Introduction. The association of bone morphogenetic protein 2 (BMP2) with BMD and risk of fracture was suggested by a recent linkage study, but subsequent studies have been contradictory. We report the results of a study of the relationship between BMP2 genotypes and BMD, annual change in BMD, and risk of fracture in male subjects. Materials and Methods. We tested three single-nucleotide polymorphisms (SNPs) across the BMP2 gene, including Ser37Ala SNP, in 342 Caucasian Englishmen, comprising 224 control and 118 osteoporotic subjects. Results. BMP2 SNP1 (Ser37Ala) genotypes were found to have similar low frequency in control subjects and men with osteoporosis. The major informative polymorphism, BMP2 SNP3 (Arg190Ser), showed no statistically significant association with weight, height, BMD, change in BMD at hip or lumbar spine, and risk of fracture. Conclusion. There were no genotypic or haplotypic effects of the BMP2 candidate gene on BMD, change in BMD, or fracture risk identified in this cohort.
A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor β gene (ESR2) is located.
The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation.
This was a population‐based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene.
The study was conducted at an academic research laboratory and medical center.
Patients and Other Participants
A total of 411 healthy men (aged 18–61 yr) and 1291 healthy premenopausal women (aged 20–50 yr) living in Indiana participated in the study.
There were no interventions.
Main Outcome Measure(s)
The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine.
Significant association of spine BMD was found with three SNPs in men and one SNP in women (P ≤ 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage.
ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.
Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-011-0972-2) contains supplementary material, which is available to authorized users.
A case–control study was conducted to examine the association between two single nucleotide polymorphisms (SNPs) in exon 2 of the bone morphogenetic protein-2 gene (BMP-2) and ossification of the posterior longitudinal ligament (OPLL), and to investigate whether SNPs of the Ser37Ala (T/G) and the Ser87Ser (A/G) in the BMP-2 gene are associated with genetic susceptibility to OPLL and its severity in Chinese subjects. The Ser87Ser (A/G) SNP has been implicated in bone mineral density (BMD) and increases the risk of OA in women. The Ser37Ala (T/G) SNP is associated with BMD and the rate of bone loss in osteoporosis and osteoporosis fractures. A total of 57 OPLL patients and 135 non-OPLL controls were studied. Radiographs of the cervical spine were analyzed to determine the presence and the severity of OPLL. The association of two SNPs with the occurrence and the extent of OPLL were statistically evaluated. There was a significant association between the Ser37Ala (T/G) polymorphism and the occurrence of OPLL in the cervical spine. However, no significant association was found between the Ser37Ala (T/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. There was a significant association between the Ser87Ser (A/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. However, there was no statistical difference between the Ser87Ser (A/G) SNP and the occurrence of OPLL in the cervical spine. In addition, the Ser87Ser (A/G) polymorphism in male patients and in female patients showed no statistical difference between cases and controls. The present results demonstrate that BMP-2 Gene is not only a factor associated with the occurrence of OPLL, but also a factor related to more extensive OPLL. The “G” allele in the Ser37Ala (T/G) polymorphism is associated with the occurrence of OPLL, but not more extensive OPLL in the cervical spine. The “G” allele in the Ser87Ser (A/G) polymorphism promotes the extent of OPLL, whereas the “A” allele in the Ser87Ser (A/G) polymorphism restricts ectopic ossification in the cervical spine at least in Chinese subjects.
OPLL; BMP-2 gene; PCR; Polymorphism; Case–control study
Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the
COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of
COLIA1 alleles in relation to these phenotypes.
Methods and Findings
Here we evaluated the role of
COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm
2 (CI, 16 to 34 mg/cm
2) lower in TT homozygotes than the other genotype groups (
p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm
2 (CI, 1 to 42 mg/cm
p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.
Allowing for the inevitable heterogeneity between participating teams, this study—which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene—demonstrates that the
COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.
A large collaborative European study finds only weak links between a much studied potential genetic risk factor and bone mineral density or fracture risk.
Background: The gene encoding oestrogen receptor α (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.
Objective: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.
Results: There was a significant association between a common haplotype "px", defined by the PvuII andXbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were ∼14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.
Conclusions: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.
Osteoporosis is a common disease with a strong genetic component. We previously described a polymorphic Sp1 binding site in the COL1A1 gene that has been associated with osteoporosis in several populations. Here we explore the molecular mechanisms underlying this association. A meta-analysis showed significant associations between COL1A1 “s” alleles and bone mineral density (BMD), body mass index (BMI), and osteoporotic fractures. The association with fracture was stronger than expected on the basis of the observed differences in BMD and BMI, suggesting an additional effect on bone strength. Gel shift assays showed increased binding affinity of the “s” allele for Sp1 protein, and primary RNA transcripts derived from the “s” allele were approximately three times more abundant than “S” allele–derived transcripts in “Ss” heterozygotes. Collagen produced from osteoblasts cultured from “Ss” heterozygotes had an increased ratio of α1(I) protein relative to α2(I), and this was accompanied by an increased ratio of COL1A1 mRNA relative to COL1A2. Finally, the yield strength of bone derived from “Ss” individuals was reduced when compared with bone derived from “SS” subjects. We conclude that the COL1A1 Sp1 polymorphism is a functional genetic variant that predisposes to osteoporosis by complex mechanisms involving changes in bone mass and bone quality.
Osteoporosis is a major public health problem. It is mainly characterized by low bone mineral density (BMD) and/or low-trauma osteoporotic fractures (OF), both of which have strong genetic determination. The specific genes influencing these phenotypic traits, however, are largely unknown. Using the Affymetrix 500K array set, we performed a case-control genome-wide association study (GWAS) in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip OF and 516 controls. We found that a SNP, rs13182402 within the ALDH7A1 gene on chromosome 5q31, was strongly associated with OF with evidence combined GWAS and replication studies (P = 2.08×10−9, odds ratio = 2.25). In order to explore the target risk factors and potential mechanism underlying hip OF risk, we further examined this candidate SNP's relevance to hip BMD both in Chinese and Caucasian populations involving 9,962 additional subjects. This SNP was confirmed as consistently associated with hip BMD even across ethnic boundaries, in both Chinese and Caucasians (combined P = 6.39×10−6), further attesting to its potential effect on osteoporosis. ALDH7A1 degrades and detoxifies acetaldehyde, which inhibits osteoblast proliferation and results in decreased bone formation. Our findings may provide new insights into the pathogenesis of osteoporosis.
Osteoporosis is a major health concern worldwide. It is a highly heritable disease characterized mainly by low bone mineral density (BMD) and/or osteoporotic fractures. However, the specific genetic variants determining risk for low BMD or OF are largely unknown. Here, taking advantage of recent technological advances in human genetics, we performed a genome-wide association study and follow-up validation studies to identify genetic variants for osteoporosis. By examining a total of 11,568 individuals from Chinese and Caucasian populations, we discovered a susceptibility gene, ALDH7A1, which is associated with hip osteoporotic fracture and BMD. ALDH7A1 might inhibit osteoblast proliferation and decrease bone formation. Our finding opens a new avenue for exploring the pathophysiology of osteoporosis.
Osteoporosis is a common skeletal disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Bone mineral density (BMD) is considered the best established risk factor for osteoporotic fractures.
Over the last years a large number of studies have pointed to the variability in many target genes and their relation with BMD and other determinants of fracture risk such as ultrasound bone properties, skeletal geometry and bone turnover markers. The importance of genetic factors in the bone quality is substantial, but no consensus exists yet on the genes that are involved.
Although osteoporosis is world healthy problem, there are many differences in human ethnics regarding both disease morbidity and drug treatment efficacy. Heterogeneity in drug response may reflect varying responsiveness to osteoporosis treatments due to allele variation in signaling pathway genes such as vitamin D receptor (VDR) or estrogen receptor α (ERα). Polymorphisms of VDR and ERαloci appear genetic determinants of their corresponding hormonal treatment response such as vitamin D and estrogens. Because of their specific ethnic distribution, polymorphisms of VDR and ERαgenes may be involved in reported human differences of osteoporosis treatment responses.
Knowledge of the molecular and functional consequences of the gene polymorphisms is crucial to fully appreciate their significance and understand their potential clinical implications. Future studies and preventive strategies to management osteoporosis need to take in account these genetic factors.
genetics; estrogen receptor; osteoporosis; pharmacogenomics; polymorphism; vitamin D receptor
Genome-wide association studies (GWAS) using high-density array of single-nucleotide polymorphisms (SNPs) offer an unbiased strategy to identify new candidate genes for osteoporosis.
We used a subset of autosomal SNPs from the Affymetrix 500K+50K SNP GeneChip marker set to examine genetic linkage with multiple highly heritable osteoporosis-related traits, including BMD of the hip and spine, heel ultrasound (attenuation and speed of sound), and geometric indices of the hip, in two generations from the Framingham Osteoporosis Study. Variance component linkage analysis was performed using normalized residuals (adjusted for age, height, BMI, and estrogen status in women).
Multipoint linkage analyses produced LOD scores ≥ 3.0 for BMD on chromosomes (chr.) 9 and 11, and for ultrasound speed of sound on chr. 5. Hip geometric traits were linked with higher LOD scores, such as with Shaft Width on chr. 4 (LOD = 3.9) and chr. 16 (LOD = 3.8), and with Shaft section modulus on chr. 22 (LOD = 4.0). LOD score ≥ 5.0 was obtained for femoral Neck Width on chr. 7.
In conclusion, with a SNP-based linkage approach, we identified several novel potential QTLs and confirmed previously identified chromosomal regions linked to bone mass and geometry. Subsequent focus on the spectrum of genetic polymorphisms in these refined regions may contribute to finding variants predisposing to osteoporosis.
quantitative trait loci; BMD; bone geometry; osteoporosis; SNP array
Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis Program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes.
Materials and Methods
The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual x-ray absorptiometry (DXA) in 879 participants (mean age ± SD = 49.8 ± 16.1 yrs, range 18–91 yrs) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed.
The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD=2.36). In sub-group analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD ≥ 2.3 except for our linkage at 17q11.2–13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report.
We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2–12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.
hip structural phenotype; bone geometry; heritability; genetics; autosome-wide scan
Increased rates of osteoporotic fractures represent a worldwide phenomenon, which result from a progressing aging in the population around the world and creating socioeconomic problems. This review will focus mostly on human genetic studies identifying genomic regions, genes and mutations associated with osteoporosis (bone mineral density (BMD) and bone loss) and related fractures, which were published during 2011. Although multiple genome-wide association studies (GWAS) were performed to date, the genetic cause of osteoporosis and fractures has not yet been found, and only a small fraction of high heritability of bone mass was successfully explained. GWAS is a successful tool to initially define and prioritize specific chromosomal regions showing associations with the desired traits or diseases. Following the initial discovery and replication, targeted sequencing is needed in order to detect those rare variants which GWAS does not reveal by design. Recent GWAS findings for BMD included WNT16 and MEF2C. The role of bone morphogenetic proteins in fracture healing has been explored by several groups, and new single-nucleotide polymorphisms present in genes such as NOGGIN and SMAD6 were found to be associated with a greater risk of fracture non-union. Finding new candidate genes, and mutations associated with BMD and fractures, also provided new biological connections. Thus, candidates for molecular link between bone metabolism and lactation (for example, RAP1A gene), as well as possible pleiotropic effects for bone and muscle (ACTN3 gene) were suggested. The focus of contemporary studies seems to move toward whole-genome sequencing, epigenetic and functional genomics strategies to find causal variants for osteoporosis.
Osteoporosis and related fractures are a significant concern for the global community. As the population continues to age, morbidity and mortality from fractures due to low bone mineral density (BMD) will likely continue to increase. Efforts should be made to screen those at risk for osteoporosis, identify and address various risk factors for falls and associated fractures, ensure adequate calcium and vitamin D intake, and institute pharmacological therapy to increase BMD when indicated. Agents which increase BMD and have been shown to decrease fractures, particularly at the hip, should be considered preferentially over those for which only BMD data are available. Drugs which have been shown to decrease the risk of age-related osteoporotic fractures include oral bisphosphonates (alendronate, ibandronate, and risedronate), intranasal calcitonin, estrogen receptor stimulators (eg, estrogen, selective estrogen receptor modulators [raloxifene]), parathyroid hormone (teriparatide), sodium fluoride, and strontium ranelate. Data are beginning to emerge supporting various combination therapies (eg, bisphosphonate plus an estrogen receptor stimulator), though more data are needed to identify combinations which are most effective and confer added fracture protection. In addition, further research is needed to identify ideal regimens in special populations such as nursing home patients and men.
osteoporosis; fracture; prevention; treatment
Osteoporosis is a bone disorder that reduces bone mineral density (BMD) and
leads to bone fracture. In addition to different factors, gene polymorphisms have been
revealed to be associated with osteoporosis. In this study, we investigated the association
between the BsmI polymorphism of vitamin D receptor (VDR) gene (rs1544410) and BMD
in a population of Iranian women.
Materials and Methods:
In this case control study, clinical risk factors for osteoporosis
were obtained from the participants through a questionnaire for a case-control study.
The World Health Organisation (WHO) criteria were applied for the diagnosis of the
disease. Peripheral blood samples were obtained from 146 pre- and or postmenopausal
Iranian women aged between 35 and 71 years (53.53 ± 9.8). The study population
was classified for BMD into normal and osteoporotic groups, who matched for age,
pregnancy status, menstrual condition, and body mass index (BMI). The BMD of the
lumbar spine (L1-4) and femoral neck was measured. Polymerase chain reactionrestriction
fragment length polymorphism (PCR-RFLP) was performed to detect and
analyze the genotype.
The frequencies of AA and GG were significantly different between the two
groups (p value<0.05), with the first genotype being higher in the patients and the second
being higher in the normal group. The GG genotype was significantly associated with
increased BMD in the lumbar spine (p value<0.05) but non-significant in the femoral neck
BsmI polymorphism of VDR gene has a significant association with BMD in
the lumbar spine and may have a minor effect on the proximal femur BMD in Iranian women.
Vitamin D Receptor; BsmI; Polymorphism; Bone Mineral Density; Osteoporosis
This study assessed whether relatives with low bone mineral density (BMD) could be identified in five large families using historical, biochemical, and genetic markers for osteoporosis. Fifty of 65 relatives had their bone density and bone turnover markers measured, together with an assessment of their risk factors for osteoporosis. Only 33% (5/15) of siblings, 50% (6/12) of children and 43% (10/23) of nephews and nieces had entirely normal BMD. There was no difference in life-style risk factors for osteoporosis, history of previous fractures or body mass index between normal subjects and those with osteopenia or osteoporosis. Osteopenic individuals had a significantly higher than normal osteocalcin value. Within families, there was no clear association between BMD and any of the genetic markers (vitamin D receptor gene polymorphisms, COL 1A1 and COL 1A2 polymorphisms of the collagen gene), either alone or in combination. The addition of genetic markers to the other risk factors for low BMD did not improve the prediction of BMD. In conclusion, we suggest that the presence of osteoporosis in a first degree relative should be one of the clinical indications for bone density measurement as the individuals at risk would not be picked up by other methods.
Postmenopausal osteoporosis is the most common bone disease, associated with low bone mineral
density (BMD) and pathological fractures which lead to significant morbidity. It is defined
clinically by a BMD of 2.5 standard deviations or more below the young female adult mean (T-score
=−2.5). Osteoporosis was a huge global problem both socially and economically
– in the UK alone, in 2011 £6 million per day was spent on treatment and social care
of the 230,000 osteoporotic fracture patients – and therefore viable preventative and
therapeutic approaches are key to managing this problem within the aging population of today. One of
the main issues surrounding the potential of osteoporosis management is diagnosing patients at risk
before they develop a fracture. We discuss the current and future possibilities for identifying
susceptible patients, from fracture risk assessment to shape modeling and in relation to the high
heritability of osteoporosis now that a plethora of genes have been associated with low BMD and
osteoporotic fracture. This review highlights the current therapeutics in clinical use (including
bisphosphonates, anti-RANKL [receptor activator of NF-κB ligand],
intermittent low dose parathyroid hormone, and strontium ranelate) and some of those in development
(anti-sclerostin antibodies and cathepsin K inhibitors). By highlighting the intimate relationship
between the activities of bone forming (osteoblasts) and bone-resorbing (osteoclasts) cells, we
include an overview and comparison of the molecular mechanisms exploited in each therapy.
BMD; fracture; bisphosphonate; strontium; denosumab; teriparatide; raloxifene
Candidate osteoporosis gene variants were examined for associations with fracture risk and bone mineral density (BMD). A total of 9704 white women were recruited at four U.S. clinical centers and enrolled into the Study of Osteoporotic Fractures, a longitudinal cohort study. Genotyping of 31 polymorphisms from 18 candidate osteoporosis genes was performed in 6752 women. Incident radiographic fractures were identified at the third and eighth examinations compared with the baseline examination. BMD was measured at the total hip by dual-energy X-ray absorptiometry. Analyses were adjusted for age, clinic site, and self-reported ethnicity. During a mean follow-up of 14.5 years, a total of 849 hip, 658 vertebral, and 2496 nonhip/nonvertebral fractures occurred in 6752 women. Women carrying the ALOX15_G48924T T/T genotype had a higher rate of hip fracture (hazard ratio [HR] = 1.33;95% confidence interval [95% CI] = 1.00–1.77) compared with the G/G genotype. Compared with those carrying the PRL_T228C T/T genotype, women with either the C/C (HR = 0.80; 95% CI = 0.67–0.95) or C/T (HR = 0.81; 95% CI = 0.68–0.97) genotype had a lower rate of nonvertebral/nonhip fractures. Women carrying theBMP2_A125611G G/G genotype had a higher rate of vertebral fracture (odds ratio [OR] = 1.51; 95% CI = 1.03–2.23) compared with the A/A genotype. Women with the ESR1_C1335G G/G genotype had a higher rate of vertebral fracture (OR = 1.64; 95% CI = 1.07–2.50) compared with the C/C genotype. Compared with those with the MMP2_C595T C/C genotype, women with the C/T (OR = 0.79; 95% CI = 0.65–0.96) or T/T (OR = 0.44; 95% CI = 0.27–0.72) genotype had a lower rate of vertebral fracture. In conclusion, polymorphisms in several candidate genes were associated with hip, vertebral, and nonhip/nonvertebral fractures but not with total hip BMD in this large population based cohort study.
Genetics; Polymorphism; Osteoporosis; BMD; Fracture
Osteoporotic fractures are a leading cause of disability and, indirectly, of death in the elderly population. Previous studies have shown that homocysteine level and the C677T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) may be involved in the development of osteoporosis and its related fracture in European populations. The aim of this study was to verify the association of this polymorphism with bone mineral density (BMD) and fractures in our 1899 Chinese postmenopausal women. The C677T T-allele frequency in this population was 39.2%. The distribution of the MTHFR genotypes followed the Hardy-Weinberg equilibrium. BMD at total body, total hip or femoral neck did not significantly vary with MTHFR C677T genotype. The T-allele carrier tended to have higher risk of having osteoporosis or osteopenia, but the difference was statistically insignificant. However, Poisson regression analysis revealed that the T-allele carriers had an increased risk of fractures (RR=1.7, 95%CI=1.1–2.7, p=0.01) which occurred before or after menopause. As far as fracture incidence after menopause was concerned, the CT or TT genotype had more than twice the risk of the CC genotype (RR=2.5, 95%CI=1.2–4.9, P=0.009). This association was independent of age, physical activity, occupation, passive smoking, height, weight, years since menopause, and total hip BMD.
Our data show that the MTHFR C677T polymorphism is an independent predictor of fracture risk, although it only had a weak effect on BMD. Further study on the mechanistic role that this polymorphism plays in the development of fractures may lead to better understanding of the etiology of osteoporotic fracture.
Methylenetetrahydrofolate Reductase Gene; Fracture; Osteoporosis; Genetics; Postmenopausal Women
Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.
Osteoporosis is a heritable disease characterized mainly by low bone mineral density (BMD) and/or osteoporotic fractures (OF). Most genome-wide association studies on osteoporosis have focused on BMD, whereas little effort has been expended to identify genetic variants directly linked to OF. To determine whether BMD-loci are also associated with OF risk, we performed a validation study to examine 23 BMD-loci reported by recent genome-wide association studies for association with hip OF risk. Our sample consisted of 700 elderly Chinese Han subjects, 350 with hip OF and 350 healthy matched controls. We identified four BMD-loci that were significantly associated with hip OF in this Chinese population, including 7q21 (FLJ42280, P = 1.17 × 10−4 for rs4729260; P = 0.008 for rs7781370), 6p21 (MHC, P = 0.004 for rs3130340), 13q14 (TNFSF11, P = 0.012 for rs9533090; P = 0.018 for rs9594759; P = 0.020 for rs9594738; P = 0.044 for rs9594751), and 18q21 (TNFRSF11A, P = 0.015 for rs884205). The SNP rs4729260 at 7q21 remained significantly associated, even after conservative Bonferroni’s correction. Our results further highlight the importance of these loci in the pathogenesis of osteoporosis, and demonstrate that it is feasible and useful to use OF as the direct phenotype to conduct genetic studies, to enhance our understanding of the genetic architecture of osteoporosis.
Osteoporotic fractures; Genome-wide association studies; BMD; SNP
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low
bone mineral density (BMD) is a major predisposing factor to fracture and is
known to be highly heritable. Site-, gender-, and age-specific genetic effects
on BMD are thought to be significant, but have largely not been considered in
the design of genome-wide association studies (GWAS) of BMD to date. We report
here a GWAS using a novel study design focusing on women of a specific age
(postmenopausal women, age 55–85 years), with either extreme high or low
hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0,
n = 1055, or −4.0 to −1.5,
n = 900), with replication in cohorts of women drawn from
the general population (n = 20,898). The study replicates
21 of 26 known BMD–associated genes. Additionally, we report suggestive
association of a further six new genetic associations in or around the genes
CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and
SOX4, with replication in two independent datasets. A novel
mouse model with a loss-of-function mutation in GALNT3 is also
reported, which has high bone mass, supporting the involvement of this gene in
BMD determination. In addition to identifying further genes associated with BMD,
this study confirms the efficiency of extreme-truncate selection designs for
quantitative trait association studies.
Osteoporotic fracture is a major cause of early mortality and morbidity in the
community. To identify genes associated with osteoporosis, we have performed a
genome-wide association study. In order to improve study power and to address
the demographic group of highest risk from osteoporotic fracture, we have used a
unique study design, studying 1,955 postmenopausal women with either extreme
high or low hip bone mineral density. We then confirmed our findings in 20,898
women from the general population. Our study replicated 21 of 26 known
osteoporosis genes, and it identified a further six novel loci (in or nearby
CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and
SOX4). For one of these loci, GALTN3, we
demonstrate in a mouse model that a loss-of-function genetic mutation in
GALNT3 causes high bone mass. These findings report novel
mechanisms by which osteoporosis can arise, and they significantly add to our
understanding of the aetiology of the disease.
Osteoporosis is a complex metabolic bone disorder. Recently it has been
appreciated that the “obesity in bone” phenomenon occurs at the expense of bone formation, and that is a key component of the pathology of this disease. Mouse models
with altered bone expression levels of peroxisome proliferator-activated receptor gamma
(PPARG) impact bone formation, but genetic studies connecting PPARG polymorphisms to skeletal phenotypes in humans have proven to be less than satisfactory. One missense polymorphism in exon one has been linked to low bone mineral density (BMD), but the most studied polymorphism, Pro12Ala, has not yet been examined in the context of skeletal phenotype. The studies to date are a promising start in leading to our understanding of the genetic contribution of PPARG to the phenotypes of BMD and fracture risk.
A significant number of patients who have experienced previous surgical treatment for an osteoporotic hip fracture experience a subsequent hip fracture (SHF) on the opposite side. This study aims to analyze the risk factors and the correlation between osteoporosis and SHF on the opposite side in order to assess the usefulness of bisphosphonate treatment for the prevention of SHFs.
Materials and Methods
We included 517 patients treated from March 1997 to April 2009 in this study. The inclusion criteria included previous unilateral hip fracture, without osteoporotic treatment, and a T-score less than -3.0 at the time of the fracture. We studied these patients in terms of death, SHF, alcoholism, living alone, dementia, dizziness, health status, osteoporotic treatment after fracture and bone mineral density (BMD). In total, 34 patients experienced a SHF. We selected another 34 patients without a SHF who had similar age, sex, body mass index, BMD, diagnosis, treatment and a follow up period for a matched pair study. We compared these two groups. The average follow up was 8.3 years and 8.1 years, respectively.
The mortality rate of the 517 patients was 138 (27%). The BMD at the time of fracture demonstrated no statistical difference between the two groups (p>0.05). Nine patients (26%) within the SHF group were prescribed Risedronate and 18 patients (53%) received the same treatment in the non-SHF group. There was a statistical relationship with the treatment of osteoporosis (p=0.026). The average BMD of patients with SHF was -5.13 and -5.02 in patients without SHF was (p>0.05).
Although primary surgical treatments are important for an excellent outcome in osteoporotic hip fractures, treatment of osteoporosis itself is just as important for preventing SHFs.
Hip fracture; osteoporosis; bone mineral density; subsequent fracture
Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future.
The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis.
We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).
Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the −2,327 bp upstream (P = 6.8 × 10−4) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA.
Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-011-1861-1) contains supplementary material, which is available to authorized users.
Association; BMD; CDX1; Periostin; Vertebral fracture
Bone mineral density (BMD) is a strong predictor of fracture, yet most fractures occur in women without osteoporosis by BMD criteria. To improve fracture-risk prediction, the World Health Organization recently developed a country-specific fracture risk index of clinical risk factors (FRAX®) that estimates 10-year probabilities of hip and major osteoporotic fracture. Within differing baseline BMD categories, we evaluated 6252 women age 65 and older in the Study of Osteoporotic Fractures using FRAX 10-year probabilities of hip and major osteoporotic fracture (hip, clinical spine, wrist, humerus) compared to incidence of fractures over 10 years of follow-up. Overall ability of FRAX to predict fracture risk based on initial BMD T-score categories (normal, low bone mass, and osteoporosis) was evaluated with receiver-operating-characteristic (ROC) analyses using area-under-the-curve (AUC). Over 10 years of follow-up, 368 women incurred a hip fracture, and 1011 a major osteoporotic fracture. Women with low bone mass represented the majority (n=3791; 61%); they developed many hip (n=176; 48%) and major osteoporotic fractures (n=569; 56%). Among women with normal and low bone mass, FRAX (including BMD) was an overall better predictor of hip fracture risk (AUC = 0.78 and 0.70, respectively) than major osteoporotic fractures (AUC = 0.64 and 0.62). Simpler models (e.g., age+prior fracture) had similar AUCs to FRAX, including among women for whom primary prevention is sought (no prior fracture or osteoporosis by BMD). The FRAX, and simpler models, predict 10-year risk of incident hip and major osteoporotic fractures in older U.S. women with normal or low bone mass.
osteopenia; osteoporosis; fracture; risk; prediction