Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis

Diffuse panbronchiolitis affecting East Asians is strongly associated with the class I human leukocyte antigen (HLA) alleles. Recent observations sugg est that a major disease-susceptibility gene may be located between the HLA -B and HLA-A loci in the class I region of the major histocompatibility com plex on chromosome 6. To test this possibility, we analyzed 14 polymorphic markers in 92 Japanese patients and 93 healthy controls. Of these, seven ma rker alleles, including HLA-B54 and HLA-A11, were significantly associated with the disease. Maximum-likelihood haplotype analysis and subsequent dire ct determination of individual haplotypes identified a group of disease-ass ociated haplotypes, one of which contained all seven disease-associated mar ker alleles. Another haplotype, containing HLA-B*5504, was also associated with the disease. All these haplotypes seem to have diverged from a common ancestral haplotype in East Asians and share a specific segment containing three consecutive markers between the S and TFIIH loci in the class I regio n. Furthermore, one of the markers within the candidate region showed the h ighest delta value, indicating the strongest association. Of 20 Korean pati ents with diffuse panbronchiolitis, 17 also shared the combination of the d isease-associated marker alleles within the candidate region. These results indicate that an HLA-associated major susceptibility gene for diffuse panb ronchiolitis is probably located within the 200 kb in the class I region 30 0 kb telomeric of the HLA-B locus on the chromosome 6p21.3.