Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disor der, The sibling recurrence risk ratio for the disease is 63 and heritabili ty assessed in twins >90%. Although MHC genes, including HLA-B27, contribut e only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the di sease or its phenotypic expression. Previous linkage and association studie s have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) loc ated at chromosome 22q13.1. We performed a linkage study of chromosome 22 i n 200 families with AS affected sibling-pairs. Association of alleles of th e CYP2D6 gene was examined by both case-control and within-family means. Fo r case-control studies, 617 unrelated individuals with AS (361 probands fro m sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed. For within-family association studies, 361 families including 161 parent-c ase trios and 200 affected sibling-pair families were employed. Homozygosit y for poor metabolizer alleles was found to be associated with AS. Heterozy gosity for the most frequent poor metabolizer allele (CYP2D6*4) was not ass ociated with increased susceptibility to AS. Significant within-family asso ciation of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS, We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.