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Human Molecular Genetics, 2000, Vol. 9, No. 11 1563-1566
© 2000 Oxford University Press

Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis

Matthew A. Brown+, Sarah Edwards, Emma Hoyle, Sarah Campbell, Steven Laval, Ann K. Daly1, Kevin D. Pile2, Andrei Calin3, Alan Ebringer4, Daniel E. Weeks5 and B. Paul Wordsworth

Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxon OX3 7BN, UK, 1Department of Pharmacological Sciences, University of Newcastle-upon-Tyne, UK, 2Queen Elizabeth Hospital, Adelaide, Australia, 3Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, UK, 4Division of Life Sciences, King’s College, London, UK and 5Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder. The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins >90%. Although MHC genes, including HLA-B27, contribute 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 disease or its phenotypic expression. Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13.1. We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs. Association of alleles of the CYP2D6 gene was examined by both case–control and within-family means. For case–control studies, 617 unrelated individuals with AS (361 probands from 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–case trios and 200 affected sibling-pair families were employed. Homozygosity for poor metabolizer alleles was found to be associated with AS. Heterozygosity for the most frequent poor metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association 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.

+ To whom correspondence should be addressed. Tel: +44 1865 287647; Fax: +44 1865 287501; Email: mbrown@well.ox.ac.uk


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