Genetic variation in the PTH pathway and bone phenotypes in elderly women: evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes
| Autor: | Kristina Åkesson, Karl J Obrant, Fiona E. McGuigan, Holger Luthman, Paul Gerdhem, Lisa Jansson, Max Tenne |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Histology Genotype Physiology Endocrinology Diabetes and Metabolism Osteoporosis Parathyroid hormone Single-nucleotide polymorphism Bone resorption Bone and Bones Receptor Parathyroid Hormone Type 2 Fractures Bone Bone Density Risk Factors Internal medicine medicine Humans Allele Aged Receptor Parathyroid Hormone Type 1 Bone growth Calcium metabolism Polymorphism Genetic business.industry Haplotype Parathyroid Hormone-Related Protein medicine.disease Endocrinology Phenotype Parathyroid Hormone Mutation Female business hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Bone. 42(4) |
| ISSN: | 8756-3282 |
| Popis: | INTRODUCTION: Parathyroid hormone (PTH) is a key regulator of calcium metabolism. Parathyroid hormone-like hormone (PTHrP) contributes to skeletal development through regulation of chondrocyte proliferation and differentiation during early bone growth. Both PTH and PTHrP act through the same receptor (PTHR1). A second receptor, PTHR2, has been identified although its function is comparatively unknown. PTH hyper-secretion induces bone resorption, whereas intermittent injection of PTH increases bone mass. To explore the effects of genetic variation in the PTH pathway, we have analysed variations in PTH, PTHLH, PTHR1 and PTHR2 in relation to bone mass and fracture incidence in elderly women. MATERIALS AND METHODS: This study includes 1044 elderly women, all 75 years old, from the Malmo Osteoporosis Prospective Risk Assessment study (OPRA). Single nucleotide polymorphisms (SNPs) from 4 genes and derived haplotypes in the PTH signaling pathway were analysed in 745-1005 women; 6 SNPs in the PTH gene and 3 SNPs each in the PTHLH, PTHR1 and PTHR2 genes were investigated in relation to BMD (assessed at baseline), fracture (434 prevalent fractures of all types over lifetime, self-reported and 174 incident fractures up to 7 years, X-ray verified) and serum PTH. RESULTS AND CONCLUSION: Individually, SNPs in the 4 loci did not show any significant association with BMD. Neither were PTHLH, PTHR1 and PTHR2 polymorphisms associated with fracture. Three of 5 common haplotypes, accounting for >98% of alleles at the PTH locus, were identified as independent predictors of fracture. Haplotype 9 (19%) was suggestive of an association with fractures of any type sustained during lifetime (p=0.018), with carriers of one or more copies of the haplotype having the lowest incidence (p=0.006). Haplotypes 1 (13%) and 5 (37%) and 9 were suggestive of an association with fractures sustained between 50 and 75 years (p=0.02, p=0.013 and p=0.034). Carriers of haplotypes 1 and 5 were more likely to suffer a fracture (haplotype 1, p=0.045; haplotype 5, p=0.008). We conclude, that while further genotyping across the gene is recommended, in this cohort of elderly Swedish women, polymorphisms in PTH may contribute to the risk of fracture through mechanisms that are independent of BMD. |
| Databáze: | OpenAIRE |
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