAFLD cryptogenic cirrhosis or NASH related cirrhosis, it was in 59% of siblings and 78% of parents of overweight/obese seen that prevalence of cirrhosis among Hispanic and children with NAFLD. The correlation of liver fat fraction African American patients was 3.1 times higher and 3.9 to BMI was stronger in families of children with NAFLD times lower than European American patients despite than without NAFLD. The authors found heritability of similar prevalence of type 2 diabetes mellitus among NAFLD as 1.000 and that of liver fat fraction as 0.386 (15). these groups (20). Wagenknecht et al. compared 795 © Translational Gastroenterology and Hepatology. All rights reserved. Transl Gastroenterol Hepatol 2021;6:2 | http://dx.doi.org/10.21037/tgh.2019.09.06 Translational Gastroenterology and Hepatology, 2021 Page 3 of 17 Hispanic-American and 347 African-American adults, aged Genetic modifiers in NAFLD 49 [22–84] years. NAFLD was present in 24% of Hispanics Two types of genetic studies are available in patients with versus 10% in African-American diagnosed on the basis of NAFLD. Candidate gene studies are hypothesis-testing CT scan. NAFLD was independently associated with insulin studies, which are done for a gene with known functions. sensitivity and visceral adipose tissue area in both ethnic Candidate gene studies look for difference regarding a groups, proportion of explained variance being higher polymorphism