title: Gene-gene interactions in RANK/RANKL/OPG system influence bone mineral density in postmenopausal women.
abstract: Receptor activator of nuclear factor kappaB (RANK) is one of the proteins in regulation of osteoclastogenesis via RANK/RANKL/OPG. Gene that codes for RANK protein (TNFRSF11A) was associated with osteoporotic fractures in a recent genome-wide association study. As variations in the RANK gene could alter its expression and activity, the aim of our study was to evaluate the influence of four RANK gene polymorphisms on bone mineral density (BMD) and biochemical markers. We evaluated 467 postmenopausal women and 117 elderly men. All subjects were genotyped for the presence of RANK polymorphisms -670G>C, +34694C>T, +34901G>A and +35966insdelC. BMD and biochemical markers were measured. Significant associations of +35966insdelC with BMD at lumbar spine (BMD-ls), total hip (BMD-th) and femoral neck (BMD-fn) were found in postmenopausal women (p=0.020, 0.024 and 0.034), but not in men. Significant gene-gene interaction was proved for two RANK polymorphisms in combination with OPG and RANKL polymorphisms studied previously in postmenopausal women. Firstly, RANK/RANKL (+34901G>A/-290C>T) combination was associated with BMD-fn, BMD-th and BMD-ls (p=0.034, 0.016 and 0.050), and secondly, RANK/OPG combination (+35966insdelC/K3N) showed influence on BMD-fn and BMD-ls (p=0.043 and 0.039). Our results suggest that gene-gene interactions between RANK and OPG, and RANK and RANKL influence BMD in postmenopausal women.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Department of Clinical Biochemistry, Ljubljana, Slovenia.
authors.forename: Janja
authors.initials: J
authors.lastname: Zupan
authors.forename: Simona
authors.initials: S
authors.lastname: Mencej-Bedrac
authors.forename: Simona
authors.initials: S
authors.lastname: Jurković-Mlakar
authors.forename: Janez
authors.initials: J
authors.lastname: Prezelj
authors.forename: Janja
authors.initials: J
authors.lastname: Marc
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D015519:Bone Density / Q000235:genetics*; D024042:Collagen Type I / Q000097:blood; D005260:Female; D005272:Femur Neck / Q000737:chemistry; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008159:Lumbar Vertebrae / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D053244:Osteoprotegerin / Q000097:blood / Q000235:genetics*; D010384:Pelvic Bones / Q000737:chemistry; D010455:Peptides / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017698:Postmenopause / Q000097:blood / Q000378:metabolism*; D053245:RANK Ligand / Q000097:blood / Q000235:genetics*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D053244:Osteoprotegerin; D010455:Peptides; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin; D000469:Alkaline Phosphatase