Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis

Hum Mol Genet. 2000 Jul 1;9(11):1563-6. doi: 10.1093/hmg/9.11.1563.

Abstract

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.

MeSH terms

  • Alleles
  • Case-Control Studies
  • Cytochrome P-450 CYP2D6 / genetics*
  • Cytochrome P-450 CYP2D6 / metabolism
  • DNA / genetics
  • Family Health
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Lod Score
  • Male
  • Nuclear Family
  • Polymorphism, Genetic
  • Spondylitis, Ankylosing / genetics*
  • Spondylitis, Ankylosing / pathology

Substances

  • DNA
  • Cytochrome P-450 CYP2D6