Osteoporosis is a common metabolic bone disease characterized by low bone mineral density (BMD) with an increased risk of fracture. Low bone mass results from an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. Microphthalmia-asso-ciated transcription factor (MITF) plays a critical role in osteoclast development and thus is an important candidate gene affecting bone turnover and BMD. In order to investigate the genetic effects of MITF variations on osteoporosis, we directly sequenced the MITF gene in 24 Koreans, and identified fifteen sequence variants. Two polymorphisms (+227719C > T and +228953A > G) were selected based on their allele frequencies, and then genotyped in a larger number of postmenopausal women (n = 560). Areal BMD (g/cm2) of the anterior-posterior lumbar spine and the non-dominant proximal femur was measured by dual-energy X-ray absorptiometry. We found that the MITF + 227719C > T polymorphism was significantly associated with low BMD of the trochanter (p = 0.005?0.006) and total femur (p = 0.02?0.03) (codominant and dominant models), while there was no association with BMD of the lumbar spine. The MITF+228953A > G polymorphism was also associated with low BMD of the femoral shaft (p = 0.05) in the recessive model. Haplotype analysis showed that haplotype 3 of the MITF gene (MITF-ht3) was associated with low BMD of the tro- chanter (p = 0.03?0.05) and total femur (p = 0.05) (dominant and codominant models). Our results suggest that MITF variants may play a role in the decreased BMD of the proximal femur in postmenopausal women.

Keywords: BMD, MITF, Osteoporosis, SNP