Biomedical subjects

Robert R Recker

Publications and source records attributed to Robert R Recker.

At least 19 recordsLinked to original sources

PubMed2007

Treatment of skeletally mature ovariectomized rhesus monkeys with PTH(1-84) for 16 months increases bone formation and density and improves trabecular architecture and biomechanical properties at the lumbar spine.

UNLABELLED: Histomorphometric studies of treatments for osteoporosis in humans are restricted to iliac crest biopsies. We studied the effects of PTH(1-84) treatment at the lumbar spine of skeletally mature ovariectomized rhesus monkeys. PTH increased bone turnover, rapidly normalized BMD, and increased vertebral compressive strength. PTH increased trabecular bone volume primarily by increasing trabecular number by markedly increasing intratrabecular tunneling. INTRODUCTION: Histomorphometric studies of the anabolic properties of PTH(1-84) (PTH) and related peptides in human bone are restricted to iliac crest biopsies. The ovariectomized (OVX) monkey is an accepted model of human postmenopausal bone loss and was used to study the effects of PTH treatment at clinically relevant skeletal sites. MATERIALS AND METHODS: Skeletally mature rhesus monkeys were OVX or sham-operated and, after a bone depletion period of 9 months, treated daily for 16 months with PTH (5, 10, or 25 microg/kg). Markers of bone formation (serum osteocalcin) and resorption (urine N-telopeptide [NTX]) and lumbar spine BMD were measured throughout the study. Trabecular architecture and vertebral biomechanical properties were quantified at 16 months. RESULTS: PTH treatment induced dose-dependent increases in bone turnover but did not increase serum calcium. Osteocalcin was significantly increased above OVX controls by 1 month. NTX was significantly elevated at 1 month with the highest dose, but not until 12 months with the 5 and 10 microg/kg doses. Lumbar spine BMD was 5% lower in OVX than in sham animals when treatment was started. All PTH doses increased BMD rapidly, with sham levels restored by 3-7 months with 10 and 25 microg/kg and by 16 months with 5 microg/kg. PTH treatment increased trabecular bone volume (BV/TV), primarily by increasing trabecular number, and dose-dependently increased bone formation rate (BFR) solely by increasing mineralizing surface. The largest effects on BV/TV and yield load occurred with the 10 microg/kg dose. The highest dose reduced trabecular thickness by markedly increasing intratrabecular tunneling. CONCLUSIONS: PTH treatment of OVX rhesus monkeys increased bone turnover and increased BV/TV, BMD, and strength at the lumbar spine. All PTH doses were safe, but the 10 microg/kg dose was generally optimal, possibly because the highest dose resulted in too marked a stimulation of bone remodeling.

Animals↗

PubMed2006

Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass.

UNLABELLED: The double-blind, randomized raloxifene alendronate comparison trial was the first study designed to compare two osteoporosis therapies head-to-head for fracture risk reduction. The original protocol planned to treat 3000 postmenopausal women with alendronate 10 mg/day (ALN) or raloxifene 60 mg/day (RLX) for 5 years, and to recruit women (50-80 years old) with a femoral neck bone mineral density (BMD) T-score between -2.5 and -4.0, inclusive, no prevalent vertebral fractures, and no prior bone-active agent use. The trial was stopped early, due to difficulty in finding treatment-naïve women to meet enrollment goals within the planned timeline, resulting in insufficient power to show non-inferiority between therapies in the primary endpoint (number of women with >or=1 new osteoporotic vertebral or nonvertebral fracture). Except for vertebral fractures, fracture analyses were based upon 1412 of the 1423 women randomized (mean age of 66 years). After 312+/-254 days (mean+/-SD), 22 women in the ALN group and 20 in the RLX group had new vertebral or nonvertebral fractures. Four women in the ALN group and none in the RLX group had moderate/severe vertebral fractures, a pre-specified endpoint (P=0.04). Lumbar spine, femoral neck, and total hip BMD were increased from baseline at 2 years in each group (P<0.001), with greater increases in the ALN group (each P<0.05). Similar numbers of women in each group had >or=1 adverse event and discontinued due to an adverse event. The only adverse events with an incidence that differed between groups were colonoscopy, diarrhea, and nausea; each was more common with ALN treatment (each P<0.05). One woman in each group had a venous thromboembolic event. One case of breast cancer occurred in each group. In summary, as this trial was terminated early, there was insufficient power to compare the fracture risks between alendronate and raloxifene. Safety profiles were as expected from clinical trial and post-marketing reports. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00035971.

Aged↗

PubMed2006

The chemokine (C-C-motif) receptor 3 (CCR3) gene is linked and associated with age at menarche in Caucasian females.

Chemokine (C-C-motif) receptor 3 (CCR3), playing an important role in endometrium related metabolic pathways, may influence the onset of menarche. To test linkage and/or association between CCR3 polymorphisms with the variation of age at menarche (AAM) in Caucasian females, we recruited a sample of 1,048 females from 354 Caucasian nuclear families and genotyped 16 SNPs spanning the entire CCR3 gene. Linkage disequilibrium and haplotype blocks were inferred by Haploview. Both single-SNP markers and haplotypes were tested for linkage and/or association with AAM using QTDT (quantitative transmission disequilibrium test). We also tested associations between CCR3 polymorphisms and AAM in a selected random sample of daughters using ANOVA (analysis of variance). We identified two haplotype blocks. Only block two showed significant results. After correction for multiple testing, significant total associations of SNP7, SNP9 with AAM were detected (P = 0.009 and 0.006, respectively). We also detected significant within-family association of SNP9 (P = 0.01). SNP14 was linked to AAM (P = 0.02) at the nominal level. In addition, there was evidence of significant total association and nominal significant linkage (P = 0.008 and 0.03, respectively) with AAM for the haplotype AGA reconstructed by SNP7, SNP9 and SNP13. ANOVA confirmed the results by QTDT. For the first time we reported that CCR3 is linked and associated with AAM variation in Caucasian women. However, further studies are necessary to substantiate our conclusions.

Aging↗

PubMed2006

A genome-wide linkage scan for quantitative trait loci underlying obesity related phenotypes in 434 Caucasian families.

To identify quantitative trait loci (QTLs) that contribute to obesity, we performed a large-scale whole genome linkage scan (WGS) involving 4,102 individuals from 434 Caucasian families. The most pronounced linkage evidence was found at the genomic region 20p11-12 for fat mass (LOD = 3.31) and percentage fat mass (PFM) (LOD = 2.92). We also identified several regions showing suggestive linkage signals (threshold LOD = 1.9) for obesity phenotypes, including 5q35, 8q13, 10p12, and 17q11.

Family↗

PubMed2006

Is a gene important for bone resorption a candidate for obesity? An association and linkage study on the RANK (receptor activator of nuclear factor-kappaB) gene in a large Caucasian sample.

In light of findings that osteoporosis and obesity may share some common genetic determination and previous reports that RANK (receptor activator of nuclear factor-kappaB) is expressed in skeletal muscles which are important for energy metabolism, we hypothesize that RANK, a gene essential for osteoclastogenesis, is also important for obesity. In order to test the hypothesis with solid data we first performed a linkage analysis around the RANK gene in 4,102 Caucasian subjects from 434 pedigrees, then we genotyped 19 SNPs in or around the RANK gene. A family-based association test (FBAT) was performed with both a quantitative measure of obesity [fat mass, lean mass, body mass index (BMI), and percentage fat mass (PFM)] and a dichotomously defined obesity phenotype-OB (OB if BMI > or = 30 kg/m(2)). In the linkage analysis, an empirical P = 0.004 was achieved at the location of the RANK gene for BMI. Family-based association analysis revealed significant associations of eight SNPs with at least one obesity-related phenotype (P < 0.05). Evidence of association was obtained at SNP10 (P = 0.002) and SNP16 (P = 0.001) with OB; SNP1 with fat mass (P = 0.003); SNP1 (P = 0.003) and SNP7 (P = 0.003) with lean mass; SNP1 (P = 0.002) and SNP7 (P = 0.002) with BMI; SNP1 (P = 0.003), SNP4 (P = 0.007), and SNP7 (P = 0.002) with PFM. In order to deal with the complex multiple testing issues, we performed FBAT multi-marker test (FBAT-MM) to evaluate the association between all the 18 SNPs and each obesity phenotype. The P value is 0.126 for OB, 0.033 for fat mass, 0.021 for lean mass, 0.016 for BMI, and 0.006 for PFM. The haplotype data analyses provide further association evidence. In conclusion, for the first time, our results suggest that RANK is a novel candidate for determination of obesity.

Adult↗

PubMed2006

Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone.

A preliminary expression profiling analysis of osteoblasts derived from tibia explants of the high bone mass LRP5 G171V transgenic mice demonstrated increased expression of canonical Wnt pathway and Wnt/beta-catenin target genes compared with non-transgenic explant derived osteoblasts. Therefore, expression of Wnt/beta-catenin target genes were monitored after in vivo loading of the tibia of LRP5 G171V transgenic mice compared with non-transgenic mice. Loading resulted in the increased expression of Wnt pathway and Wnt/beta-catenin target genes including Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43 in both genotypes; however, there was a further increased in transcriptional response with the LRP5 G171V transgenic mice. Similar increases in the expression of these genes (except cyclin D1) were observed when non-transgenic mice were pharmacologically treated with a canonical Wnt pathway activator, glycogen synthase kinase 3beta inhibitor and then subjected to load. These in vivo results were further corroborated by in vitro mechanical loading experiments in which MC3T3-E1 osteoblastic cells were subjected to 3400 microstrain alone for 5 h, which increased the expression of Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43. Furthermore, when MC3T3-E1 cells were treated with either glycogen synthase kinase 3beta inhibitor or Wnt3A to activate Wnt signaling and then subjected to load, a synergistic up-regulation of these genes was observed compared with vehicle-treated cells. Collectively, the in vivo and in vitro mechanical loading results support that Wnt/beta-catenin signaling is a normal physiological response to load and that activation of the Wnt/beta-catenin pathway enhances the sensitivity of osteoblasts/osteocytes to mechanical loading.

Animals↗

PubMed2006

HDC gene polymorphisms are associated with age at natural menopause in Caucasian women.

Histidine decarboxylase gene (HDC) encodes histidine decarboxylase which is the crucial enzyme for the biosynthesis of histidine. Studies have shown that histamine is likely to be involved in the regulation of reproduction system. To find the possible correlation between HDC gene and AANM (age at natural menopause), we selected 265 postmenopausal women from 131 nuclear families and performed a transmission disequilibrium test. Significant within-family associations with AANM for SNP rs854163 and SNP rs854158 of HDC gene were observed (P values=0.0018 and 0.0197, respectively). After 1000 permutations, SNP rs854163 still remained significant within-family association with AANM. Consistently, we also detected a significant within-family association between haplotype block 2 (defined by SNP rs854163 and rs860526) and AANM in the haplotype analyses (P value=0.0397). Our results suggest that the HDC gene polymorphisms are significantly associated with AANM in Caucasian women.

Age Factors↗

PubMed2006

Genetic and environmental correlations between bone geometric parameters and body compositions.

The purpose of this study was to determine the genetic and environmental correlations between weight, lean mass and bone geometric parameters (sub-periosteal diameter, W; cross-sectional area, CSA; cortical thickness, CT; section modulus, Z; and buckling ratio, BR) of femoral neck. The sample was composed of 512 Caucasian pedigrees, including 2667 females and 1822 males. Bivariate quantitative genetic analyses were performed to evaluate the genetic (rho(G)), environmental (rho(E)) and phenotypic (rho(P)) correlations between the study traits. Univariate genetic analyses showed that the heritabilities (h(2)) for bone geometric parameters were significant (P < 0.001) ranging from 0.50 to 0.60. The significant common household effects indicated the common environment shared by household members for W, CSA, CT, Z and BR (P < 0.05), but the magnitude was small compared with heritabilities. rho(E), rho(G) and rho(P) between bone geometric parameters and weight, lean mass were generally significant. Interestingly, lean mass showed both stronger genetic and environmental correlations with the bone geometric parameters than weight. In addition, according to the magnitude of correlation coefficients, the rho(G) between body compositions and bone geometric parameters were generally stronger than rho(E) (except for that between BR and body compositions). These data suggested that the geometric parameters of femoral neck are under strong genetic control. Furthermore, some common genetic and environmental factors are shared by bone geometric parameters and weight, lean mass. The results may help understand the intertwined relationships between bone metabolisms, mechanical loading and body compositions.

Absorptiometry, Photon↗

PubMed2006

Assessment of genetic linkage and parent-of-origin effects on obesity.

CONTEXT: Obesity is a growing health care problem worldwide and is a major underlying risk factor for common diseases such as diabetes. Parent-of-origin effect has been reported to be involved in the development of obesity. But the genes with imprinting effects related to obesity are largely unknown. OBJECTIVE: The objective of the study was to identify obesity-related genetic loci, both with and without imprinting effects. DESIGN AND SUBJECTS: We conducted genome-wide linkage analyses for obesity with and without consideration of imprinting effects in a large sample including more than 4000 individuals. In addition to body mass index (BMI), we also used a more stringent and accurate obesity definition, which simultaneously considers BMI and percentage of fat mass (PFM) in a gender-specific manner. Simulations were performed to identify the genome-wide significant and suggestive significant thresholds. RESULTS: In nonimprinted linkage analyses, we detected suggestive linkage at 2q31 (LOD = 2.23) and 16q22 (LOD = 1.87) for BMI and 2q37 (LOD = 2.23) for BMI and PFM. Interestingly, 2q37 also achieved a significant maternal linkage with BMI and PFM (LOD=3.34) in imprinted linkage analyses. Imprinted linkage analyses revealed suggestive linkage evidence for BMI at three additional genomic regions, including 3p14 (LOD = 2.20, paternal), 3q24 (LOD = 1.97, maternal), and 19q13 (LOD = 1.81, maternal). CONCLUSION: We reported linkage and imprinting effects for obesity on several chromosome regions and suggested the potential importance of parent-of-origin effects and phenotype definition of obesity in delineating the genetic basis of obesity.

Adipose Tissue↗

PubMed2006

Polymorphisms of estrogen-biosynthesis genes CYP17 and CYP19 may influence age at menarche: a genetic association study in Caucasian females.

Variation in age at menarche (AAM) is known to be substantially influenced by genetic factors, but the true causal genes remain largely unidentified. Because the increased amplitude of estrogen exposure of tissues initiates the onset of menarche, the genes involved in estrogen biosynthesis are natural candidate genes underlying AAM. Our study aimed to identify whether the CYP17 and CYP19, the two key genes involved in the biosynthesis of estrogen, are associated with AAM variation in 1048 females from 354 Caucasian nuclear families. We genotyped 38 SNPs and established the linkage disequilibrium blocks and haplotype structures that covered the full transcript length of those two genes. Family-based and population-based statistical analyses were used to test for associations with all of the single SNPs and haplotypes. Both methods consistently detected significant associations for five SNPs of CYP19 with AAM. Haplotype analyses corroborated our single-SNP results by showing that the haplotypes in block 1 were highly significant to AAM in population-based analyses. However, we could not find any association of CYP17 with AAM. Our study is the first to suggest the important effect of CYP19 on AAM variation in Caucasian females. It will be valuable to replicate and confirm these findings in other independent studies, aiming at eventually finding the hidden genetic mechanisms underlying the variation in AAM.

Adolescent↗

PubMed2006

Association analyses of CYP19 gene polymorphisms with height variation in a large sample of Caucasian nuclear families.

Human height is a complex trait regulated by multiple genetic and environmental factors. CYP19 (cytochrome P450 19) encodes aromatase, which catalyses the rate-limiting step in the conversion of androgens to estrogens. Deleterious mutations in CYP19 can result in estrogen deficiency that will influence adult height to certain extent. In the present study, we aimed to test the associations between the CYP19 gene polymorphisms with adult height variation, using family-based association methods, such as QTDT (quantitative transmission disequilibrium test) and FBAT (family-based association test) in 1,873 subjects from 405 Caucasian nuclear families. We found one SNP (rs730154) significantly associated with height by both QTDT (P=0.0030) and FBAT (P=0.0016) analyses. Haplotype analyses corroborated our single-marker results by showing that the haplotypes in block 4 containing rs730154 were significantly associated with height variation. We thus concluded that CYP19 could be one of the genetic factors influencing adult height in Caucasians. Further studies are required to identify the causal functional variants responsible for Caucasian height within the CYP19 gene.

Adult↗

PubMed2006

Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study.

BACKGROUND: The low-density lipoprotein receptor-related protein 5 (LRP5) gene, essential for glucose and cholesterol metabolism, may have a role in the aetiology of obesity, an important risk factor for diabetes. PARTICIPANTS AND METHODS: To investigate the association between LRP5 polymorphisms and obesity, 27 single-nucleotide polymorphisms (SNPs), spacing about 5 kb apart on average and covering the full transcript length of the LRP5 gene, were genotyped in 1873 Caucasian people from 405 nuclear families. Obesity (defined as body mass index (BMI) >30 kg/m(2)) and three obesity-related phenotypes (BMI, fat mass and percentage of fat mass (PFM)) were investigated. RESULTS: Single markers (12 tagging SNPs and 4 untaggable SNPs) and haplotypes (5 blocks) were tested for associations, using family-based designs. SNP4 (rs4988300) and SNP6 (rs634008) located in block 2 (intron 1) showed significant associations with obesity and BMI after Bonferroni correction (SNP4: p<0.001 and p = 0.001, respectively; SNP6: p = 0.002 and 0.003, respectively). The common allele A for SNP4 and minor allele G for SNP6 were associated with an increased risk of obesity. Significant associations were also observed between common haplotype A-G-G-G of block 2 with obesity, BMI, fat mass and PFM with global empirical values p<0.001, p<0.001, p = 0.003 and p = 0.074, respectively. Subsequent sex-stratified analyses showed that the association in the total sample between block 2 and obesity may be mainly driven by female subjects. CONCLUSION: Intronic variants of the LRP5 gene are markedly associated with obesity. We hypothesise that such an association may be due to the role of LRP5 in the WNT signalling pathway or lipid metabolism. Further functional studies are needed to elucidate the exact molecular mechanism underlying our finding.

Adult↗

PubMed2006

Genetic linkage of human height is confirmed to 9q22 and Xq24.

Human height is an important and heritable trait. Our previous two genome-wide linkage studies using 630 (WG1 study) and an extended sample of 1,816 Caucasians (WG2 study) identified 9q22 [maximum LOD score (MLS)=2.74 in the WG2 study] and preliminarily confirmed Xq24 (two-point LOD score=1.91 in the WG1 study, 2.64 in the WG2 study) linked to height. Here, with a much further extended large sample containing 3,726 Caucasians, we performed a new genome-wide linkage scan and confirmed, in high significance, the two regions' linkage to height. An MLS of 4.34 was detected on 9q22 and a two-point LOD score of 5.63 was attained for Xq24. In an independent sub-sample (i.e., the subjects not involved in the WG1 and WG2 studies), the two regions also achieved significant empirical P values (0.002 and 0.004, respectively) for "region-wise" linkage confirmation. Importantly, the two regions were replicated on a genotyping platform different from the WG1 and WG2 studies (i.e., a different set of markers and different genotyping instruments). Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature. With the largest sample from a single population of the same ethnicity in the field of linkage studies for complex traits, our current study, together with two previous ones, provided overwhelming evidence substantiating 9q22 and Xq24 for height variation. In particular, our three consecutive whole genome studies are uniquely valuable as they represent the first practical (rather than simulated) example of how significant increase in sample size may improve linkage detection for human complex traits.

Adult↗

PubMed2006

Genomewide linkage scan for quantitative trait loci underlying variation in age at menarche.

CONTEXT: Age at menarche (AAM) is an important anthropological variable that has major implications for a woman's health later in life. Genetic influence has been shown to contribute greatly to AAM, but the specific genetic determinants are largely unknown. OBJECTIVE: The objective of this study was to identify the quantitative trait loci (QTL) underlying the variations in AAM. METHODS: We performed a large-scale, genomewide, linkage scan in 2461 Caucasian women from 402 pedigrees. All subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome. Using the variance component method, we conducted multipoint linkage analyses and two-locus tests for epistatic interaction. RESULTS: The strongest linkage signal was obtained at the genomic region of 22q13 (LOD, 3.70); the other two suggestive linkages were on 22q11 (LOD, 2.68) and 11q23 (LOD, 1.98), respectively. We also detected significant epistatic interaction between genomic regions 22q13 and 3q13. CONCLUSIONS: The identification of QTL and epistatic interaction in a large female sample laid a foundation for independent replication and fine-mapping studies as well as positional and functional candidate gene studies aimed at finding the causal genetic variants and hidden mechanisms concerning the variations in AAM.

Age Factors↗

PubMed2006

Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study.

OBJECTIVE: Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. METHODS: In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55-80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2-L4] bone mineral density [BMD] T score less than -2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. RESULTS: At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. CONCLUSION: As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.

Administration, Oral↗

PubMed2006

Paternal uniparental isodisomy of the entire chromosome 3 revealed in a person with no apparent phenotypic disorders.

Uniparental disomy (UPD) is a rare genetic abnormality. During a whole genome linkage study we identified a case of paternal uniparental isodisomy 3 serendipitously. This is the first ascertained human paternal UPD for chromosome 3 (UPD3pat). The finding of this paternal UPD case of the entire chromosome 3 with no apparent phenotypic disorders suggests that there are no paternal imprinted genes causing rare genetic disorders on chromosome 3.

Alleles↗

PubMed2006

Tests of linkage and association of PTH/PTHrP receptor type 1 gene with bone mineral density and height in Caucasians.

Parathyroid hormone/parathyroid hormone-related peptide receptor type 1 (PTHR1) plays an important role in calcium metabolism. It was previously shown to influence variation in bone mineral density (BMD). To investigate its importance in a typical U.S. Caucasian population, we tested linkage or association of the PTHR1 gene with BMD and height. Altogether, 1873 subjects from 405 Caucasian nuclear families were studied. BMD was measured at the lumbar spine (L1-L4) and total hip (femoral neck, trochanter, and intertrochanter regions). Four single nucleotide polymorphisms (SNPs) in the PTHR1 gene were genotyped. Sixteen haplotypes were reconstructed. Only two major haplotypes had frequencies >3% and were thus used for the analysis. Analyses were performed for BMD and height in the total sample and for peak BMD (PBMD) achieved in offspring subjects aged 20-50 in a subsample of 387 nuclear families. We found suggestive evidence for total association between haplotype 13 (AATG) and hip PBMD (P = 0.031). For height, evidence of within-family association was suggested for SNP1, SNP2, and haplotype 4 (GGCA) (P < or = 0.05). Our findings suggest that the PTHR1 gene may be important for PBMD, height variation, or both, although the significance is dampened by correction for multiple testing.

Absorptiometry, Photon↗

PubMed2006

CA repeat polymorphism of the TNFR2 gene is not associated with bone mineral density in two independent Caucasian populations.

Osteoporosis has a strong genetic component, but the genes involved are poorly defined. Genome-wide scans in multiple populations have identified chromosome 1p36 as one region linked to bone mineral density (BMD). The tumor necrosis factor receptor 2 (TNFR2) at 1p36 is a positional and functional candidate gene in osteoporosis. In this study, we conducted linkage and association tests between the CA repeat polymorphism of the TNFR2 gene and BMD in two large independent samples using the quantitative transmission disequilibrium test (QTDT) program. The first group of subjects was composed of 1836 individuals from 79 multigeneration pedigrees. The second group was a randomly ascertained set of 636 individuals from 157 nuclear families. We found no evidence of association or linkage for spine or hip BMD in the samples of the multigenerational pedigrees or nuclear families. Through testing for association and for linkage, our data do not support the TNFR2 gene as a QTL underlying hip or spine BMD variation in our Caucasian populations.

Adult↗