Fibroblast growth factor 23 (FGF23), a bone-derived hormone, participates in the hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25-dihydroxyvitamin D, plasma phosphate (Pi), and diet. Inappropriately high serum FGF23, seen in certain genetic and acquired disorders, results in urinary phosphate wasting and impaired bone mineralization. This study investigated the impact of FGF23 gene variation on phosphate homeostasis and bone health. The study included 183 children and adolescents (110 girls) aged 7-19 years (median 13.2years). Urine and blood parameters of calcium and phosphate homeostasis were analyzed. Bone characteristics were quantified by DXA and peripheral quantitative computed tomography (pQCT). Genetic FGF23 variation was assessed by direct sequencing of coding exons and flanking intronic regions. Nine FGF23 polymorphisms were detected; three of them were common: rs3832879 (c.212-37insC), rs7955866 (c.716C>T, p.T239M) and rs11063112 (c.2185A>T). Four different haplotypes and six different diplotypes were observed among these three polymorphisms. The variations in FGF23 significantly associated with plasma PTH and urinary Pi excretion, even after adjusting for relevant covariates. FGF23 variations independently associated with total hip BMD Z-score, but not with other bone outcomes. In instrument analysis, genetic variance in FGF23 was considered a weak instrument as it only induced small variations in circulating FGF23, PTH and Pi concentrations (F statistic less than 10). The observed associations between FGF23 variations and circulating PTH, and Pi excretion and total hip BMD Z-scores suggest that FGF23 polymorphisms may play a role in mineral homeostasis and bone metabolism.
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n?=?5,878) followed by replication (n?=?1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p?=?3.6×10?¹4; LOC285735, rs271170, p?=?2.7×10?¹²; OPG, rs7839059, p?=?1.2×10?¹°; and ESR1/C6orf97, rs6909279, p?=?1.1×10??). The trabecular vBMD GWA meta-analysis (n?=?2,500) followed by replication (n?=?1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p?=?1.9×10??). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n?=?729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Cites: Nat Genet. 2010 Jul;42(7):565-920562875
Cites: J Bone Miner Res. 2010 Aug;25(8):1886-9420222106
A polymorphism in an Sp1 site in the collagen Ialpha1 (COLIA1) gene has recently been identified and the Ss and ss genotypes were shown to be potentially important determinants of low bone mass in postmenopausal women. Additionally, in a Dutch population, the association of the COLIA1 polymorphism with low bone mineral density (BMD) was more pronounced with increasing age, suggesting a genotype effect on the rate of bone loss. We have investigated the relationship between the COLIA1 Sp1 polymorphism and the rate of bone loss in a longitudinal study with a total of 133 postmenopausal women followed for 18 years. The frequencies of the genotypes were SS 70.7%, Ss 27.8%, ss 1.5% and were in Hardy-Weinberg equilibrium. No association of the COLIA1 genotype with rate of bone loss was detected and there was no difference between the genotype groups with respect to BMD at the femoral neck or lumbar spine. Women with the Ss or ss genotypes, who have been postulated to have low BMD, had even higher BMD at the lower forearm than women with the SS genotype. The levels of serum osteocalcin and urinary collagen type I degradation products were not found to be associated with the COLIA1 Sp1 polymorphism. In conclusion, this study does not support the hypothesis that the Ss COLIA1 genotype predisposes women to increased rate of bone loss or low BMD. However, because of a low absolute number of the ss genotype, it was not possible to reach a conclusion on this particular genotype with regard to an association with low BMD or rate of bone loss.
Polymorphisms at the binding site of the Sp 1 transcription factor of the collagen type I alpha1 gene have recently been suggested to be an important marker for low bone mineral density (BMD) and vertebral fracture in a population of predominantly postmenopausal British women. We examined whether the unfavorable "s" allele was associated with low BMD in 64 patients with primary osteoporosis and in 72 healthy controls. We found no statistically significant differences between COLIA1 genotypes with regard to BMD at the spine and femoral neck. In 36 patients with severe osteoporosis with vertebral fracture the genotype frequencies were similar to that observed in 67 age-matched controls. These data indicate that the Sp 1 polymorphisms in the COLIA1 gene are unlikely to be of clinical value in identifying Swedish subjects who are at risk of postmenopausal osteoporosis.
ALOX12 and ALOX15 encode arachidonate lipoxygenases which produce lipid metabolites involved in inflammatory processes. Metabolites generated by ALOX12 and ALOX15 can activate the expression of the potent pro-inflammatory cytokine IL-6, and produce endogenous ligands for PPARG. In this study, polymorphisms in ALOX12, ALOX15, IL6 and PPARG were investigated for association with bone properties in young and elderly Swedish women.
Three SNPs in ALOX12, five in ALOX15, one each in IL6 and PPARG were genotyped in the cohorts PEAK-25 (n=1061 women; all 25y) and OPRA (n=1044 women; all 75y). Bone mineral density (BMD) and quantitative ultrasound (QUS) were analyzed in both cohorts; trabecular bone score (TBS) in PEAK-25; bone loss, fracture incidence and serum C-reactive protein (CRP) were assessed in OPRA.
In the elderly women ALOX15 (rs2619112) was associated with CRP levels (p=0.004) and incident fracture of any type (p=0.014), although not with BMD or ultrasound. In young women, carrying the common T allele (ALOX 15 rs748694) was associated with lower QUS values (p=0.002-0.006). The IL6 SNP was associated with lower BMD in PEAK-25 (femoral neck p=0.034; hip p=0.012). TBS was not associated with variation in any gene. Variants in the ALOX12 and PPAR? were not associated with BMD in either cohort.
This study suggests that variation in inflammation related genes ALOX15 and IL6 was associated with bone microarchitecture and density in young adult women, but appears to be less important in the elderly, despite an observed association with CRP as a marker of inflammation and incident fracture.
The present study investigated the effects of first degree relatives' fractures on fracture incidence after the menopause. Sister's, but not other relatives', wrist or hip fracture history was associated with increased risk of fragility fractures after the menopause. This suggests genetic predisposition to bone fragility among postmenopausal women.
The aim of the present study was to investigate the association between first degree relatives' fractures and perimenopausal bone fragility.
The study sample of 971 perimenopausal women was extracted from randomly selected Kuopio Osteoporosis Risk Factor and Prevention cohort and measured with dual X-ray absorptiometry in femoral neck (FN) in baseline (1989-1991), in 5 years (1994-97), and in 10 years (1999-2001). All low-trauma energy fractures during the 10-year follow-up were recorded based on self-reports and validated from medical records. First degree relatives' history of life-time hip and wrist fractures (exact classification or trauma energy not specified) was questioned by postal inquiries.
There was a significant correlation between fathers' vs. brothers' and mothers' vs. sisters' fractures (p
A BsmI restriction enzyme polymorphism in the vitamin D receptor (VDR) gene has been reported to be associated with bone mineral density (BMD) and bone turnover. However, findings in other studies suggest the presence of considerable interaction by race, body size, and environmental factors. Therefore, we VDR BsmI genotyped 200 healthy perimenopausal Danish white women (mean age 50.8 years, mean calcium intake 900 mg/day) in a comprehensive, longitudinal, community-based population study. Bone loss was assessed by dual-energy X-ray absorptiometry (DXA) using cross-calibrated Hologic QDR-1000W and QDR-2000 densitometers, with a mean follow-up period of 4 years (range 1-5 years). Despite a distribution of genotypes similar to that of other white populations (28% bb, 49% Bb, 23% BB), VDR genotypes were not associated with lumbar or femoral baseline BMD, subsequent bone loss rates, or biochemical markers of bone metabolism (bone-specific alkaline phosphatase, urinary hydroxyproline, and serum osteocalcin). Controlling for body size, calcium intake, and serum levels of 25-hydroxyvitamin D3 [25(OH)D3] did not alter this finding. The possible existence of a threshold effect was subsequently investigated by restricting analysis to women with low serum 25(OH)D3 levels or low calcium intake. VDR BsmI genotypes showed no significant impact on bone density or bone loss in healthy Danish early postmenopausal women, even when allowance was made for calcium intake, serum 25(OH)D3, and body size.