Identifying genes that cause disease: HLA-B27, the paradigm, the promise, the perplexity

Medicine is entering an era that will be completely reshaped by the ability to identify genes that either cause or control the susceptibility to disease. Virtually all diseases including atherosclerosis, cancers, and infections have a genetic component. As the effort to sequence the human genome rapidly advances, progress has been made in identifying susceptibility loci for many illnesses. Some diseases like retinoblastoma and certain retinal dystrophies can result from the malfunction of a single gene. Most diseases, however, including age related cataract, glaucoma,1 2 and macular degeneration3 are undoubtedly multigenic. The identification of a susceptibility gene opens a Pandora’s box; locating a susceptibility locus is only the first step toward unravelling the mystery of disease causation. In this regard, the tale of the HLA-B27 gene might be an instructive paradigm.

HLA (human leucocyte antigen) gene products are cell surface glycoproteins that are widely distributed on many cells. HLA antigens are intimately involved in the immune response. Consequently one’s HLA genotype influences susceptibility to diseases that have an immunopathogenesis. There are dozens of autoimmune diseases that fit this description. Of …