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Biomedical subjects

Robert R Recker

Publications and source records attributed to Robert R Recker.

At least 73 records · Page 4Linked to original sources
PubMed2003

Several genomic regions potentially containing QTLs for bone size variation were identified in a whole-genome linkage scan.

Bone size is an important determinant of osteoporotic fractures. For a sample of 53 pedigrees that contains more than 10,000 relative pairs informative for linkage analyses, we performed a whole-genome linkage scan using 380 microsatellite markers to identify genomic regions that may contain QTLs of bone size (two dimensional measurement by dual energy X-ray absorptiometry). We conducted two- and multi-point linkage analyses. Several potentially important genomic regions were identified. For example, the genomic region 17q23 may contain a QTL for wrist (ultra distal) bone size variation; a LOD score of 3.98 is achieved at D17S787 in two-point analyses and a maximum LOD score (MLS) of 3.01 is achieved in multi-point analyses in 17q23. 19p13 may contain a QTL for hip bone size variation; a LOD score of 1.99 is achieved at D19S226 in two-point analyses and a MLS of 2.83 is achieved in 19p13 in multi-point analyses. The genomic region identified on chromosome 17 for wrist bone size seems to be consistent with that identified for femur head width variation in an earlier whole-genome scan study. The genomic regions identified in this study and an earlier investigation on one-dimensional bone size measurement by radiography are compared. The two studies may form a basis for further exploration with larger samples and/or denser markers for confirmation and fine mapping studies to eventually identify major functional genes and the associated etiology for osteoporosis.

Age Factors↗
PubMed2003

Polymorphisms of four bone mineral density candidate genes in Chinese populations and comparison with other populations of different ethnicity.

Studies on polymorphisms of candidate genes and their association with bone mineral density (BMD) have been reported in many populations, but few have been reported in Chinese populations. We investigated polymorphisms of the following five commonly used markers of four prominent BMD candidate genes with the purpose of identifying useful genetic markers for osteoporosis genetic research in Chinese: the Sp1 and RsaI polymorphisms of the collagen type 1 alpha l (Col1a1) gene, the -174G/C promoter polymorphism of the interleukin 6 (IL-6) gene, the Asn363Ser polymorphism of the glucocorticoid receptor (GR) gene, and the T --> C polymorphism in intron 5 of the transforming growth factor beta(1) (TGF-beta(1)) gene. We evaluated these polymorphisms using PCR-RFLP in samples of at least 124 random individuals. We compared the polymorphisms of these five markers with other populations using the chi(2) test and Fisher's exact two-tailed test. For the RsaI polymorphism, only three heterozygotes but no variant homozygote were identified. For the -174G/C polymorphic site, only one GC heterozygote and no CC homozygote were found. Alleles s, Ser, and A(1) at the Sp1, Asn363Ser, and T --> C marker sites that have been found to be polymorphic in other populations were not found in Chinese. Significant differences of allele and genotype frequency distributions were observed at these polymorphisms ( P < 0.001) after comparing with other populations. Our results suggest that variant alleles of the five markers are absent or too rare to be useful genetic makers in Chinese, despite the fact that they have been commonly used as polymorphic markers in osteoporosis genetic research in other populations.

Base Sequence↗
PubMed2003

Estrogen receptor alpha gene polymorphisms and peak bone density in Chinese nuclear families.

PBD is an important determinant of osteoporotic fractures. Few studies were performed to search for genes underlying PBD variation in Chinese populations. We tested linkage and/or association of the estrogen receptor alpha gene polymorphism with PBD in 401 Chinese nuclear families. This study suggests the ER-alpha gene may have some minor effects on PBM variation in the Chinese population. Low peak bone density (PBD) in adulthood is an important determinant of osteoporotic fractures in the elderly. PBD variation is mainly regulated by genetic factors. Extensive molecular genetics studies have been performed to search for genes underlying PBD variation, largely in whites. Few studies were performed in Chinese populations. In this study, we simultaneously test linkage and/or association of the estrogen receptor alpha (ER-alpha) gene polymorphism with PBD in 401 Chinese nuclear families (both parents plus their female children) of 1260 subjects, with the 458 children generally between 20 and 40 years of age. All the subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at polymorphic PvuII and XbaI sites inside the ER-alpha gene. Bone mineral density was measured at the lumbar spine (L1-L4) and hip (femoral neck, trochanter, and intertrochanteric region). Raw bone mineral density values were adjusted by age, height, and weight as covariates. We detected marginally significant results for within-family association (transmission disequilibrium; p = 0.054) between the spine bone mineral density variation and the ER-alpha XbaI genotypes. For the hip bone mineral density variation, significant (p < 0.05) linkage results were generally found for the two intragenic markers. Analyses of the haplotypes defined by the two markers confer further evidence for linkage of the ER-alpha with the hip PBD variation. In conclusion, this study suggests that the ER-alpha gene may have minor effects on PBD variation in our Chinese population.

Asian People↗
PubMed2003

Molecular studies of identification of genes for osteoporosis: the 2002 update.

We aim to give a comprehensive review, updated to 2002, of the most important and representative molecular genetic studies, performed mainly within the past decade, that aimed to identify the gene(s) involved in osteoporosis. Early reviews were largely confined to association studies in humans, but we review here, separately, the results of both association and linkage studies in humans, and quantitative trait locus (QTL) mapping in animal models. The main results of all the studies are tabulated for comparison and ease of reference, and to provide a comprehensive retrospective view of molecular genetics studies of osteoporosis. The most striking findings and the most representative studies are singled out for comment regarding the immediacy of their influence on present understanding of the genetics of osteoporosis and on the current status of genetic research in osteoporosis. This is particularly relevant for studies on the association of the vitamin D receptor (VDR) gene, for which there has been a large body of studies and reviews published. The format adopted by this review should be ideal for accommodating future new advances and studies in a fairly young field that is still developing rapidly.

Animals↗
PubMed2003

Molecular and genetic mechanisms of obesity: implications for future management.

Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed.

Adipose Tissue↗
PubMed2002

A whole-genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature.

Human height is a complex trait under the control of both genetic and environment factors. In order to identify genomic regions underlying the variation of stature, we performed a whole-genome linkage analysis on a sample of 53 human pedigrees containing 1,249 sib pairs, 1,098 grandparent-grandchildren pairs, 1,993 avuncular pairs, and 1,172 first-cousin pairs. Several genomic regions were suggested by our study to be linked with human height variation. These regions include 5q31 at 144 cM from pter on chromosome 5 (with a maximum LOD score of 2.14 in multipoint linkage analyses), Xp22 at the marker DXS1060, and Xq25 at DXS1001 on the X chromosome (with LOD scores of 1.95 and 1.91, respectively, in two-point linkage analyses). Noticeably, Xp22 happens to be the very region where a newly identified gene underlying idiopathic short stature, SHOX, maps. Based on our findings, further confirmation and fine-mapping studies are to be pursued on expanded samples and/or with denser markers for eventual identification of major functional genes involved in human height variation.

Body Height↗
PubMed2002

A genomewide linkage scan for quantitative-trait loci for obesity phenotypes.

Obesity is an increasingly serious health problem in the world. Body mass index (BMI), percentage fat mass, and body fat mass are important indices of obesity. For a sample of pedigrees that contains >10,000 relative pairs (including 1,249 sib pairs) that are useful for linkage analyses, we performed a whole-genome linkage scan, using 380 microsatellite markers to identify genomic regions that may contain quantitative-trait loci (QTLs) for obesity. Each pedigree was ascertained through a proband who has extremely low bone mass, which translates into a low BMI. A major QTL for BMI was identified on 2q14 near the marker D2S347 with a LOD score of 4.04 in two-point analysis and a maximum LOD score (MLS) of 4.44 in multipoint analysis. The genomic region near 2q14 also achieved an MLS >2.0 for percentage of fat mass and body fat mass. For the putative QTL on 2q14, as much as 28.2% of BMI variation (after adjustment for age and sex) may be attributable to this locus. In addition, several other genomic regions that may contain obesity-related QTLs are suggested. For example, 1p36 near the marker D1S468 may contain a QTL for BMI variation, with a LOD score of 2.75 in two-point analysis and an MLS of 2.09 in multipoint analysis. The genomic regions identified in this and earlier reports are compared for further exploration in extension studies that use larger samples and/or denser markers for confirmation and fine-mapping studies, to eventually identify major functional genes involved in obesity.

Adipose Tissue↗
PubMed2002

Transmission disequilibrium test with discordant sib pairs when parents are available.

The transmission disequilibrium test (TDT) has been employed to map disease susceptibility loci (DSL), while being immune to the problem of population admixture. The customary TDT test (TDT(D)) was developed for affected child(ren) and their parents and was most often applied to case-parent trios. Recently, the TDT has been extended to the situations when (1) parents are not available but affected and nonaffected sibs from each family are available, (2) unrelated control-parent trios are available for combined analyses with case-parent trios (TDT(DC)), and (3) large pedigrees. For many diseases, affected children in the case-parent trios enlisted into the TDT(D) have unaffected sibs who can be recruited. We present an extension of the TDT by effectively incorporating one unaffected sib of each of the affected children in the case-parent trios into a single analysis (TDT(DS), where DS denotes discordant sib pairs). We have developed a general analytical method for computing the statistical power of the TDT(DS) under any genetic model, the accuracy of which is validated by computer simulations. We compare the power of the TDT(D), TDT(DC), and TDT(DS) under a range of parameter space and genetic models. We find that the TDT(DS) is generally more powerful than the TDT(DC) and TDT(D), particularly when the disease is prevalent (>30%) in the population. The relative power of the TDT(D) and the TDT(DS) largely depends upon the allele frequencies and genetic effects at the DSL, whereas the recombination rate, the degree of linkage disequilibrium, and the marker allele frequencies have little effect. Importantly, the TDT(DS) not only may be more powerful, it also has the advantage of being able to test for segregation distortion that may yield false linkage/association in the TDT(D).

Alleles↗
PubMed2002

Mutation patterns at dinucleotide microsatellite loci in humans.

Microsatellites are a major type of molecular markers in genetics studies. Their mutational dynamics are not clear. We investigated the patterns and characteristics of 97 mutation events unambiguously identified, from 53 multigenerational pedigrees with 630 subjects, at 362 autosomal dinucleotide microsatellite loci. A size-dependent mutation bias (in which long alleles are biased toward contraction, whereas short alleles are biased toward expansion) is observed. There is a statistically significant negative relationship between the magnitude (repeat numbers changed during mutation) and direction (contraction or expansion) of mutations and standardized allele size. Contrasting with earlier findings in humans, most mutation events (63%) in our study are multistep events that involve changes of more than one repeat unit. There was no correlation between mutation rate and recombination rate. Our data indicate that mutational dynamics at microsatellite loci are more complicated than the generalized stepwise mutation models.

Alleles↗
PubMed2002

Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases.

We investigate the relevance of the genetic determination of bone mineral density (BMD) variation to that of differential risk to osteoporotic fractures (OF). The high heritability (h(2)) of BMD and the significant phenotypic correlations between high BMD and low risk to OF are well known. Little is reported on h(2) for OF. Extensive molecular genetic studies aimed at uncovering genes for differential risks to OF have focussed on BMD as a surrogate phenotype. However, the relevance of the genetic determination of BMD to that of OF is unknown. This relevance can be characterized by genetic correlation between BMD and OF. For 50 Caucasian pedigrees, we estimated that h(2) at the hip is 0.65 (P < 0.0001) for BMD and 0.53 (P < 0.05) for OF; however, the genetic correlation between BMD and OF is nonsignificant (P > 0.45) and less than 1% of additive genetic variance is shared between them. Hence, most genes found important for BMD may not be relevant to OF at the hip. The phenotypic correlation between high BMD and low risk to OF at the hip (approximately -0.30) is largely due to an environmental correlation (rho(E) = -0.73, P < 0.0001). The search for genes for OF should start with a significant h(2) for OF and should include risk factors (besides BMD) that are genetically correlated with OF. All genes found important for various risk factors must be tested for their relevance to OF. Ideally, employing OF per se as a direct phenotype for gene hunting and testing can ensure the importance and direct relevance of the genes found for the risk of OF. This study may have significant implications for the common practice of gene search for complex diseases through underlying risk factors (usually quantitative traits).

Adult↗
PubMed2002

Differences in bone mineral density, bone mineral content, and bone areal size in fracturing and non-fracturing women, and their interrelationships at the spine and hip.

Osteoporotic fractures are a major public health problem, particularly in women. Bone mineral density (BMD), bone mineral content (BMC), and bone size have been regarded as important determinants of osteoporotic fractures. In 1449 women over age 30 years, we studied the detailed relationship, at the spine and hip, between BMD, BMC, and bone areal size (all measured by dual-energy X-ray absorptiometry) and compared their relative magnitudes in fracturing and non-fracturing individuals. We find that, (1) BMD and BMC are significantly higher at the spine and hip in non-fracturing women. Bone areal size is significantly larger at the spine in non-fracturing women; however, the significance disappears when adjustment is made for the significant difference of height (stature) between fracturing and non-fracturing women. In contrast to the spine, bone areal size is always significantly largerin fracturing women at the hip. (2) The relationship among BMD, BMC, and bone areal size is different at the spine and hip. Specifically, at the spine, BMD increases with bone areal size linearly. At the hip, BMD has a quadratic relationship with bone areal size, so that BMD increases at lower bone areal sizes, then (after an intermediate zone of values) decreases with increasing bone areal size. However, BMD adjusted for BMC always decreases with increasing bone areal size, as expected by the definition of BMD. With no adjustment for BMC, the increase in BMD with bone areal size is due to a more rapid increase of BMC than increasing bone areal size, thus explaining the observations of association of both larger BMD and larger bone areal size with stronger bone. (3) At the spine, 86.2% of BMD variation is attributable to BMC and 12.6% to bone areal size. At the hip, 98.0% of BMD variation is due to BMC and 1.1% due to bone areal size. The current study may be important in understanding the relationship among BMD, BMC, and bone size as risk determinants of osteoporotic fractures.

Absorptiometry, Photon↗
PubMed2002

Bone microstructure in osteoporosis: transilial biopsy and histomorphometry.

The bone fragility of osteoporosis is not fully explained by a deficit in bone mass. Histomorphometric examination of transilial bone biopsies has identified microstructural defects that-in light of what is known about the mechanical properties of structural materials-further compromise bone strength. Histomorphometric measures describe the biopsy specimen, the configuration of its trabeculae in space, and the extent to which its trabecular lattice is intact. In postmenopausal women with established osteoporosis, a deficit of both cortical and cancellous bone is typical, i.e., both cortical thickness and cancellous bone volume tend to be substantially reduced. Much of the cancellous bone deficit can be attributed to loss of entire trabecular elements rather than to generalized thinning of trabeculae. Direct measures of trabecular connectivity confirm this impression: women with established osteoporosis have fewer trabecular nodes and more termini than healthy women, even at the same cancellous bone volume. Evidence for accumulated microdamage in transilial biopsies is circumstantial, and the phenomenon itself may well be localized to fracture sites. Histomorphometric data from transilial biopsies comprise a large body of information about the structural and functional character of osteoporosis and provide valuable information about the effects of new treatments on bone microstructure.

Biopsy↗
PubMed2002

A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait Loci for osteoporosis.

Osteoporosis is an important health problem, particularly in the elderly women. Bone mineral density (BMD) is a major determinant of osteoporosis. For a sample of 53 pedigrees that contain 1249 sibling pairs, 1098 grandparent-grandchildren pairs, and 2589 first cousin pairs, we performed a whole- genome linkage scan using 380 microsatellite markers to identify genomic regions that may contain quantitative trait loci (QTL) of BMD. Each pedigree was ascertained through a proband with BMD values belonging to the bottom 10% of the population. We conducted two-point and multipoint linkage analyses. Several potentially important genomic regions were suggested. For example, the genomic region near the marker D10S1651 may contain a QTL for hip BMD variation (with two-point analysis LOD score of 1.97 and multipoint analysis LOD score of 2.29). The genomic regions near the markers D4S413 and D12S1723 may contain QTLs for spine BMD variation (with two-point analysis LOD score of 2.12 and 2.17 and multipoint analysis LOD score of 3.08 and 2.96, respectively). The genomic regions identified in this and some earlier reports are compared for exploration in extension studies with larger samples and/or denser markers for confirmation and fine mapping to eventually identify major functional genes involved in osteoporosis.

Bone Density↗
PubMed2002

Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.

The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr. New vertebral fractures was assessed from radiographs taken at baseline, yr 2-4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr. The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr. Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.

Aged↗
PubMed2002

Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density.

Bone mineral density (BMD) is a major determinant of osteoporotic fractures (OFs). The heritability of BMD ranges from 50% to 90% in human populations. Extensive molecular genetic analyses have been performed through traditional linkage or association approaches to test and identify genes or genomic regions underlying BMD variation. The results, particularly those concerning the vitamin D receptor (VDR) gene, have been inconsistent and controversial. In this study, we simultaneously test linkage and/or association of the genes for VDR, osteocalcin (also known as bone Gla protein [BGP]), and parathyroid hormone (PTH) with BMD in 630 subjects from 53 human pedigrees. Each of these pedigrees was ascertained through a proband with an extreme BMD value at the hip or spine (Z score < or = -1.28). For the raw BMD values, adjusting for significant covariate effects of age, sex, and weight, we performed tests for linkage alone, association alone, and then both linkage and association. For the spine BMD, at the two markers (ApaI and FokI) inside the VDR gene we found evidence for linkage (p < 0.05) and for both linkage and association by the transmission disequilibrium test (TDT; p < 0.05); association was detected (p < 0.07) with regular statistical testing by analyses of variance (ANOVA). In addition, significant results were found for association alone (p < 0.05), linkage alone (p = 0.0005), and for linkage and association (p = 0.0019) for the intragenic marker HindIII of the BGP gene for the hip BMD. Through testing for association, linkage, and linkage and association simultaneously, our data support the VDR gene as a quantitative trait locus (QTL) underlying spine BMD variation and the BGP gene as a QTL underlying hip BMD variation. However, our data do not support the PTH gene as a QTL underlying hip or spine BMD variation. This is the first study in the broad field of bone genetics that tests candidate genes as QTLs for BMD by testing simultaneously for association alone, for linkage alone, and for association and linkage (via the TDT).

Adult↗