Search tips
Search criteria

Results 1-8 (8)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis 
Jama  2008;299(11):1277-1290.
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.
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.
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.
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.
PMCID: PMC3282142  PMID: 18349089
2.  Loci at chromosomes 13, 19 and 20 influence age at natural menopause 
Nature genetics  2009;41(6):645-647.
We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; −0.4 year per T allele (39%); P = 6.3 × 10−11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10−11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10−8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.
PMCID: PMC3000545  PMID: 19448619
3.  SIRT1 Genetic Variation Is Related to BMI and Risk of Obesity 
Diabetes  2009;58(12):2828-2834.
SIRT1 has pleiotropic metabolic functions. We investigated whether SIRT1 genetic variation is associated with obesity.
In 6,251 elderly subjects from the prospective, population-based Rotterdam Study, three single nucleotide polymorphisms (SNPs) in the SIRT1 gene were studied in relation to BMI and risk of obesity (BMI ≥30 kg/m2) and prospectively with BMI change after 6.4 years of follow-up. We used cross-sectional data from 2,347 participants from the Erasmus Rucphen Family (ERF) study for replication.
Minor alleles of rs7895833 (G = 20.2%) and rs1467568 (A = 36.8%) were associated with lower BMI in the Rotterdam Study (P = 0.02 and 0.04) and in the replication cohort ERF study (P = 0.03 and 0.008) and in both studies combined (P = 0.002 for both SNPs), with a 0.2–0.4 kg/m2 decrease in BMI per allele copy. Carriers of these alleles had 13–18% decreased risk of obesity (for rs7895833 in the Rotterdam Study: odds ratio 0.79 [95% CI 0.67–0.94], P = 0.007; in the ERF study: 0.93 [0.73–1.19], P = 0.37; and in the studies combined 0.87 [0.77–0.97], P = 0.02; for rs1467568 in the Rotterdam Study: 0.80 [0.68–0.94], P = 0.007; in the ERF study: 0.85 [0.72–0.99], P = 0.04; and in the studies combined: 0.82 [0.73–0.92], P = 0.0009). In the Rotterdam Study, the two variants were also associated with a lower BMI increase during 6.4 years of follow-up (P = 0.01 and 0.08).
Two common variants in SIRT1 are associated with lower BMI in two independent Dutch populations. Carriers of these variants have 13–18% decreased risk of obesity and gain less weight over time. The availability of SIRT1 stimulators makes these findings relevant in light of the growing obesity epidemic.
PMCID: PMC2780870  PMID: 19741164
4.  Vitamin D Binding Protein Genotype and Osteoporosis 
Calcified Tissue International  2009;85(2):85-93.
Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D3 for haplotype 1 (P = 3 × 10−4) and haplotype 2 (P = 3 × 10−6), respectively. Similar associations were observed for 1,25-(OH)2D3. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06–2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism.
PMCID: PMC2729412  PMID: 19488670
DBP; VDR; Haplotype; Calcium intake; Fracture
5.  A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation 
Human Molecular Genetics  2009;18(18):3516-3524.
Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (Pcombined = 3.4 × 10−9). Notably, a second SNP (rs6718438) located ∼450 bp away and in strong LD (r2 = 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (Pcombined = 2.1 × 10−7). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.
PMCID: PMC2729669  PMID: 19570815
6.  The -1997 G/T and Sp1 Polymorphisms in the Collagen Type I alpha1 (COLIA1) Gene in Relation to Changes in Femoral Neck Bone Mineral Density and the Risk of Fracture in the Elderly: The Rotterdam Study 
Calcified Tissue International  2007;81(1):18-25.
The COLIA1 Sp1 polymorphism has been associated with bone mineral density (BMD) and fracture. A promoter polymorphism, -1997 G/T, also has been associated with BMD. In this study, we examined whether these polymorphisms alone and in the form of haplotypes influence bone parameters and fracture risk in a large population-based cohort of elderly Caucasians. We determined the COLIA1 -1997 G/T (promoter) and Sp1 G/T (intron) polymorphisms in 6,280 individuals and inferred haplotypes. Femoral neck BMD and BMD change were compared across COLIA1 genotypes at baseline and follow-up (mean 6.5 years). We also investigated the relationship between the COLIA1 polymorphisms and incident nonvertebral fractures, which were recorded during a mean follow-up period of 7.4 years. Vertebral fractures were assessed by radiographs on 3,456 genotyped individuals. Femoral neck BMD measured at baseline was 3.8% lower in women carrying two copies of the T-Sp1 allele (P for trend = 0.03). No genotype dependent differences in BMD loss were observed. In women homozygous for the T allele of the Sp1 polymorphism, the risk of fragility fracture increased 2.3 times (95% confidence interval 1.4–3.9, P = 0.001). No such association was observed with the promoter polymorphism. In men, no association with either the Sp1 or the -1997 G/T promoter polymorphism was seen with BMD or fracture. High linkage disequilibrium (LD; D′ = 0.99, r2 = 0.03) exists between the two studied polymorphisms. We observed three haplotypes in our population: haplotype 1 (Gpromoter–Gintron) frequency (f) = 69%, haplotype 2 (Gpromoter–Tintron) f = 17.6%, and haplotype 3 (Tpromoter–Gintron) f = 13.4%. Haplotype 2 was associated with a 2.1-fold increased risk of fragility fracture in women (95% confidence interval 1.2–3.7, P = 0.001). We confirm that the COLIA1 Sp1 polymorphism influences BMD and the risk of fracture in postmenopausal Caucasian women. In contrast, we found no independent effect of the -1997 G/T promoter polymorphism on BMD or fracture.
PMCID: PMC1914224  PMID: 17551768
Bone; Osteoporosis; Bone mineral density; Fracture; COLIA1
8.  Large-Scale Evidence for the Effect of the COLIA1 Sp1 Polymorphism on Osteoporosis Outcomes: The GENOMOS Study  
PLoS Medicine  2006;3(4):e90.
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 2), ( 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.
PMCID: PMC1370920  PMID: 16475872

Results 1-8 (8)