Genetics Meets Therapy? Exome‐wide Association Study Reveals a Loss‐of‐Function Variant in 17‐Beta‐Hydroxysteroid Dehydrogenase 13 That Protects Patients From Liver Damage and Nonalcoholic Fatty Liver Disease Progression

Abstract

Knowledge of the genetic component of nonalcoholic fatty liver disease (NAFLD) has significantly contributed to the understanding of the disease pathogenesis. Genetic studies based either on genome wide association-strategies or candidate-genes approaches showed that variants in loci involved in lipid metabolism and/or lipid-droplets biology have predominant and reproducible effects on the disease phenotype (1). However, it has been a major challenge to translate this information into molecularly-plausible and clinically-safe therapeutic targets. In fact, largest effects are given by missense variants (PNPLA3-I148M and TM6SF2-E167K) that while explaining modest changes in gene / protein expression levels do not represent "druggable" targets. Specifically, variants associated with the progression of NAFLD or alcoholic liver disease (ALD) are located in genes with either pleiotropic metabolic effect/s, for instance PNPLA3-I148M (rs738409) (2), or are associated with dual and opposite effects on critical phenotypes, particularly TM6SF2-E167K variant (3). Consequently, any pharmaceutical drug targeted to modulate PNPLA3 or TM6SF2-enzymatic activity, would be of limited use because of potential undesirable effects. A new study by Abul-Husn et al. reveals that a loss-of-function variation in HSD17B13 (17-beta-hydroxysteroid dehydrogenase 13) gene confers protection against chronic liver injury and mitigates the progression of NAFLD and ALD in European Americans (4). These new findings open the possibility that therapeutic inhibition of HSD17B13 could represent a new strategy to treat NAFLD and ALD. This article is protected by copyright. All rights reserved.

Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

“…Variants associated with the greatest effects on NAFLD and NASH are indeed missense SNPs (PNPLA3-I148M and TM6SF2-E167K) that not only explain modest changes in gene/protein expression levels but hardly represent "druggable" targets. 106 These two loci present either pleiotropic metabolic effects, 69 or are associated with dual and opposite effects on critical phenotypes, particularly TM6SF2-E167K variant, as already mentioned. 14 Hence, the potential use of these proteins as pharmacological targets by modulating their protein and/or enzymatic activity is rather limited.…”

“…Yet, the use of polygenic risk scores in personalized NAFLD care should be tested and optimized to perform well in diverse ethnic groups because the frequency of the risk alleles varies significantly among populations. 2,[11][12][13][14]23,106 Remarkable examples of allele frequency disparity among populations are PNPLA3-rs738309, of which the frequency of the G-risk allele varies from 12% in African population to 48% in South American (Mexican, Colombian, Peruvian, and Puerto Rican) population (as shown in http://www.ensembl.org), and HSD17B13-rs72613567, of which the frequency of the Aprotective insertion allele varies from 5% in African population to 34% among East Asian population (figures of population genetics were extracted from the 1000 Genomes Project, http://www.internationalgenome.org/).…”

“…14 Hence, the potential use of these proteins as pharmacological targets by modulating their protein and/or enzymatic activity is rather limited. 106 As a proof-of-concept, we performed an in silico "druggability" prediction of known NAFLD GWAS-discovered genes -including PNPLA3, TM6SF2, GCKR, and HSD17B13-based on protein structural druggability, ligand-based druggability, and network-based druggability implemented by the canSAR resource (http://cansar.icr.ac.uk/). This resource contains information of the whole human proteome, as well as 2,136 model organisms and 8,631 protein families.…”

Impact of HSD17B13 rs72613567 genotype on hepatic decompensation and mortality in patients with portal hypertension

“…Our results indicate liver disease severity‐ and possibly aetiology‐dependent differences in the clinical impact of the T > TA variant. Thus, it clearly requires further experimental and clinical studies before 17β‐HSD13 can be considered as a potential therapeutic target for chronic liver disease …”

“…Upregulation of this lipid droplet‐associated protein has previously been observed in NAFLD patients and also increased the number and size of lipid droplets in cultured hepatocytes . Despite the limited knowledge on its role in the pathophysiology of chronic liver diseases, 17β‐HSD13 has already been proposed as a therapeutic target …”