Familiar sarcoidosis is linked to the major histocompatibility complex region

Sarcoidosis is a systemic granulomatous disorder associated with high CD4cell activity, but no pathogen is detectable. Clustering in families occurs , and the existence of a genetic predisposition to sarcoidosis is widely ac cepted. The major histocompatibility complex (MHC) is believed to contribut e to this susceptibility. Many studies testing this hypothesis have produce d conflicting results. We have genotyped 122 affected siblings from 55 fami lies for seven DNA polymorphisms that flank and cover the MHC region on chr omosome 6, and for HLA-DPB1, a candidate gene for granulomatous disorders. Multipoint nonparametric linkage (NPL) analysis showed linkage (NPL score > 2.5; p < 0.006) for the entire MHC region with a maximum NPL score of 3.2 (p = 0.0008) at marker locus D6S1666 in the Class III gene cluster. There w as a significant excess of marker haplotype sharing among affected siblings . However, the frequency of HLA-DPB1 alleles on 104 shared chromosomes did not differ from that of a control group of founders from the family panel. Transmission disequilibrium was found for allele DPB1*0201, but only nine f amilies contributed to this result. We conclude that genes of the MHC are i nvolved in the genetic predisposition to sarcoidosis, but HLA-DPB1 alone do es not sufficiently explain this fact.