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Robert R Recker

Publications and source records attributed to Robert R Recker.

At least 55 records · Page 3Linked to original sources
PubMed2005

Searching for obesity genes: progress and prospects.

Obesity is a condition of excess body fat that causes or exacerbates several major public health problems. Remarkable progress has been made in the molecular elucidation of monogenic forms of obesity both in rodents and in humans. The most common form of obesity, however, is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Identification and characterization of susceptibility genes underlying obesity will contribute to a greater understanding of the pathogenesis of obesity and ultimately will assist in the development of better strategies for prevention and therapeutic intervention. In this article, we discuss the current status and future perspectives for the genetic dissection of obesity, with a focus on the most striking or representative findings.

Animals↗
PubMed2005

Risedronate for prevention and treatment of osteoporosis in postmenopausal women.

Risedronate sodium is an N-containing bisphosphonate that has been approved for the prevention and treatment of osteoporosis in postmenopausal women. An increase in the rate of bone remodelling is a regular feature of oestrogen withdrawal during the menopausal transition, but excessive remodelling leads to bone fragility. Risedronate and similar compounds reduce the rate of bone remodelling by suppressing the action of osteoclasts. The antifracture efficacy of risedronate is impressive. In large clinical trials of postmenopausal women with osteoporosis-related fracture(s) at entry, the risk of incident vertebral and non-vertebral fractures was reduced by approximately 40%. In older women at risk for hip fracture, incident hip fractures were also reduced by approximately 40%. Antifracture efficacy develops within the first 6 months, and treatment has been followed for as long as 5 years without deleterious effects on bone. We await reports of experience with risedronate in 'real-world' cases of greater complexity (i.e., in patients with co-morbidities and medications that would have excluded them from published clinical trials).

Animals↗
PubMed2005

Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women.

OBJECTIVE: To compare medication adherence with daily vs weekly bisphosphonate dosing for the treatment or prevention of osteoporosis in a broad US retail pharmacy database population. PATIENTS AND METHODS: From October 2002 through September 2003, the medication possession ratio (MPR = days of supply/365 days) was used to assess medication adherence. The MPR was calculated by use of daily and weekly bisphosphonate doses in a longitudinal cohort of patients who received prescriptions from 14,000 US retail pharmacies. Patient prescription Information was from a database accessed through NDCHealth in Atlanta, Ga. Adequate adherence was defined as sufficient medication supply to ensure antifracture efficacy (MPR, > or =80%). The effects of patients' age, method of prescription payment, and pattern of past osteoporosis medication use on medication adherence also were evaluated. RESULTS: Of 211,319 study patients, 177,552 (84%) were taking weekly bisphosphonates vs 33,767 (16%) taking the daily prescription. Although significantly more patients taking the weekly compared with the daily bisphosphonates had adequate medication adherence, only about one third of patients in the daily dosing group and fewer than one half in the weekly dosing group achieved adequate adherence. Patients new to bisphosphonates had the worst medication adherence over the year (25.2% for weekly vs 13.2% for daily dosing; P<.001). The highest proportion of adequately adherent patients was among those continuing to take their existing weekly bisphosphonates; however, even in this group, only about 48% exhibited adequate medication adherence. CONCLUSIONS: Once-weekly dosing of bisphosphonates for the treatment or prevention of osteoporosis was associated with better medication adherence than daily dosing during a 1-year observation period. However, even with weekly dosing, adherence remained inadequate in more than one half of patients. These findings indicate that ways to improve medication adherence in the treatment or prevention of osteoporosis are still needed.

Aged↗
PubMed2004

Nonreplication in genetic studies of complex diseases--lessons learned from studies of osteoporosis and tentative remedies.

Inconsistent results have accumulated in genetic studies of complex diseases/traits over the past decade. Using osteoporosis as an example, we address major potential factors for the nonreplication results and propose some potential remedies. Over the past decade, numerous linkage and association studies have been performed to search for genes predisposing to complex human diseases. However, relatively little success has been achieved, and inconsistent results have accumulated. We argue that those nonreplication results are not unexpected, given the complicated nature of complex diseases and a number of confounding factors. In this article, based on our experience in genetic studies of osteoporosis, we discuss major potential factors for the inconsistent results and propose some potential remedies. We believe that one of the main reasons for this lack of reproducibility is overinterpretation of nominally significant results from studies with insufficient statistical power. We indicate that the power of a study is not only influenced by the sample size, but also by genetic heterogeneity, the extent and degree of linkage disequilibrium (LD) between the markers tested and the causal variants, and the allele frequency differences between them. We also discuss the effects of other confounding factors, including population stratification, phenotype difference, genotype and phenotype quality control, multiple testing, and genuine biological differences. In addition, we note that with low statistical power, even a "replicated" finding is still likely to be a false positive. We believe that with rigorous control of study design and interpretation of different outcomes, inconsistency will be largely reduced, and the chances of successfully revealing genetic components of complex diseases will be greatly improved.

Animals↗
PubMed2004

Genome scan for QTLs underlying bone size variation at 10 refined skeletal sites: genetic heterogeneity and the significance of phenotype refinement.

To identify quantitative trait loci (QTLs) underlying variation in bone size, we conducted a whole-genome linkage scan in 53 pedigrees with 630 subjects using 380 microsatellite markers. Lumbar area 1, 2, 3, and 4 at the spine, femoral neck, trochanter, intertrochanter areas at the hip, ultradistal, mid-distal, and one-third distal areas at the wrist were measured by dual-energy X-ray absorptiometry (DXA), and adjusted for age, height, weight, and sex. Two-point and multipoint linkage analyses were performed for skeletal bone size at each site and their composite measurements using the SOLAR package. Two chromosomal regions (1q22 and 10q21) were identified with significant evidence of linkage (LOD > 4.32) to one-third distal area, and three were identified with suggestive evidence of linkage (LOD > 2.93) to bone size in one skeletal site. Our results indicated that the low power of QTLs mapping for composite phenotypic measurements may result from genetic heterogeneity of complex traits.

Bone and Bones↗
PubMed2004

Tests of linkage and/or association of the LEPR gene polymorphisms with obesity phenotypes in Caucasian nuclear families.

Genetic variations in the leptin receptor (LEPR) gene have been conceived to affect body weight in general populations. In this study, using the tests implemented in the statistical package QTDT, we evaluated association and/or linkage of the LEPR gene with obesity phenotypes in a large sample comprising 1,873 subjects from 405 Caucasian nuclear families. Obesity phenotypes tested include body mass index (BMI), fat mass, percentage fat mass (PFM), and lean mass, with the latter three measured by dual-energy X-ray absorptiometry (DXA). Three single nucleotide polymorphisms (SNPs), namely Lys109Arg (A/G), Lys656Asn (G/C), Pro1019Pro (G/A), in the LEPR gene were analyzed. Significant linkage disequilibrium (0.394 < or = |D'| < or = 0.688, P < 0.001) was observed between pairs of the three SNPs. No significant population stratification was found for any SNP/phenotype. In single-locus analyses, evidence of association was observed for Lys656Asn with lean mass (P = 0.002) and fat mass (P = 0.015). The contribution of this polymorphism to the phenotypic variation of lean mass and fat mass was 2.63% and 1.15%, respectively. Subjects carrying allele G at the Lys656Asn site had, on average, 3.16% higher lean mass and 2.71% higher fat mass than those without it. In the analyses for haplotypes defined by the three SNPs, significant associations were detected between haplotype GCA (P = 0.005) and lean mass. In addition, marginally significant evidence of association was observed for this haplotype with fat mass (P = 0.012). No statistically significant linkage was found, largely due to the limited power of the linkage approach to detect small genetic effects in our data sets. Our results suggest that the LEPR gene polymorphisms contribute to variation in obesity phenotypes.

Adult↗
PubMed2004

Current limitations of SNP data from the public domain for studies of complex disorders: a test for ten candidate genes for obesity and osteoporosis.

BACKGROUND: Public SNP databases are frequently used to choose SNPs for candidate genes in the association and linkage studies of complex disorders. However, their utility for such studies of diseases with ethnic-dependent background has never been evaluated. RESULTS: To estimate the accuracy and completeness of SNP public databases, we analyzed the allele frequencies of 41 SNPs in 10 candidate genes for obesity and/or osteoporosis in a large American-Caucasian sample (1,873 individuals from 405 nuclear families) by PCR-invader assay. We compared our results with those from the databases and other published studies. Of the 41 SNPs, 8 were monomorphic in our sample. Twelve were reported for the first time for Caucasians and the other 29 SNPs in our sample essentially confirmed the respective allele frequencies for Caucasians in the databases and previous studies. The comparison of our data with other ethnic groups showed significant differentiation between the three major world ethnic groups at some SNPs (Caucasians and Africans differed at 3 of the 18 shared SNPs, and Caucasians and Asians differed at 13 of the 22 shared SNPs). This genetic differentiation may have an important implication for studying the well-known ethnic differences in the prevalence of obesity and osteoporosis, and complex disorders in general. CONCLUSION: A comparative analysis of the SNP data of the candidate genes obtained in the present study, as well as those retrieved from the public domain, suggests that the databases may currently have serious limitations for studying complex disorders with an ethnic-dependent background due to the incomplete and uneven representation of the candidate SNPs in the databases for the major ethnic groups. This conclusion attests to the imperative necessity of large-scale and accurate characterization of these SNPs in different ethnic groups.

Asian People↗
PubMed2004

Genetics of bone mineral density: evidence for a major pleiotropic effect from an intercontinental study.

UNLABELLED: BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors. INTRODUCTION: BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors MATERIALS AND METHODS: A bivariate complex segregation analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America. RESULTS AND CONCLUSIONS: The genetic correlation between BMD measures ranged between 0.50 +/- 0.09 and 0.79 +/- 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 +/- 0.07 to 0.66 +/- 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk.

Adolescent↗
PubMed2004

The elusive concept of bone quality.

This paper outlines information from recent publications that aid our understanding of bone quality in relation to osteoporosis. In practical terms, bone quality designates the properties of bone that contribute to strength but are not assessed by bone densitometry. While osteoporosis is still defined in terms of bone density, the limitations of this approach, long questioned, have become indisputable. In parallel, the results of treatment trials of antiresorptive agents demonstrate that bone density is a flawed surrogate for bone fragility and a weak indicator of antifracture efficacy. The case for emphasizing bone turnover in assessing fracture risk, has become increasingly strong, and a redefinition of osteoporosis on this basis may well occur. New technologies for studying bone microstructure and matrix composition, merging with sophisticated biomechanical assessments, are advancing our ideas regarding bone "damageability" and its effects over time.

Absorptiometry, Photon↗
PubMed2004

Test of linkage and/or association between the estrogen receptor alpha gene with bone mineral density in Caucasian nuclear families.

Extensive studies have been performed on the association between the estrogen receptor alpha (ER-alpha) gene and bone mineral density (BMD). Despite considerable efforts, the studies using limited markers and relatively small sample size have yielded largely inconsistent results. In this study, 1873 Caucasian subjects from 405 nuclear families containing 1512 sib pairs were recruited. BMD at the lumbar spine (LS) and femoral neck (FN) was measured by dual-energy X-ray absorptiometry (DXA). Seven single-nucleotide polymorphisms (SNPs) spanning from exon 1 to 8 in the ER-alpha gene were genotyped. The program QTDT (quantitative transmission disequilibrium test) was applied to test linkage and/or association of the ER-alpha gene and BMD variation using individual SNP markers and reconstructed haplotypes. Linkage disequilibrium (LD) was generally detected for SNPs in the ER-a gene (P < 0.05). Associations were observed between SNP rs932477 and FN BMD (P = 0.028), and between the most predominant three-marker haplotype (GCG) containing SNP rs932477 and FN BMD (P = 0.010). Within-family association (present only with both linkage and association) between SNP rs2228480 (G2014A) and FN BMD (P = 0.015) was observed. The most predominant seven-SNP haplotype (TCGCGGG) was associated with higher LS BMD (P = 0.015). However, after correction for multiple testing, these associations did not reach statistical significance. Denser markers may be necessary to better define the relationship between the ER-alpha gene and BMD variation in our sample.

Absorptiometry, Photon↗
PubMed2004

A follow-up linkage study for bone size variation in an extended sample.

Bone size, which has strong genetic determination, is an important determinant of bone strength and a risk factor of osteoporotic fractures. We previously reported an approximately 10-cm genome-wide linkage scan in 630 subjects from 53 US Caucasian pedigrees. The strongest evidence of linkage was obtained on chromosome 17q22 near the marker D17S787, with a two-point LOD score of 3.98 and a multipoint maximum LOD score (MLS) of 3.01. Additionally, suggestive linkages (1.54 < MLS < 2.83) were found at the other four chromosomal regions. In the present study, with an attempt to further examine our previous findings, we perform a follow-up linkage analysis in an expanded sample of 79 pedigrees with 1816 subjects. The total sample contains >80,000 informative relative pairs for linkage analyses, including 3846 sib pairs. Fifteen markers covering the above five promising regions are genotyped, narrowing the average genomic distance from approximately 10 to 5 cm. In the total 79 pedigrees, support of linkage was achieved for the wrist bone size at 17q22 with a two-point LOD score of 2.27 (P = 0.0006) and MLS of 1.78 (P = 0.002). The genomic region 17q22 includes COL1A1, a strong candidate gene that is significantly associated with osteoporotic fracture risk. Our data suggest that this region is promising for further exploratory studies.

Adult↗
PubMed2004

Association between COL1A1 gene polymorphisms and bone size in Caucasians.

Bone size is an important determinant of bone strength and a risk factor of osteoporotic fracture. Several studies indicate that bone size has a high heritability. Thus, a better understanding of genetic factors regulating bone size might have important clinical implications. In the present study, we examined the relationship between the collagen type I alpha 1 (COL1A1) gene and bone size at the spine, hip and wrist in a sample of 1873 subjects of Caucasian origin from 405 nuclear families. Three single-nucleotide polymorphisms (SNPs) in the COL1A1 gene were analyzed. The minor allele frequencies were 15.4, 18.8, and 1.9% for SNP1, SNP2, and SNP3, respectively. Haplotypes were reconstructed based on the family information as well as marker genotypes using the program Genehunter. We did not find evidence of population stratification, within-family association, or linkage for either single SNPs or haplotypes at any skeletal site. Suggestive evidence of total association was observed for the wrist size at SNP2 (P=0.011). After adjusting age, sex, height, and weight, subjects with the T allele of SNP2 had, on average, 3.05% smaller wrist size than noncarriers. When the subjects were divided into families with only female offspring and families with male offspring only, similar total associations were found at the wrist size for SNP2 with P-values of 0.011 and 0.010, respectively. In conclusion, the COL1A1 gene may have some effects on bone size variation at the wrist, but not at the spine or hip in our Caucasian nuclear families.

Adult↗
PubMed2004

Genetic dissection of human stature in a large sample of multiplex pedigrees.

Recently, we reported a whole genome scan on a sample of 630 Caucasian subjects from 53 human pedigrees. Several genomic regions were suggested to be linked to height. In an attempt to confirm the identified genomic regions, as well as to identify new genomic regions linked to height, we conducted a whole genome linkage study on an extended sample of 1,816 subjects from 79 pedigrees, which includes the 53 pedigrees containing the original 630 subjects from our previous whole genome study and an additional 128 new subjects, and 26 further pedigrees containing 1,058 subjects. Several regions achieved suggestive linkage signals, such as 9q22.32 [MLS (multipoint LOD score) = 2.74], 9q34.3 [MLS = 2.66], Xq24 [two-point LOD score = 2.64 at the marker DXS8067], and 7p14.2 [MLS = 2.05]. The importance of the above regions is supported either by other whole genome studies or by candidate genes within these regions relevant to linear growth or pathogenesis of short stature. In addition, this study has tentatively confirmed the Xq24 region's linkage to height, as this region was also detected in the previous whole genome study. To date, our study has achieved the largest sample size in the field of genetic linkage studies of human height. Together with the findings of other studies, the current study has further delineated the genetic basis of human stature.

Adult↗
PubMed2004

A follow-up linkage study for quantitative trait loci contributing to obesity-related phenotypes.

We have recently reported a whole-genome scan in a sample of 630 subjects from 53 extended pedigrees, in which several genomic regions that may contain quantitative trait loci (QTLs) for obesity were suggested. In the present study, with an attempt to confirm our previous findings, we performed a follow-up linkage study in an expanded sample of 79 pedigrees with 1816 subjects (including expanded previous 53 pedigrees and 26 newly recruited pedigrees containing 1058 subjects). A new set of microsatellite markers spanning previously identified regions were selected, with the average genomic distance narrowed from approximately 10 cM to approximately 5 cM in this study. Using a variance component method, we performed two- and multipoint linkage analyses in the following three sample sets: expanded previous 53 pedigrees (758 subjects), 26 new pedigrees, and 79 total pedigrees. For body mass index, analyses of the expanded 53 pedigrees attained a LOD score of 2.32 near marker D1S468 in two-point analysis and a maximum LOD score (MLS) of 2.21 in multipoint analysis; 2q14 near marker D2S347 attained a LOD score of 3.42 in two-point analysis and a MLS of 3.93 in multipoint analysis. The linkage peaks at 1p36 and 2q14 were further supported in the analyses of all 79 pedigrees, with multipoint MLS being 1.38 and 0.90, respectively. For fat mass, genomic region 6q27 achieved a LOD score of 1.24 in two-point analysis and an MLS of 0.92 in multipoint analysis in all 79 pedigrees. Our data support that 1p36, 2q14, and 6q27 are promising regions that may harbor QTLs for obesity phenotypes.

Adult↗
PubMed2003

Searching for osteoporosis genes in the post-genome era: progress and challenges.

Osteoporosis is a common skeletal disease characterized by low bone mineral density (BMD), deterioration of bone microarchitecture and increased fracture risk. It is a complex disease that has high social and economic costs. Osteoporosis and its associated phenotypes are under the strong genetic control. Identification and characterization of specific loci or genes involved in determining osteoporosis and its associated phenotypes will contribute to a greater understanding of the pathogenesis of osteoporosis, and ultimately might lead to the development of better diagnosis, prevention and treatment strategies. Efforts to identify osteoporosis genes have focused on three approaches: animal models, candidate gene approach, and genome-wide scans. In this article, we review the current status for mapping and identification of genes for osteoporosis, with a focus on some promising regions and future prospects.

Animals↗
PubMed2003

Linkage and association of the CA repeat polymorphism of the IL6 gene, obesity-related phenotypes, and bone mineral density (BMD) in two independent Caucasian populations.

Genetic factors play an important role in osteoporosis and obesity, two serious public health problems in the world. We investigated the relationships between obesity-related phenotypes, bone mineral density (BMD) and the CA repeat polymorphism of the IL6 gene in two large independent samples using the quantitative transmission disequilibrium test (QTDT). The first sample consisted of 1,816 individuals from 79 multigenerational pedigrees. Each pedigree was identified through a proband with BMD Z-scores </=-1.28 at the hip or spine. The second sample was a randomly ascertained set of 636 individuals from 157 nuclear families. Ten alleles containing 9-18 CA repeats were identified in our Caucasian populations. For body mass index (BMI), fat mass and percentage fat mass (PFM), highly significant (P<0.01) or significant (P<0.05) results were found for linkage in our sample of nuclear families and for association in the multigenerational pedigrees. We also observed weak evidence for linkage (P=0.069) with spine BMD and for association with hip BMD in the sample of multigenerational pedigrees. Our results suggest that genetic variation in or near the IL6 locus may be involved in the etiology of obesity and osteoporosis.

Adult↗