Genetics and PSC

[Guest guest]

Falk Symposium 146

GUT-LIVER INTERACTIONS: BASIC AND CLINICAL CONCEPTS

Innsbruck (Austria)

March 11-12, 2005

p. 73-75

http://www.falkfoundation.com/pdf/FS146e_Abstractband-Internet.pdf

Basic concepts in PSC

Dr T. son, Ph.D.

School of Clinical Medical Sciences - Liver, University of

Newcastle, Newcastle upon Tyne, Great Britain

The aetiology of PSC remains largely unknown. Despite being consider

one of the three common " autoimmune " liver diseases, PSC does not

fit the classical definition of an autoimmune disease. The majority

of patients are male, do not respond to corticosteroid therapy and

organ or tissue specific autoantibodies have not been identified.

One observation which does support the concept of autoimmunity is the

consistent reports of strong genetic associations with specific HLA

haplotypes. Yet even this may be questioned. Strong HLA associations

have also been reported in viral liver disease and liver diseases

due to adverse drug reactions [1]. Whatever the answer to this

debate, it is clear that genetics may be very informative in PSC.

Indeed genetics may be at the heart of understanding PSC.

The basic concept to consider is that genetics may be useful in

understanding disease pathology and may have applications in disease

management. The most important questions, for us to consider in this

presentation are: - how does genetics inform both our understanding

of disease pathogenesis and how can this information be used in

disease management?

Genetically PSC behaves like most " autoimmune diseases. " Thus, genes

alone are not sufficient to explain PSC. PSC is a

genetically " complex disease " (i.e. it does not display a simple

Mendelian pattern of inheritance). Consequently, there is no single

PSC gene, rather one or more genes may act (either alone or in

concert) to increase (or reduce) the risk of disease or of a

particular clinical phenotype. In PSC the most obvious phenotypes

(clinical subgroups) relate to the presence or absence of

inflammatory bowel disease (IBD), cholangiocarcinoma and the rate of

disease progression or fibrosis.

The majority of genetic studies in PSC involve case-control

association studies of the major histocompatibility complex (MHC).

So far six different HLA haplotypes have been found to be associated

with PSC (table 1). There are currently three possibilities to

explain these HLA associations:

[1]. That susceptibility maps to the HLA class II region of the MHC.

According to this theory HLA class II alleles associated with an

increased risk of PSC may have properties that favour binding and

presentation of one or more autoantigenic epitopes and thereby

increase the risk of disease in susceptible individuals. A number of

models have been proposed to explore this hypothesis [2].

Conceptually this proposal would favour PSC being a T-cell mediated

autoimmune (or infectious) disease.

[2]. That susceptibility maps to the MHC class III region (between

HLA B and HLA DR). One proposal is that the primary susceptibility

locus is the MICA (MHC-class I chain-like A) locus, which may be

important in regulating NK and NK/T cell function [3]. This proposal

favours the possibility that relative differences in the regulation

of innate immunity may provide an immune response profile favourable

for the genesis of PSC and this may suggest PSC is an infectious as

opposed to an autoimmune disease. Though the distinction may be

academic as infectious agents may also trigger latent autoimmunity

in a susceptible host.

[3]. That there are multiple susceptibility alleles on each

haplotype. Conceptually this may explain some of the phenotypic

variation in PSC with different risk haplotypes promoting different

immune response profiles each having different downstream

consequences. In this regard it is important to note the central

role played by NK cells in tumour surveillance and consider the

hypothesis that possession of specific MICA alleles may be

permissive for tumour development. It is also important to note

that there are marked differences in the HLA associations in

patients with and without IBD.

Aside from these MHC haplotypes there are many other potential

candidate PSC promoting alleles in the human genome. There are

currently three major areas of interest. First, many investigators

have sought to identify defects in molecular transporters in PSC

patients. Most studies have been negative [4]. Though there is

some (albeit controversial) suggestion of a relationship between PSC

and mutations in the Cystic Fibrosis gene - CFTR. Second, PSC is

essentially a fibrogenic disease and inherited variation in genes

controlling matrix metabolism have identified some interesting

associations, most notably with the matrix metalloproteinase-3 (MMP3)

locus. Fibrosis is a common pathway in disease and therefore any

genetic any association with such genes is unlikely to be disease

specific [5]. Third, the majority of PSC patients have IBD, and

considerable progress has been made in the search for IBD alleles.

It is very likely that one or more of these IBD allleles will be

implicated in the pathogenesis of PSC [2].

In terms of the basic concepts in PSC these are very exciting times.

Genetic data are beginning to inform both pathogenesis and prognosis

in other related diseases (especially in Crohn's disease). The hope

is that this type of information will be applicable to understanding

the aetiology of PSC and its many phenotypic characteristics. In

diseases like PSC genetics offers one of the best options for

understanding disease pathogenesis – but it is not the only option.

The advantage of this approach is that whilst pathology progresses,

changing with time, the patient's genes do not change (in this

context) offering a timeless window into disease pathology.

Table 1: The principle HLA haplotypes in PSC.2, 3

Haplotype Odds Ratio

B8-TNFA*2-MICA*008-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201 2.69

DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603 3.8

DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 1.52

DRB4*-DRB1*04-DQA1*0301-DQB1*0302 0.26

DRB4*-DRB1*0701-DQA1*0201-DQB1*0303 0.15

MICA*002 0.12

References:

1. son PT. Gut 2004; 53: 599-608.

2. son PT, Norris S. Autoimmunity 2002; 35: 555-564.

3. Norris et al., Gastroenterology 2001; 120: 1475-1482.

4. i-Magnus C et al., Hepatology 2004; 39: 779-791.

5. Satsangi et al., Gastroenterology 2001; 121: 124-130.