Using GWAS to identify genetic predisposition in hepatic autoimmunity

Abstract

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) represent the three major hepatic autoimmune conditions. Patient morbidity and mortality remain high across these three diseases, and an unmet need for rational therapy exists. Disease understanding has focused on combining clinical and laboratory based science to provide better insights into the joint host and environmental factors necessary for the initiation, and perpetuation, of hepato-biliary inflammation. Twin studies, family studies, population studies and an inter-relationship with other autoimmune phenomena suggest a genetic component to risk for each disease. Until recently, understanding of this genetic risk has been limited to HLA haplotypes. Associations with risk-conferring and protective HLA haplotypes are present in all three diseases. Over the last few years, genome-wide association studies (GWAS), and related genetic association studies, have greatly increased understanding of the genetic risk signature of these three diseases and autoimmunity in general. Here we consider the rationale for GWAS in general and with specific reference to hepatic autoimmunity. We consider the process of GWAS, and highlight major findings to date. Potential functional implications of key findings are discussed including the IL-12/STAT4 pathway in PBC and the CD28/IL-2 pathway in PSC. We describe the marked pleiotropy demonstrated by PBC and PSC, which is consistent with other autoimmune diseases. Further, we focus on specific gene associations including SH2B3, which is common to all three diseases, and FUT2 in PSC, which represents a link between environment and genetics. We review attempts to translate GWAS findings into basic laboratory models including in vivo systems and highlight where clinical observations relate to genetics. Finally we describe deficiencies in GWAS to date and consider future study of genetics in hepatic autoimmunity.

The Pathogenesis of Autoimmune Liver Disease

“…Associations with risk-conferring and protective HLA haplotypes are present in all 3 diseases. Genetic observational studies have suggested that the presence of certain HLA alleles are associated with cholestatic liver disease, in particular, HLA-DR8 in PBC and HLA-B * 08 with PSC [9] . In addition, in AIH, the presence of the HLA haplotype DRB1 * 03-DRB1 * 04 is associated with a more aggressive disease phenotype [10] .…”

Genetic Risk Factors for Autoimmune Thyroid Disease might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis

“…genetic studies, including GWAS, performed in patients with PBC have led to the identification of risk loci for this disease [9]. Data concerning genetic modifiers of PBC progression as well as variants that increase the risk of developing autoimmune conditions other than PBC are, in turn, scarce.…”

“…Prevalence of thyroid disorder is confirmed by the presence of positive thyroid antibodies, and is clinically manifested mainly as Hashimoto thyroiditis (HT) or Graves' disease (GD). An extensive number of genetic studies, including analyzes of twin pairs, family studies and genome-wide association studies (GWAS), revealed the evidence of a significant genetic component of hepatic autoimmunity [9,10]. Given the fact that patients with PBC often develop extrahepatic autoimmune conditions one could hypothesize that genetic background might be responsible for this phenomenon, and that it also might have an impact on the natural history of PBC.…”

<i>CTLA-4, ICOS, PD1</i> and <i>PTPN22</i> Gene Polymorphisms and Susceptibility to Autoimmune Hepatitis Type 1

“…Nonetheless, the genetic predisposition conferred by HLA is neither adequate nor necessary for disease development [1]. In this regard, several other loci outside the MHC region particularly those encoding proteins that regulate the function of T lymphocyte, could be involved in the pathogenesis of AIH-1 [2,6].…”