HLA and Diseases: Involvement of More than One HLA‐Linked Determinant of Disease Susceptibility

After 15 years of work on "HLA and disease" and numerous publications on this subject, a number of points are now generally accepted. a) Due to the complexity of the HLA-system and the many possibilities of subdividing patient materials there is an almost unlimited opportunity for statistical artefacts. Nevertheless there is a growing number of diseases for which the relationship with HLA is established beyond any reasonable doubt. b) With very few exceptions, the HLA-associated diseases show a significant discordance for monozygotic twins, thus indicating that environmental factors are necessary to trigger such a disease. c) For most HLA-associated diseases immunological processes are thought to play a major role in the pathogenesis. d) With the exception of hemochromatosis and C-21 hydroxylase-deficiency there is no simple mendelian mode of inheritance for any HLA-associated disease, although some diseases show a pattern of inheritance which is almost compatible with one major dominant gene with reduced penetrance (e.g. Ankylosing spondylitis). In other diseases like Coeliac Disease, Juvenile onset Diabetes mellitus (JOD) or Psoriasis there is evidence for the association with more than one allelic HLA specificity. e) Due to the linkage disequilibrium between the alleles of the HLA-gene cluster there frequently is difficulty in determining which ofthe markers on one haplotype (e.g. Al, B8, BfS, DR3) represents the primary association. For this reason, some investigators use the term "disease haplotypes" or "super-