Association of Klotho, Bone Morphogenic Protein 6 and Annexin A2 Polymorphisms with Sickle Cell Osteonecrosis

Clinton Baldwin(1,2), Vikki G. Nolan(2), Diego F. Wyszynski(2,3), Qian-Li Ma(2), Paola Sebastiani(4), Stephen H. Embury(5), Alice Bisbee(6), John Farrell(2), Lindsay Farrer(2,3), Martin H. Steinberg(2)

1-Center for Human Genetics, Departments of Pediatrics, Boston University School of Medicine
2-Department of Medicine, Boston University School of Medicine
3-Department of Epidemiology, Boston University School of Public Health
4-Department of Biostatistics, Boston University School of Public Health
5-Department of Medicine, University of California at San Francisco and San Francisco General
6-Data Coordinating Center, Boston University School of Public Health

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 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 comprised of several SNPs in bone morphogenetic protein 6, annexin 2, 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.

Supplementary material

  • Original manuscript: under revision. Contact the corresponding author Clinton T Baldwin
  • Assay design
  • Table 1: Patients characteristics.
  • Figure 1: Gene structure and SNP location in the KL, BMP6 and ANXA2 genes.
  • Figure 2: Linkage disequilibrium between SNPs typed in KL.
  • Figure 3: Linkage disequilibrium between SNPs typed in ANXA2. 
  • Figure 4: Linkage disequilibrium between SNPs typed in BMP6.

updated 8.28.09