Anna Wawrzyniak1, Marzena Skrzypczak-Zielinska2, Iwona Krela-Kazmierczak3, Michal Michalak4, Daria Marszalek5, Michalina Marcinkowska1, Oliwia Zakerska-Banaszak5, Ryszard Slomski5. 1. Department of Family Medicine, Poznan University of Medical Sciences, Poznan, Poland. 2. Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. Electronic address: marzena.skrzypczak-zielinska@igcz.poznan.pl. 3. Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland. 4. Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland. 5. Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
Abstract
PURPOSE: We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. PATIENTS AND METHODS: The study included 114 postmenopausal osteoporosis patients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. RESULTS: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). CONCLUSIONS: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.
PURPOSE: We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. PATIENTS AND METHODS: The study included 114 postmenopausal osteoporosispatients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. RESULTS: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). CONCLUSIONS: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.