“Return to sender, address unknown.…” Are variant addressins involved in PSC?

Abstract

See Article, pages 704–710 The past decades have witnessed an explosion in the identification of genes associated with relatively rare mendelian diseases. With the current DNA amplification and sequence technology and the availability of sufficient affected families it is feasible to find the responsible gene provided that the disease is monogenic (i.e., caused by a single gene) and that its phenotype is unambiguously defined (i.e., the patient group is really homogeneous and not composed of patients with similar but genetically different diseases). The principles of this successful strategy are also applied to more complex and more common diseases, based on the idea that such diseases also have a (partial) genetic background. However, there are many pitfalls in such screening strategies. In the present issue Bowlus et al. [1] report negative results that contrast a previously described association between addressin genes and the occurrence of PSC. In genetic association studies screening for SNPs (single nucleotide polymorphisms) has become a highly valuable tool. The human genome contains about 6–12 million SNPs [2], which are essentially single nucleotide changes in the genome that occur with a certain frequency (>1%) in the population. The great majority of these SNPs have no effect on health because they are not in the coding region of a gene or, if they are present in the coding sequence they may not alter the function of the encoded protein. Yet, these SNPs are useful because they can be used as markers for a potential disease gene. A set of SNPs in a certain region of the chromosome constitute a haplotype which can be used as a ‘‘barcode’’ for a certain (unknown) mutation in that region. Analysis of the linkage between the haplotype frequency in a disease group vs. controls can elucidate whether a gene in that region plays a role in this particular disease or not. A minority of SNPs represent changes that directly affect function of a gene product. As a consequence such SNPs potentially cause or aggravate a disease and these SNPs can be used directly in genetic screening studies. The search for an association between a disease phenotype and certain SNPs or haplotypes is complicated if several or even many loci play a role in disease initiation or development. The higher the number of loci, the more patients and individuals will have to be screened for a polymorphism or haplotype to detect a significant association. Such searches are even more hampered if a disease phenotype is not unequivocally defined and the patient group in fact consist of patients with similar symptoms but a different disease etiology. Primary sclerosing cholangitis is a disease of intra- and extrahepatic bile ducts, characterized by concentric obliterative fibrosis and bile duct strictures. It is an immunemediated disease, rather than a classical autoimmune disorder. There is a clear association with certain HLA haplotypes, but no specific autoantigens are observed. Rather, a wide range of autoantibodies are observed of which anti-neutrophil antibodies are the most frequent. This contrasts for example with Primary Biliary Cirrhosis in which a specific autoantigen (pyruvate dehydrogenase complex, PDC) appears to play a key role. The primary trigger in the pathogenesis of PSC is unknown, but it is clear that the affected bile ducts have