A linkage disequilibrium between genes at the serine protease inhibitor gene cluster on chromosome 14q32.1 is associated with Wegener's granulomatosis.

The frequency of carriers of the alpha1-antitrypsin (alpha1-AT) deficiency allele PI*Z is increased in patients with Wegener's granulomatosis (WG). The polymorphic protease inhibitor (PI) gene is part of a cluster of serine protease inhibitor (serpin) genes (AACT; alpha1-antichymotrypsin, PCI; protein C inhibitor, CBG; corticosteroid binding globulin, PIL; PI-like pseudogene) at chromosome 14q32.1. In this study we investigated whether the serpin gene cluster contributes to the background of Wegener's granulomatosis. Therefore, phenotyping of alpha1-AT was performed and simple tandem repeat polymorphisms (STRP) in the genes for CBG, PI, and PCI as well as two STRP (D14S55 and D14S48) flanking the centromeric and one (D14S51) flanking the telomeric region of the gene cluster were examined in a population of 79 patients with WG and 128 unrelated healthy controls. In WG patients an increased frequency of the PI*Z defective allele is demonstrated as well as a linkage disequilibrium between all members of this gene cluster plus the centromeric and telomeric STRP. These results indicate an involvement of the serpin genes in the pathogenesis of Wegener's granulomatosis and it is possible that other genes located in the vicinity of D14S55 or D14S51 contribute to the genetic background of the disease. Copyright 2000 Academic Press.