Genetics of tumour necrosis factor (TNF) in autoimmune liver diseases: red hot or red herring?
Authors: A.Gerry Wilson
Journal: Journal of Hepatology (1999)

Amajor thrust of medical research at present involves the localisation and characterisation of those genetic variants that contribute to the development of common diseases. A large number of diseases have a multifactorial basis, with both environmental and genetic factors being important in the aetiology and/or clinical severity. For many of these diseases multiple genetic variants are believed to contribute, with a threshold number of variants possibly being required. Localisation of this relatively small number of variants, among the total of around 100 000 genes contained within the 3 billion bases that make up the human genome, is a major task. Two approaches have been used: whole genome or candidate gene scans. The former relies on identification based on position, and generally involves typing of 200–300 polymorphic markers scattered across the genome, frequently at 10–20-million base (mb) intervals. Initial genome scans have been reported in a number of polygenic diseases such as insulin-dependent diabetes mellitus and rheumatoid arthritis (1.Davies JL Kawaguchi Y Bennett ST Copeman JB Cordell HJ Pritchard LE et al.A genome-wide search for human type 1 diabetes susceptibility genes.Nature. 1994; 371: 130-135Crossref PubMed Scopus (1265) Google Scholar, 2.Cornélis F Fauré S Martinez M Prud'homme J Fritz P Dib C et al.New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study.Proc Natl Acad Sci USA. 1998; 95: 10746-10750Crossref PubMed Scopus (448) Google Scholar). These studies have mainly involved large numbers of sib pairs concordant for disease. The second approach, the candidate gene approach, involves genetic screening of a gene whose encoded protein has been implicated in the pathogenesis of the disease under study. In diseases with a significant inflammatory component potential candidates genes are those encoding cytokines, adhesion molecules and apoptotic factors. The gene for tumour necrosis factor alpha (TNFA) has attracted much attention as a possible contributor in autoimmune diseases because of the activities of the encoded protein and because TNFA lies within the human major histocompatibility complex. This is a 4 mb stretch of DNA on chromosome 6 that encodes over 200 genes, many of which are immunologically relevant (Fig. 1). Of the large number of diseases with an autoimmune component, most show genetic association with MHC alleles, with most studies implicating the class II loci HLA-DR and -DQ (3.Sinha AA Lopez MT McDevitt HO Autoimmune diseases: the failure of self tolerance.Science. 1990; 248: 1380-1388Crossref PubMed Scopus (396) Google Scholar). TNFA lies less than 1 mb from the DR locus, which is, in genetic terms, very close. A number of polymorphisms within TNFA have been described. Four polymorphisms lie in the promoter region and a fifth is located within the first exon (4.Hermann SM Ricard S Nicaud V Mallet C Arveiler D Evans A et al.Polymorphisms of the tumour necrosis factor-α gene, coronary heart disease and obesity.Eur J Clin Invest. 1998; 28: 59-66Crossref PubMed Scopus (236) Google Scholar). Most interest has centred on position −308, which contains a biallelic variant; the common allele is designated TNF-308G (TNF1) and the uncommon allele TNF-308A (TNF2) (5.Wilson AG di Giovine FS Blakemore AIF Duff GW Single base polymorphism in the human Tumour Necrosis Factor alpha (TNFα) gene detectable by Ncol restriction of PCR product.Hum Mol Genet. 1992; 1: 353Crossref PubMed Scopus (861) Google Scholar). Genetic studies have shown that TNF2 lies on the HLA A1-B8-DR3-DR2 haplotype (6.Wilson AG de Vries N Pociot F di Giovine FS van de Putte LBA Duff GW An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with the HLA A1, B8 and DR3 allelcs.J Exp Med. 1993; 177: 560-577Crossref Scopus (691) Google Scholar). This is of interest for a number of reasons: individuals with this haplotype produce high levels of TNFα and are more susceptible to a range of autoimmune diseases (3.Sinha AA Lopez MT McDevitt HO Autoimmune diseases: the failure of self tolerance.Science. 1990; 248: 1380-1388Crossref PubMed Scopus (396) Google Scholar). Several studies have addressed the functional significance of this polymorphism using reporter gene constructs. While not all studies are in agreement, the majority have shown that the TNF2 promoter fragment is a more powerful transcriptional activator (7.Kroeger KM Carville KS Abraham LJ The −308 tumor necrosis factor-α promoter polymorphism effects transcription.Mol Immunol. 1997; 34: 391-399Crossref PubMed Scopus (832) Google Scholar, 8.Braun N Michel U Ernst BP Metzner R Bitsch R Weber F Rieckmann P Gene polymorphism at position −308 of the tumor-necrosis-factor-α (TNF-α) in multiple sclerosis and it's influence on the gene regulation of TNF-α production.Neurosci Lett. 1996; 215: 75-78PubMed Google Scholar, 9.Wilson AG Symons JA McDowell TL McDevitt HO Duff GW Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activity.Proc Natl Acad Sci USA. 1997; 94: 3195-3199Crossref PubMed Scopus (2120) Google Scholar), possibly due to the differential binding of a nuclear protein to this allele (7.Kroeger KM Carville KS Abraham LJ The −308 tumor necrosis factor-α promoter polymorphism effects transcription.Mol Immunol. 1997; 34: 391-399Crossref PubMed Scopus (832) Google Scholar, 10.Sullivan KE Wooten C Schmeckpeper B Goldman D Oh M Petri M A tumor necrosis factor alpha promoter polymorphism is associated with SLE in African Americans and binds a macrophage-specific DNA-binding protein.Arthritis Rheum. 1997; 40 ([abstract]): 251Google Scholar). These results have led to extensive investigation into the importance of TNFA genetics in autoimmune and infectious diseases (see (11.Wilson AG di Giovine FS Duff GW Genetics of tumour necrosis factor-α in autoimmune, infectious, and neoplastic illnesses.J Inflamm. 1995; 45: 1-12PubMed Google Scholar)). The most significant findings have been in infectious diseases, such as malaria (12.McGuire W Hill AVS Allsopp CEM Greenwood BM Kwiatkowski D Cerebral malaria is associated with a polymorphism in the promoter region of the human TNF-α gene.Nature. 1994; 371: 508-511Crossref PubMed Scopus (1113) Google Scholar), leishmaniasis (13.Cabrera M Shaw MA Sharpes C Williams H Castes M Convit J Blackwell JM Polymorphism in tumor necrosis factor genes associated with Mucocutaneous Leishmaniasis.J Exp Med. 1995; 182: 1259-1264Crossref PubMed Scopus (416) Google Scholar) and trachoma (14.Conway DJ Holland MJ Bailey RL Campbell AE Mahdi OSM Jennings R et al.Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-α) gene promoter and with elevated TNF-α levels in tear fluid.Infect Immun. 1997; 65: 1003-1006PubMed Google Scholar), in which carriage of TNF2 is associated with a poorer prognosis. Studies in autoimmune diseases have been less convincing, although there is evidence in several autoimmune rheumatic diseases of a genetic contribution from the TNF locus (15.Mulcahy B Waldron-Lynch F McDermott MF Adams C Amos CI Zhu DK et al.Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis.Am J Hum Genet. 1996; 59: 676-683PubMed Google Scholar, 16.Sullivan KE Wooten C Schmeckpeper BJ Goldman D Petri MA A promoter polymorphism of tumor necrosis factor α associated with systemic lupus erythematosus in African-Americans.Arthritis Rheum. 1997; 40: 2207-2211Crossref PubMed Scopus (157) Google Scholar, 17.Höhler T Schäper T Schneider PM Zum Büschenfelde KM Märker-Hermann E Association of different tumor necrosis factor α promoter alleles frequencies with ankylosing spondylitis in HLA-B27 positive individuals.Arthritis Rheum. 1998; 41: 1489-1492Crossref PubMed Scopus (95) Google Scholar). A number of studies published in this journal have investigated the role of TNFA polymorphism in autoimmune hepatic diseases. Primary biliary cirrhosis (PBC) is associated with HLA-DR8. Two groups have examined TNFA genotypes in PBC patients and controls. Interestingly, one concluded that TNF2 was under-represented in patients compared with healthy controls, suggesting protection against disease susceptibility (18.Gordon MA Gleeson D Oppenheim E di Giovine FS Camp NC Duff GW Tumour necrosis factor genetic polymorphism and primary bilary cirrhosis.Hepatology. 1996; 24 ([abstract]): 166Google Scholar), while another found under-representation in patients with severe disease, suggesting a modulating effect on disease severity (19.Jones DEJ Watt FE Grove J Newton JL Daly AK Gregory WL et al.Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis.J Hepatol. 1999; 30: 232-236Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). It may, at first, seem surprising that carriage of a high TNFα-producing allele should be protective against an autoimmune disease. However, a similar association has been described in human systemic lupus erythematosus (20.Jacob CO Fronek Z Lewis GD Koo M Hansen JA McDevitt HO Heritable major histocompatibility complex class II-associated differences in production of tumour necrosís factor α: relevance to genetic predisposition to systemic lupus erythematosus.Proc Natl Acad Sci USA. 1990; 87: 1233-1237Crossref PubMed Scopus (617) Google Scholar), and administration of recombinant TNFα to an animal model of lupus protects against a severe phenotype (21.Jacob CO McDevitt HO Tumour necrosis factor-α in murine autoimmune 'lupus' nephritis.Nature. 1988; 31: 356-358Crossref Scopus (575) Google Scholar). A recent study has suggested a possible mechanism for these observations: chronic administration of TNFα to T cell receptor transgenic mice suppressed T cell responsiveness and function, so perhaps in PBC higher TNFα levels may downmodulate the immune activity that is directed against the liver (22.Cope AP Liblau RS Yang X-D Congia M Laudanna C Schreiber RD et al.Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signalling.J Exp Med. 1997; 185: 1573-1584Crossref PubMed Scopus (259) Google Scholar). Primary sclerosing cholangitis shows a strong association with the HLA A1-B8-DR3-DQ2 haplotype, with the telomeric limit of the MHC-encoded susceptibility lying in the vicinity of the HLA C locus (23.Moloney MM Thomson LJ Strettell MJ Williams R Donaldson PT Human leukocyte antigen-C genes and susceptibility to primary sclerosing cholangitis.Hepatology. 1998; 28: 660-662Crossref PubMed Scopus (29) Google Scholar). A report in this journal has now localised the region containing the disease-related genetic variant to the region containing TNF and HLA B (24.Bernal W Moloney M Underhill J Donaldson PT Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis.J Hepatol. 1999; 30: 237-241Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). The rapid accumulation of the genomic sequence and large number of well-characterised polymorphic markers within this region of the genome will be key to further genetic studies (25.Foissac A Crouau-Roy B Fauré S Thomsen M Cambon-Thomsen A Microsatellites in the HLA region: an overview.Tissue Antigens. 1997; 49: 197-214Crossref PubMed Scopus (61) Google Scholar, 26.Gillaudeux T Janer M Wong GK Spies T Geraghty DE The complete genomic sequence of 424,015 bp at the centromeric end of the HLA class I region: gene content and polymorphism.Proc Natl Acad Sci USA. 1998; 95: 9494-9499Crossref PubMed Scopus (55) Google Scholar). The localisation of the MHC disease-related variants in autoimmune liver disease will be greatly facilitated by this information. Future studies, using a dense array of polymorphic markers in this region of the MHC, should give a clearer indication if genetic variation within TNFA, rather than a nearby linked gene, is the reason for the genetic association of this region with autoimmune hepatic diseases.