title: Association between the T-786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur.
abstract: BACKGROUND
  Nitric oxide regulates bone turnover by osteoblasts and osteoclasts. Nitric oxide production is impaired by the T-786C eNOS single nucleotide polymorphism, with a substitution of the nucleotide thymine by cytosine at a locus 786 base pairs upstream of the eNOS gene. This leads to vasoconstriction, platelet aggregation, reduced angiogenesis, and reduced bone formation, all of which may be associated with osteonecrosis of the hip. We studied relationships between the T-786C eNOS polymorphism and idiopathic and secondary necrosis of the head of the femur in order to better understand the pathophysiology of osteonecrosis.
  
  
  METHODS
  With use of polymerase chain reaction methodology, the T-786C eNOS polymorphism was compared in ninety-five patients with femoral head necrosis (including thirty-six nonsmokers with idiopathic necrosis and fifty-nine patients with secondary necrosis) and seventy-two healthy normal adult controls.
  
  
  RESULTS
  Homozygosity for the mutant eNOS allele (TT) was present in eight (22%) of thirty-six patients with idiopathic osteonecrosis as compared with one (3%) of thirty-six race, gender, and age-matched controls; heterozygosity (TC) was present in nineteen patients (53%) as compared with ten controls (28%); and the wild-type normal genotype (CC) was present in nine patients (25%) as compared with twenty-five controls (69%) (p = 0.0004). Logistic regression revealed that the T-786C eNOS mutant allele was positively associated with idiopathic osteonecrosis of the femoral head (odds ratio, 6.0; 95% confidence interval, 2.51 to 14.4). The fifty-nine patients with secondary osteonecrosis did not differ from fifty-two race, gender, and age-matched controls in terms of the distribution of the T-786C eNOS polymorphism (p = 0.19) or in terms of mutant allele frequency (30% compared with 21%; p = 0.15). The thirty-six patients with idiopathic osteonecrosis differed from the fifty-nine patients with secondary osteonecrosis in that they were more likely to have mutant eNOS genotypes (p = 0.033) and to have a higher mutant T allele frequency (49% compared with 30%; p = 0.009).
  
  
  CONCLUSIONS
  The T-786C eNOS polymorphism and resultant reduction of nitric oxide production is associated with, and may contribute to, the pathogenesis of idiopathic osteonecrosis of the femoral head.
  
  
  METHODS
  Prognostic Level III. See Instructions to Authors for a complete description of levels of evidence.
authors.affiliation: Cholesterol Center, Jewish Hospital of Cincinnati, 3200 Burnet Avenue, Cincinnati, OH 45229, USA. glueckch@healthall.com
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Glueck
authors.forename: Richard A
authors.initials: RA
authors.lastname: Freiberg
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oghene
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fontaine
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000328:Adult; D005260:Female; D005271:Femur Head Necrosis / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III