Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people

Hyperhomocysteinemia may contribute to the development of osteoporosis. The relationship of Hcy and vitamin B12 with bone turnover markers, BUA, and fracture incidence was studied in 1267 subjects of the Longitudinal Aging Study Amsterdam. High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk. Introduction: Hyperhomocysteinemia may contribute to the development of osteoporosis. Vitamin B12 is closely correlated to homocysteine (Hcy). The main objective of our study was to examine the association of Hcy and vitamin B12 status and the combined effect of these two with broadband ultrasound attenuation (BUA), bone turnover markers, and fracture. Materials and Methods: Subjects were 615 men and 652 women with a mean age of 76 ± 6.6 (SD) years of the Longitudinal Aging Study Amsterdam (LASA). At baseline (1995/1996), blood samples were taken after an overnight fast for dairy products. Plasma Hcy was measured with IMx, serum vitamin B 12 with competitive immunoassay (IA) luminescence, serum osteocalcin (OC) with immunoradiometric assay (IRMA), and urinary excretion of deoxypyridinoline (DPD) with competitive IA and corrected for creatinine (Cr) concentration. CVs were 4%, 5%, 8%, and 5%, respectively. BUA was assessed in the heel bone twice in both the right and left calcaneus. Mean BUA value was calculated from these four measurements. CV was 3.4%. After baseline measurements in 1995, a 3-year prospective follow-up of fractures was carried out until 1998/1999. Subjects were grouped by using two different approaches on the basis of their vitamin B12 concentration, normal versus low (15 μM) or highest quartile (Q4) versus normal quartiles (Q1-Q3). Analysis of covariance was performed to calculate mean values of BUA, OC, and DPD/Crurine based on the specified categories of Hcy and vitamin B12 and adjusted for several confounders (potential confounders were age, sex, body weight, body height, current smoking [yes/no], mobility, cognition). The relative risk (RR) of any fracture was assessed with Cox regression analysis. Quartiles were used when Hcy and vitamin B12 were separately studied in their relationship with fracture incidence. Results: Fourteen percent of the men and 9% of the women had high Hcy (>15 μM) and low vitamin B12 (15 μM had lower BUA, higher DPD/Cr, and higher OC concentrations than their counterparts. In men, no differences were found between the different Hcy and vitamin B12 categories in adjusted means of BUA, OC, or DPD/Crurine. Twenty-eight men and 43 women sustained a fracture during the 3-year follow-up period. The adjusted RR for fractures (95% CI) for men with high Hcy and/or low vitamin B12 concentrations was 3.8 (1.2-11.6) compared with men with normal Hcy and vitamin B12 concentrations. Women with high Hcy and/or low vitamin B 12 concentrations had an adjusted RR for fractures of 2.8 (1.3-5.7). Conclusions: High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk