Novel insights into autoimmune liver diseases provided by genome-wide association studies.
Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify molecular targets for pharmacotherapy. Early genetic studies consisted of HLA association studies and non-HLA candidate gene association studies, designed to identify association with selected HLA or non-HLA loci. HLA association studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak associations detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide association studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clinical conditions. The specific genetic basis of these PBC and PSC associated inflammatory themes as determined by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
George F
GF
Mells
Arthur
A
Kaser
Tom H
TH
Karlsen
D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics*; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000235:genetics*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006680:HLA Antigens / Q000235:genetics; D019693:Hepatitis, Autoimmune / Q000150:complications / Q000235:genetics*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000235:genetics*; D008957:Models, Genetic
D006680:HLA Antigens
Autoimmune hepatitis; Genome-wide association studies; Primary biliary cirrhosis; Primary sclerosing cholangitis