Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.
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.
Brown
M A
MA
Wellcome Trust Centre for Human Genetics, Headington, Oxon, UK. mbrown@well.ox.ac.uk
Edwards
S
S
Hoyle
E
E
Campbell
S
S
Laval
S
S
Daly
A K
AK
Pile
K D
KD
Calin
A
A
Ebringer
A
A
Weeks
D E
DE
Wordsworth
B P
BP
D000483:Alleles; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D009679:Nuclear Family; D011110:Polymorphism, Genetic; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000473:pathology
D004247:DNA; D019389:Cytochrome P-450 CYP2D6