Genetics of liver disease: immunogenetics and disease pathogenesis

Abstract

Understanding the genetic basis of "complex disease" has been heralded as one of the major challenges of the post genome era. However what are "complex diseases" and how will understanding the genetics of such diseases advance medical science? There has been a great deal of "hype" about the potential of the human genome mapping project. The three major claims are that this information will: (a) be used in diagnosis; (b) provide useful prognostic indices for disease management (including the development of individualised treatment regimens, based on the findings of both immunogenetic and pharmacogenetic studies); and (c) provide insight into the pathogenesis of these diseases. Of these three objectives the last has the greatest potential and is the least exaggerated claim. In this review I shall highlight major associations, discuss some of the practical issues that arise, and outline how current knowledge of the immunogenetic basis of chronic liver disease is beginning to inform the debate about disease pathogenesis.

Figure 1

Interleukin 1 (IL-1) regulation: a simplified example of a complex system. The IL-1 gene family includes genes for two agonist forms of IL-1 (α and β) and a receptor antagonist (IL-1ra). In addition, there are at least two different IL-1 receptors (IL-1r1 and r2). The agonists IL-1α and IL-1β (represented by green stars) interact with the first of these receptors (IL1-r1 green diamonds) but the IL-1 receptor antagonist (red crosses) competes for binding with IL-1r1, blocking the IL-1 agonists (IL-1α or β), and the second receptor (Il-1r2, red arrow) acts as a decoy receptor, binding surplus IL-1α and IL-1β. In addition, transcribed IL-1β is produced in an inactive form within the cell (pro-IL-1β) and requires activation by an IL-1 converting enzyme (ICE, also known as caspase 1) for release into the extracellular compartment. All of the genes in this family are polymorphic. This greatly oversimplified example shows how naive the requirement for “functional status” may be when applied to a single nucleotide polymorphism (SNP) or single gene locus in isolation, representing a single element in such a tightly controlled system. In the above example, how biologically meaningful is it to consider “functionality” of a specific SNP or SNP haplotype at the IL1B locus without also considering the other members of the IL-1 family?

Figure 2

Lysine-71 and susceptibility to type 1 autoimmune hepatitis (AIH). Lysine-71 and arginine-71 versus alanine-71 basis of major histocompatibility complex (MHC) encoded susceptibility and resistance to type 1 AIH. DRB1 alleles, amino acid motifs (DRβ-67 to DRβ-72), and amino acids at position-71 of the DRβ polypeptide. The key molecular differences between human leucocyte antigen alleles that encode susceptibility to type 1 AIH (represented in yellow) and those that encode resistance (represented in blue) are shown. Within the six amino acid motif represented by the single letter code LLEQKR (positions 67–72), the critical amino acid appears to be that found at position 71—namely, lysine (K) or arginine (R) on susceptibility alleles and alanine (A) on resistance alleles. The three amino acids vary in terms of polarity and overall charge, as illustrated. Both lysine and arginine have two positively charged amino groups and a single (negatively charged) carboxyl group while alanine has only a single amino group and carboxyl group. This may be the basis of MHC encoded genetic susceptibility to type 1 AIH.

Figure 3

Representation of human leucocyte antigen class II molecules and relationship between lysine at position 71 of the DRβ polypeptide and the bound peptide. The expressed major histocompatibility complex (MHC) class II molecule is a heterodimer of two polypeptide chains, each with two Ig domains. (A) The structure is folded to create a platform supporting a single antigen binding cleft into which short antigenic peptides are bound. The majority of genetic polymorphism results in amino acid substitutions in and around the antigen binding cleft. Substituting amino acids at critical sites may profoundly affect physical interaction between the MHC molecule and the antigenic peptide, and may favour binding of peptides with specific physical properties. In particular, the MHC binding cleft has pockets along its length where there is interaction with the side chains of the antigenic peptide. Molecular changes will also influence the orientation of the bound peptide in the cleft and therefore may influence the dynamics of the interaction with the T cell receptor. In this diagram (B), the peptide, illustrated by the coloured ovals, is shorter than that usually found in an MHC class II molecule. You are asked to imagine that possession of lysine at position 71 (K71) favours binding of a peptide which has the red-yellow-green motif (residues 4–6 counting in from the right hand side of the picture). Perhaps peptides with this red-yellow-green motif will be more efficiently bound by MHC molecules that possess lysine at position 71 than those with alanine-71. Were this red-yellow-green motif to be an essential component of the autoantigen for type 1 autoimmune hepatitis, more efficient interaction between lysine 71 may be an important factor in promoting disease in those with lysine-71 bearing alleles, whereas alanine, with less efficient binding, may have a protective effect.

Figure 4

Key genetic components of the major histocompatibility complex (MHC) and their main functions in immunobiolgoy. The human MHC encodes nearly 200 genes in 4 Mb of DNA. The key components of the MHC include the classical transplantation antigens HLA A, B, Cw, DR, DQ, and DP (yellow and light brown) but the region also includes key complement genes (light blue), tumour necrosis factor genes (TNF) (green), and other genes with critical function in both innate and adaptive immunity. All of the genes illustrated are polymorphic and thus the extended MHC haplotypes may carry multiple disease promoting or disease resistance alleles.