Nitric oxide (NO) regulates bone turnover by osteoblasts-osteoclasts. NO production is impaired by T-786C eNOS and stromelysin 1 5A6A polymorphisms that lead to vasoconstriction, platelet aggregation, reduced angiogenesis, and bone formation, all of which may be associated with osteonecrosis (ON) of the hip. eNOS and stromelysin polymorphisms were compared in 95 hip ON cases (54 idiopathic [18 smokers], 41 secondary [9 smokers]) and 72 healthy normal adult controls. TT eNOS homozygosity was present in 11 of 54 (20%) idiopathic ON cases versus 1 of 51 (2%) race-/gender-/age-matched controls, TC heterozygosity in 28 of 54 (52%) cases versus 17 of 51 (33%) controls, and CC (wild-type normal) in 15 of 54 (28%) cases versus 33 of 51 (65%) controls, p = .0001. The eNOS mutant allele frequency in idiopathic ON was 50 of 108 (46%), higher than in race-/gender-/age-matched controls, 19 of 102 (19%), p < .0001. The case-control TT versus CC odds ratio (OR) was 24.2 (p = .0002), 95% CI 2.86-204.9, TC versus CC OR was 3.62 (p = .003), 95% CI 1.54-8.54, and TT versus combined TC with CC OR was 8.78 (p = .003), 95% CI 1.59-103.1. By logistic regression, the eNOS T-786 mutant allele was independently associated with idiopathic ON (p < .0001), OR 4.59, 95% CI 2.26-9.34. Secondary ON cases did not differ from 41 race-/gender-/age-matched controls in the distribution of the T-786C eNOS polymorphism (p = .52) or in mutant allele frequency (24% vs 23%, p = .85). The 54 cases with idiopathic ON differed from 41 cases with secondary ON, more likely to have mutant TT eNOS genotypes (p = .008) and having a higher mutant T allele frequency (p = .002). Idiopathic and secondary ON did not differ from controls for the distribution of the stromelysin 1 5A6A polymorphism (p > .7) or for the 6A allele frequency (p > .4). The eNOS T-786C polymorphism is associated with and may contribute to the pathogenesis of idiopathic ON.
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