THE IMMUNOGLOBULIN HEAVY-CHAIN AND DISEASE ASSOCIATION - APPLICATION TO PEMPHIGUS-VULGARIS

Genes involved in the immune response are generally encoded from a com plex cluster of gene segments. Studies of the association of diseases with such genes require well-defined genetic markers throughout the se lected region. A set of 15 polymorphic loci that span 1500 kb of the i mmunoglobulin heavy chain (IGH) complex, 8 in the variable (VH) region and 7 in the constant (CH) region, were selected for the study of dis ease association. We present a protocol for the use of multiple immuno globulin heavy chain (IGH) polymorphisms for general application in di sease association studies. No microsatellite repeat markers are availa ble for this region. To demonstrate the applicability of this approach , we have examined these IGH polymorphisms in families with individual s affected with pemphigus vulgaris (PV), an autoimmune dermatologic di sease. Allele frequencies in 12 patients with PV were compared with th ose found in their spouses, and with those in a white Canadian control population. A significant difference was found between PV patients an d both control groups for the presence of the VH gene VH3f-R4, and pos sibly for the absence of VH3f-R3, suggesting the possibility of suscep tibility factors in these regions. Examination of the frequencies of t he IGH region Cy-haplotypes of PV patients indicated that, while the p atients did not differ significantly from their spouses (chi(2)=1.79), both groups were found to differ significantly from the white Canadia n control group (chi(2)=10.10), emphasizing the importance of matching the ethnic background of controls with that of the patient test group in disease association studies. Unexpectedly, two patients had large deletions of genes in the IGH constant region, which could play a role in the development of PV and require further investigation.