title: Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis.
abstract: 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.
authors.affiliation: Center for Human Genetics, Department of Pediatrics, Boston University School of Medicine, 715 Albany St, W408, Boston, MA 02118, USA. cbaldwin@bu.edu
authors.forename: Clinton
authors.initials: C
authors.lastname: Baldwin
authors.forename: Vikki G
authors.initials: VG
authors.lastname: Nolan
authors.forename: Diego F
authors.initials: DF
authors.lastname: Wyszynski
authors.forename: Qian-Li
authors.initials: QL
authors.lastname: Ma
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Embury
authors.forename: Alice
authors.initials: A
authors.lastname: Bisbee
authors.forename: John
authors.initials: J
authors.lastname: Farrell
authors.forename: Lindsay
authors.initials: L
authors.lastname: Farrer
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
mesh_terms: D000755:Anemia, Sickle Cell / Q000453:epidemiology / Q000235:genetics*; D017306:Annexin A2 / Q000235:genetics*; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005966:Glucuronidase; D006239:Haplotypes; D006801:Humans; D000090265:Klotho Proteins; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics*; D010020:Osteonecrosis / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D008565:Membrane Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins