Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk.

Objective: Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of 24 single nucleotide polymorphisms (SNPs) located in five genes--alkaline phosphatase, matrix metalloproteinase-2, tissue inhibitor of metalloproteases-2 (TIMP2), fibroblast growth factor receptor-1 (FGFR1), and fatty acid-binding protein-3 (FABP3)--previously not associated with OP.

Design: We performed a genotype-phenotype association study at a university hospital.

Methods: A total of 360 Hungarian postmenopausal women were involved in the study. Bone mineral density (BMD) was determined at spine, hip, and distal radius. Genomic DNA was extracted from venous blood samples and a high-throughput genotyping method based on single-based primer extension was applied for allelic discrimination. Robust statistical tools were utilized for multiplex data analysis.

Results: SNP rs6996321 in FGFR1 was significantly related to spine BMD (P=0.002) and rs10914367 in FABP3 was associated with hip BMD (P=0.028). Non-vertebral fracture risk was significantly increased in carriers of 'A' allele of rs9900972 in TIMP2 (odds ratio=2.06, P=0.0187). We could also identify validated gene-gene interactions significantly affecting BMD and fracture risk.

Conclusions: We identified two previously unreported SNPs in FGFR1 and FABP3 associated with BMD and a third SNP in TIMP2 related to risk for non-vertebral osteoporotic fractures. This is the first report about the association between these allelic variants and the phenotypes of postmenopausal OP. Further studies need to clarify the role of these genes and their polymorphisms in the process of bone loss.