The 677C-->T mutation of the methylene-tetrahydrofolate reductase gene in the pathogenesis of osteonecrosis of the femoral head.

Abstract

We investigated the presence of the 677C→T methylenetetrahydrofolate reductase (MTHFR) mutation in 66 patients with osteonecrosis (ON) of the femoral head and 300 healthy controls. Homozygosity for the MTHFR mutation was present in 26.1% of patients with idiopathic ON and in 10% of controls (odds ratio: 3.2 [95% confidence interval: 1.2-8.7]). The homozygous state of the 677C→T MTHFR mutation appears to be associated with idiopathic osteonecrosis. The etiology of non-traumatic osteonecrosis (ON) of the femoral head has not been elucidated. However, intravascular coagulation appears to constitute a pathogenetic mechanism through which various environmental and genetic risk factors lead to bone ischemia and death.1 Protein C and S deficiency, elevated lipoprotein (a), and the factor V Leiden mutation represent genetic risk factors for hypercoagulability and ON.2-4 The 677C→T mutation of the 5,10-methylene-tetrahydrofolate reductase (MTHFR) gene has been identified as a common cause of MTHFR enzyme deficiency and has been postulated as a genetic risk factor for thrombotic events.5,6 The purpose of our study was to evaluate the potential association of this MTHFR mutation with non-traumatic ON of the femoral head. The study population consisted of 66 consecutively identified Caucasian patients with non-traumatic ON of the femoral head and 300 healthy controls. There were 48 male and 18 female patients with a mean age of 31 years. In 43 patients the disease was considered secondary to various factors (administration of steroids in 34 patients, alcoholism in 7, and systemic lupus erythematosus in 2) and was considered idiopathic in the remaining 23 patients, since no risk factor was known to be present. The control group consisted of 300 consecutive Caucasian healthy blood donors (mean age 36 years) who presented at the University Hospital of Ioannina. The presence of the homozygous (677TT genotype) and heterozygous (677CT genotype) state of the 677C→T mutation in the MTHFR gene was investigated by restriction enzyme digestion of an amplified gene fragment using the primers and polymerase chain reaction conditions described by Frosst et al.7 Odds ratios with 95% confidence intervals were calculated for the homozygous versus the other genotypes. Allele frequencies at the 677 locus were found to be in HardyWeinberg equilibrium for both patients and controls. The prevalence of homozygosity for the 677C→T mutation was 18.2% (12 of 66) in the patient group and 10% (30 of 300) in the control group. The odds ratio was 2.0 (95% confidence interval: 1.0- 4.2), which was marginally not statistically significant with the numbers available. In the idiopathic ON subgroup, homozygosity for the mutation was present in 26.1% of patients (6 of 23). The odds ratio was 3.2 (95% confidence interval: 1.2-8.7) and this was statistically significant (Table 1). The 677C→T mutation of the MTHFR gene leads to hyperhomocysteinemia, which is associated with an increased risk of thrombosis, 8 and the MTHFR mutation has been postulated as a genetic