Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis

Blood. 2005 Jul 1;106(1):372-5. doi: 10.1182/blood-2005-02-0548. Epub 2005 Mar 22.


In patients with sickle cell disease, clinical complications including osteonecrosis can vary in frequency and severity, presumably due to the effects of genes that modify the pathophysiology initiated by the sickle mutation. Here, we examined the association of single nucleotide polymorphisms (SNPs) in candidate genes (cytokines, inflammation, oxidant stress, bone metabolism) with osteonecrosis in patients with sickle cell disease. Genotype distributions were compared between cases and controls using multiple logistic regression techniques. An initial screen and follow-up studies showed that individual SNPs and haplotypes composed of several SNPs in bone morphogenic protein 6, annexin A2, and klotho were associated with sickle cell osteonecrosis. These genes are important in bone morphology, metabolism, and vascular disease. Our results may provide insight into the pathogenesis of osteonecrosis in sickle cell disease, help identify individuals who are at high risk for osteonecrosis, and thus allow earlier and more effective therapeutic intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anemia, Sickle Cell / epidemiology
  • Anemia, Sickle Cell / genetics*
  • Annexin A2 / genetics*
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Proteins / genetics*
  • Genetic Predisposition to Disease / epidemiology
  • Glucuronidase
  • Haplotypes
  • Humans
  • Klotho Proteins
  • Linkage Disequilibrium
  • Membrane Proteins / genetics*
  • Osteonecrosis / epidemiology
  • Osteonecrosis / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors


  • ANXA2 protein, human
  • Annexin A2
  • BMP6 protein, human
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Proteins
  • Membrane Proteins
  • Glucuronidase
  • Klotho Proteins