CONTEXT Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect ...osteoporosis risk in the general population. OBJECTIVE To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 number of participants with available data; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 × 10−5) and 8 mg/cm2 (P = 5.0 × 10−6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio OR, 1.26; 95% confidence interval CI, 1.08-1.47 for Met667 2001 fractures among 20 488 individuals and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 1988 fractures among 20 096 individuals). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele 7876 fractures among 31 435 individuals)) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele 7802 fractures among 31 199 individuals). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance herein, unadjusted P < 10−7 that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
CONTEXT Both bone mineral density (BMD) and fracture risk have a strong genetic
component. Estrogen receptor α (ESR1) is a
candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms ...in this field were hampered by small sample size,
lack of standardization, and inconclusive results. OBJECTIVE To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI
dbSNP: rs9340799 and PvuII dbSNP: rs2234693 and
promoter TA repeats microsatellite) and haplotypes thereof are associated
with BMD and fractures. DESIGN AND SETTING Meta-analysis of individual-level data involving standardized genotyping
of 18 917 individuals in 8 European centers. MAIN OUTCOME MEASURES BMD of femoral neck and lumbar spine; all fractures and vertebral fractures
by genotype. RESULTS No between-center heterogeneity was observed for any outcome in any
genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically
significant effect on BMD in adjusted or unadjusted analyses, and estimated
differences between genetic contrasts were 0.01 g/cm2 or less.
Conversely, we found significant reductions in fracture risk. In women homozygous
for the absence of an XbaI recognition site, the
adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 95%
CI, 0.71-0.93; P = .002) and vertebral
fractures by 35% (odds ratio, 0.65 95% CI, 0.49-0.87; P = .003). Effects on fractures were independent of BMD and
unaltered in adjusted analyses. No significant effects on fracture risk were
seen for PvuII and TA repeats. CONCLUSIONS ESR1 is a susceptibility gene for fractures,
and XbaI determines fracture risk by mechanisms independent
of BMD. Our study demonstrates the value of adequately powered studies with
standardized genotyping and clinical outcomes in defining effects of common
genetic variants on complex diseases.
Abstract Introduction The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between ...bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1 , although these studies have yielded conflicting results. Methods We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G − 1639 -A (G − 800 -A, rs1800468), C − 1348 -T (C − 509 -T, rs1800469), T29 -C (Leu10Pro, rs1982073), G74 -C (Arg25Pro, rs1800471) and C788 -T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures. Results There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (− 12 mg/cm2 ) in men with the T − 1348 allele ( p < 0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09–2.64), p < 0.05. Conclusions This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C − 1348 -T and lumbar spine BMD in men and between C788 -T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.