Alimentary Pharmacology & Therapeutics | 2021
Editorial: the polygenic risk of cirrhosis development
Abstract
In a large collaborative analysis Buch et al1 explored the potential role of genetic variants in conferring susceptibility to develop advanced liver disease in a wide population of individuals with hereditary hemochromatosis (HH). More than 1000 C282Y homozygote patients with mildtomoderate liver fibrosis and 171 cirrhotic patients from six European centres were included. A positive association between PNPLA3, TM6SF2 and PCSK7 variants and the risk of developing cirrhosis in hereditary hemochromatosis, accounting for approximately 30% of the overall susceptibility, was observed. Notably, an MBOAT7 variant, a wellknown driver of liver fibrogenesis, did not show any significance. Despite differences between the cohorts across the centres and nonstandardized assessments of environmental risk factors, the study is remarkable, as it identifies a compound effect of the genetic variants and is supportive of the concept of polygenetic risk stratification in this population. Evidence from several genomewide association studies (GWAS) conducted in large populations have highlighted the importance of genetic background in defining a more advanced phenotype of liver disease. Nonalcoholic liver disease (NAFLD) represents a disease model where the role of these variants has been recognized, but intriguing results have also emerged from liver diseases of other aetiology.2 The relevance of genetic variants as a cofactor of the liver phenotype irrespective of the underlying aetiology, suggests shared pathways of liver injury (Table 1). Nonetheless, the interaction between genes and environment is highly variable and may act on different features of disease, thus bearing a diverse grade and form of susceptibility. PNPLA3 gene variation has been identified as a key modifier in the natural history of NAFLD. Susceptible individuals have worse inflammatory activity, rapid fibrosis progression and higher risk of developing hepatocellular carcinoma. This contributes to the interethnic and interindividual variability of disease.3 Additionally, this gene locus has been recognized as independent risk factor for cirrhosis in alcoholic liver disease (ALD)4 and a more advanced fibrosis and progressiveness in chronic hepatitis C (CHC).5 Similarly, TM6SF2 and MBOAT7 variants, for which a detrimental role in NAFLD is wellestablished, promote a higher risk for cirrhosis in ALD populations as well.4 Data emerging from a large metaanalysis conducted on CHC populations showed a significant association of a TM6SF2 variant with steatosis and fibrosis, without significant impact on inflammation.6 Whereas, the MBOAT7 variant increases inflammation, and fibrosis, in both CHC and chronic hepatitis B (CHB) cohorts.7 The effect of a PCSK7 variant, instead, seems to be restricted to NAFLD8 and hereditary