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Biomedical subjects

David M Reid

Publications and source records attributed to David M Reid.

At least 19 recordsLinked to original sources
PubMed2007

Large-scale population-based study shows no association between common polymorphisms of the TGFB1 gene and BMD in women.

UNLABELLED: The TGFB1 gene is a strong functional candidate for regulating genetic susceptibility to osteoporosis. We studied five common polymorphisms of TGFB1 in relation to osteoporosis-related phenotypes in a population-based cohort of 2975 British women, but found no significant association with bone mass, bone loss, bone markers, or fracture. INTRODUCTION: The gene encoding TGFB1 is a strong functional candidate for genetic susceptibility to osteoporosis. Several polymorphisms have been identified in TGFB1, and previous work has suggested that allelic variants of TGFB1 may regulate BMD and susceptibility to osteoporotic fracture. MATERIALS AND METHODS: We studied the relationship between common polymorphisms of TGFB1 and several osteoporosis-related phenotypes including BMD at the lumbar spine and femoral neck, measured by DXA; bone loss over a 6-year period; biochemical markers of bone turnover (urinary free deoxypyridinoline and free pyridinoline/creatinine ratio and serum N-terminal propeptide of type 1 collagen), and fractures in a population-based study of 2975 women from the United Kingdom. Participants were genotyped for single nucleotide polymorphisms (SNPs) in the TGFB1 promoter (G-800A; rs1800468; C-509T; rs1800469), exon 1 (T29C; rs1982073 and G74C; rs1982073); and exon 5 (C788T; rs1800471) on PCR-generated fragments of genomic DNA. Haplotypes were constructed from genotype data using the PHASE software program, and genotypes and haplotypes were related to the phenotypes of interest using general linear model ANOVA, with correction for confounding factors including age, height, weight, menopausal status, hormone replacement therapy (HRT) use, physical activity score, and dietary calcium intake. RESULTS: The polymorphisms were in strong linkage disequilibrium, and four common haplotypes accounted for >95% of alleles at the locus. There was no association between individual SNPs and BMD, bone loss, or biochemical markers of bone turnover. Haplotype analysis showed a nominally significant association with femoral neck BMD (p = 0.042) and with incident osteoporotic fracture (p = 0.013), but these were not significant after correcting for multiple testing. CONCLUSIONS: Common polymorphic variants of the TGFB1 gene did not influence BMD or bone loss in this population.

Absorptiometry, Photon↗
PubMed2006

Lumbar disc degeneration: association between osteophytes, end-plate sclerosis and disc space narrowing.

BACKGROUND: Lumbar disc degeneration is characterised radiologically by the presence of osteophytes, end-plate sclerosis and disc space narrowing. AIM: To determine the strength of the association between increasing severity of combinations of these features in a population sample of men and women. METHODS: Men and women aged >or=50 years were recruited from a primary care-based community health index in Aberdeen, UK. Participants had lateral spinal radiographs performed according to a standard protocol. The intervertebral disc spaces (L1/2-L4/5) were evaluated for the presence of anterior osteophytes, end-plate sclerosis and disc space narrowing using a graded semiquantitative score (grade 0-3). Log linear modelling was used to determine the associations (pairwise) between increasing severity of these features, with the results expressed as beta coefficients and 95% confidence intervals (CIs). RESULTS: There were 286 men (mean age 65.3 years) and 299 women (mean age 65.2 years) with spinal radiographs, yielding a total of 2340 assessable lumbar vertebral levels. In all, 73% of vertebral levels had evidence of osteophytes, 26% of sclerosis and 37% of disc space narrowing. Increasing severity of osteophyte grade was associated with an increasing severity both of sclerosis and of disc space narrowing, whereas the severity of sclerosis was associated with the severity of narrowing. This was true at all vertebral levels. The strongest association, however, was between osteophytes and sclerosis (beta coefficient = 2.7, 95% CI 2.4 to 3.1). For sclerosis and narrowing the beta coefficient was 1.9 (95% CI 1.7 to 2.1), whereas for osteophytes and narrowing the beta coefficient was much weaker at 1.2 (95% CI 1.1 to 1.3). There was no important influence of vertebral level on any of these associations. CONCLUSION: The association between increasing severity of osteophytes and end-plate sclerosis is stronger than for other combinations of radiographic features of lumbar disc degeneration.

Aged↗
PubMed2006

The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.

BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures. DESIGN: Prospective multicenter large-scale association study. SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. PARTICIPANTS: 26,242 participants (18,405 women). MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

Adult↗
PubMed2006

Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women.

CONTEXT: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1. OBJECTIVE: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women. DESIGN: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program. MAIN OUTCOME MEASURES: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298). RESULTS: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LS-BMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/+1245G) had increased BMD (P = 0.007 for LS-BMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype. CONCLUSIONS: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.

Absorptiometry, Photon↗
PubMed2006

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.

BACKGROUND: 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/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (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. CONCLUSIONS: 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.

Adult↗
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

Growth and ethylene evolution by shade and sun ecotypes of Stellaria longipes in response to varied light quality and irradiance.

Plants growing in the shade receive both low light irradiance and light enriched in far red (FR) (i.e., light with a low red (R) to FR ratio). In an attempt to uncouple the R/FR ratio effects from light irradiance effects, we utilized Stellaria longipes because this species has two distinct natural population ecotypes, alpine (dwarf) and prairie (tall). The alpine population occupies the open, sun habitat. By contrast, the prairie population grows in the shade of other plants. Both 'sun' and 'shade' ecotypes responded with increased stem elongation responses under low irradiance, relative to growth under 'normal' irradiance, and this increased growth was proportionally similar. However, only the shade ecotype had increased shoot elongation in response to a low R/FR ratio. By contrast, the sun ecotype showed increased stem elongation in response to increasing R/FR ratio. Varying the R/FR ratios had no significant effect on ethylene evolution in either sun or shade ecotype. Under low irradiance, only the sun ecotype showed a significantly changed (decreased) ethylene evolution. We conclude that R/FR ratio and irradiance both regulate growth, and that irradiance can also influence ethylene evolution of the sun ecotype. By contrast, R/FR ratio and irradiance, while having profound influences on growth of the shade ecotype, do not appear to regulate these growth changes via effects on ethylene production.

Ethylenes↗
PubMed2006

Involvement of gibberellins in the stem elongation of sun and shade ecotypes of Stellaria longipes that is induced by low light irradiance.

Plants from two ecotypes of Stellaria longipes, alpine (an open, sunny habitat) and prairie (where adjacent plants provide a shaded habitat), were grown under normal and reduced levels of photosynthetically active radiation (PAR). Growth under low PAR is significantly promoted in both ecotypes. When quantified by the stable isotope dilution method, endogenous gibberellins (GAs) (GA1, GA8, GA20, GA19) were significantly elevated under low PAR in both 'sun' and 'shade' ecotypes, as was GA53 in the shade ecotype. Changes in endogenous GA1 levels were significantly correlated with stem growth during a 28 d growth cycle and with relative growth rate (RGR) for height under low PAR for both ecotypes. Interestingly, under low irradiance PAR, changes (both increases and decreases) in GA8, the 2beta-hydroxylated 'inactive' catabolite of GA1, closely parallel bidaily stem growth changes for both ecotypes. Because the significantly greater stem elongation of both ecotypes in response to low irradiance PAR is associated with significant increases in the endogenous levels of five GAs (GA53, GA19, GA1, GA8) in the early 13-hydroxylation GA biosynthesis pathway (measured at days 7,14 and 21), we conclude that the low irradiance PAR has very likely induced an overall increase in GA biosynthesis.

Gibberellins↗
PubMed2006

Alendronic acid produces greater effects than risedronic acid on bone density and turnover in postmenopausal women with osteoporosis : results of FACTS -international.

BACKGROUND: The objective of the study was to evaluate the effects of alendronic acid once weekly relative to risedronic acid once weekly on bone mineral density (BMD), markers of bone turnover and tolerability in the treatment of osteoporosis in postmenopausal women. METHODS: This was a randomised, double-masked, double-dummy multicentre international study (75 centres in 27 countries in Europe, the Americas and Asia-Pacific). A total of 1303 women were screened and 936 with low bone density (T-score < or = -2.0 at the spine, hip trochanter, total hip or femoral neck) were randomised; 91% (n = 854) completed the study. Patients were randomised to treatment with either active alendronic acid 70 mg weekly (Fosamax) and placebo identical to risedronic acid weekly or active risedronic acid 35 mg weekly (Actonel) and placebo identical to alendronic acid weekly for 12 months. The primary efficacy endpoint was the percentage change from baseline in hip trochanter BMD at 12 months. Secondary endpoints included the percentage change from baseline in lumbar spine, total hip and femoral neck BMD; biochemical markers of bone turnover (including serum bone-specific alkaline phosphatase [BSAP] and urinary type I collagen N-telopeptides [NTx]); and safety and tolerability as assessed by reporting of adverse experiences. RESULTS: Alendronic acid produced greater increases in BMD than did risedronic acid at 12 months at all sites measured. Mean percentage increases from baseline in hip trochanter BMD at month 12 were 3.56% and 2.71% in the alendronic acid and risedronic acid groups, respectively (treatment difference [95% CI]: 0.83% [0.22, 1.45; p = 0.008]). Mean percentage increases from baseline were greater with alendronic acid than risedronic acid at the lumbar spine, total hip and femoral neck BMD at month 12 (p = 0.002, p < 0.001, p = 0.039, respectively). Increases in BMD with alendronic acid compared with risedronic acid were also significantly greater at 6 months at the trochanter and total hip. There was a greater reduction in bone turnover with alendronic acid compared with risedronic acid: NTx decreased 58% with alendronic acid compared with 47% with risedronic acid at 12 months (p < 0.001); and BSAP decreased 45% with alendronic acid compared with 34% with risedronic acid at 12 months (p < 0.001). Overall tolerability and upper gastrointestinal tolerability were similar for both agents. CONCLUSIONS: Alendronic acid once weekly produced greater BMD increases at both hip and spine sites and greater reductions in bone turnover relative to risedronic acid once weekly. Both agents were well tolerated with no significant difference in upper gastrointestinal adverse experiences. Clinicians should consider these results when making treatment decisions for postmenopausal women with osteoporosis.

Aged↗
PubMed2005

Long-term fracture prediction by DXA and QUS: a 10-year prospective study.

UNLABELLED: This study investigated the ability of DXA and QUS to predict fractures long term when measured around the time of the menopause. We found both DXA and QUS are able to predict both any fracture and "osteoporotic" fractures and that QUS can predict independently of BMD. INTRODUCTION: There are now many treatments available for prevention of osteoporotic fracture. To be cost-effective, we need to target those most at risk. This study examines the ability of DXA and QUS to predict fractures in an early postmenopausal population of women. MATERIALS AND METHODS: We prospectively measured 3883 women who had been randomly selected from a community-based register. At baseline, they were measured using DXA of spine and hip (Norland XR-26) and QUS of the heel (Walker Sonix UBA 575). Follow-up had a mean of 9.7 +/- 1.1 (SD) years. All incident fractures were identified and validated by examination of X-ray reports, and these were compared with those without fracture in a Cox-regression model to calculate hazard ratios (HRs). RESULTS: We found adjusted HRs for any fracture per 1 SD reduction in spine BMD to be 1.61 (1.42-1.83), whereas neck of femur BMD was 1.54 (1.34-1.75). Areas under the curve (AUC) for a receiver operator characteristic (ROC) analysis were 0.62 for spine BMD and 0.59 for neck BMD. In a subgroup where QUS was also measured, the HR for a 1 SD reduction in BMD was 1.69 (1.29-2.22) for spine BMD and 1.55 (1.17-2.06) for neck BMD. The HR for a 1 SD reduction in broadband ultrasound attenuation (BUA) was 1.53 (1.19-1.96), and 1.44 (1.12-1.86) when further adjusted for neck BMD. The AUCs were 0.63 for spine BMD, 0.59 for neck BMD, and 0.62 for BUA. When only osteoporotic fractures were examined, the HRs increased in all situations. BUA showed the highest HR of 2.25 (1.51-3.34), and when further adjusted for neck BMD was 2.12 (1.38-3.28). CONCLUSIONS: In conclusion, it may be possible to scan women around the time of the menopause to predict future fractures. It seems that, for "osteoporotic" fractures, BUA may be an improved predictor of fractures in comparison with DXA, because the relative risk is highest for BUA, and independent of BMD.

Absorptiometry, Photon↗
PubMed2005

Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22.

Bone mineral density (BMD) is a complex trait with a strong genetic component and an important predictor of osteoporotic fracture risk. Here we report the use of a cross-species strategy to identify genes that regulate BMD, proceeding from quantitative trait mapping in mice to association mapping of the syntenic region in the human genome. We identified a quantitative trait locus (QTL) on the mouse X-chromosome for post-maturity change in spine BMD in a cross of SAMP6 and AKR/J mice and conducted association mapping of the syntenic region on human chromosome Xp22. We studied 76 single nucleotide polymorphisms (SNP) from the human region in two sets of DNA pools prepared from individuals with lumbar spine-BMD (LS-BMD) values falling into the top and bottom 13th percentiles of a population-based study of 3100 post-menopausal women. This procedure identified a region of significant association for two adjacent SNP (rs234494 and rs234495) within the Xp22 locus (P<0.001). Individual genotyping for rs234494 in the BMD pools confirmed the presence of an association for alleles (P=0.018) and genotypes (P=0.008). Analysis of rs234494 and rs234495 in 1053 women derived from the same population who were not selected for BMD values showed an association with LS-BMD for rs234495 (P=0.01) and for haplotypes defined by both SNP (P=0.002). Our study illustrates that interspecies synteny can be used to identify and refine QTL for complex traits and represents the first example where a human QTL for BMD regulation has been mapped using this approach.

Absorptiometry, Photon↗
PubMed2005

Large-scale population-based study shows no evidence of association between common polymorphism of the VDR gene and BMD in British women.

UNLABELLED: The VDR is a candidate gene for osteoporosis. Here we studied five common polymorphisms of VDR in relation to calcium intake and vitamin D status in a population-based cohort of 3100 British women, but found no significant association with bone mass, bone loss, or fracture. INTRODUCTION: Population studies of vitamin D receptor (VDR) polymorphisms have produced conflicting results. We performed a comprehensive study dealing with all potential confounders in a large population to determine whether polymorphisms in the VDR gene influence bone health. MATERIALS AND METHODS: We studied 3100 women (50-63 years old) with bone markers, 25-hydroxyvitamin D, calcium, PTH, diet, and physical activity collected in 1998-2000. BMD was measured in 1990-1994 and 1998-2000. Fracture prevalence was assessed in 2002. Women were genotyped for five polymorphisms in the VDR gene: Cdx-2, Fok1, Bsm1, Apa1, and Taq1. The relationship between VDR and BMD, and interactions between VDR genotype, dietary calcium, and 25-hydroxyvitamin D, were examined using analysis of covariance. RESULTS: Compared with carriers of the G allele, homozygotes for the rare Cdx-2 A polymorphism (n = 136) had less bone loss (-0.5 +/- 1.2 versus -0.7 +/- 1.0%/year [SD]; p = 0.01) and lower PTH (3.0 +/- 1.6 versus 3.4 +/- 2.0 pM; p = 0.03) despite similar vitamin D status. The association was not significant after correction for multiple testing or adjustment for confounders. At low calcium intakes, AA homozygotes had greater femoral neck (FN) BMD compared with carriers of the G allele, but at higher calcium intakes, the association was reversed. At low calcium intake, homozygotes for the b allele of Bsm1 had greater BMD compared with carriers of the B allele, but at higher calcium intakes, there was no difference. Similar results were seen for the Taq1 polymorphism. There was no evidence of gene-nutrient interaction when adjusted for body weight. No interactions between genotypes and vitamin D status on BMD were observed. CONCLUSIONS: VDR does not seem to influence BMD or bone turnover in early postmenopausal white women with adequate calcium intake. Gene-nutrient interactions on BMD may be an indirect consequence of interactions between genotype and calcium intake on weight.

Alleles↗
PubMed2005

Polymorphisms of the CLCN7 gene are associated with BMD in women.

UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects. INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population. MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age. RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site. CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

Adult↗
PubMed2005

Alterations of the glutathione redox state improve apical meristem structure and somatic embryo quality in white spruce (Picea glauca).

In white spruce, an improvement of somatic embryo number and quality can be achieved through experimental manipulations of the endogenous levels of reduced (GSH) and oxidized (GSSG) glutathione. An optimal protocol for embryo production included an initial application of GSH in the maturation medium, followed by replacement with GSSG during the remaining maturation period. Under these conditions, the overall embryo population more than doubled, and the percentage of fully developed embryos increased from 22% to almost 70%. These embryos showed improved post-embryonic growth and conversion frequency. Structural studies revealed remarkable differences between embryo types, especially in storage product deposition pattern and organization of the shoot apical meristem (SAM). Compared with their control counterparts, glutathione-treated embryos accumulated a larger amount of starch during the early stages of development, and more protein and lipid bodies during the second half of development. Differences were also noted in the organization of SAMs. Shoot meristems of control embryos were poorly organized and were characterized by the presence of intercellular spaces, which caused separation of the subapical cells. Glutathione-treated embryos had well-organized meristems composed of tightly packed cells which lack large vacuoles. The improved organization of the shoot apical meristems in treated embryos was ascribed to a lower production of ethylene. Differences in meristem structure between control and treated embryos were also related to the localization pattern of HBK1, a shoot apical meristem 'molecular marker' gene with preferential expression to the meristematic cells of the shoot pole. Expression of this gene, which was localized to the apical cells in control embryos, was extended to the subapical cells of treated embryos. Overall, it appears that meristem integrity and embryo quality are under the direct control of the glutathione redox state.

Germination↗
PubMed2005

Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study.

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men < or =50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women >50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.

Bone Density↗
PubMed2005

Longitudinal changes in dietary intake in Scottish women around the menopause: changes in dietary pattern result in minor changes in nutrient intake.

OBJECTIVE: To examine dietary change that has occurred over 5 to 6 years. SUBJECTS: A cohort of Scottish women (n=898) with a mean age of 47.5 years (range 45-54 years) at baseline. DESIGN: Dietary intake was assessed by validated food-frequency questionnaire (FFQ) and analysed using the UK Composition of Foods database. RESULTS: Since the first dietary assessment, mean daily energy intake had decreased from 8.2+/-2.3 to 7.9+/-2.2 MJ. The degree of low energy reporting (defined as ratio of energy intake to basal metabolic rate <1.1) had increased from 18.7% at baseline to 25.6% at follow-up. Low energy reporters were significantly heavier than 'normal' energy reporters (mean weight at follow-up, 68.9+/-12.6 vs. 66.8+/-11.3 kg) and could be deliberately restricting intake rather than underreporting. Overall there were decreases in intakes of red meat, processed meat and cheese, but increases in poultry and non-oily fish consumption. Consumption of bread, biscuits and cakes had gone down and there was an increase in cereal and rice/pasta consumption. Intake of potatoes had decreased whereas fruit intake had increased. There were small but statistically significant differences in intakes for most nutrients (<8% change). Nutrient intakes at both visits were similar across menopausal status and usage groups of hormone replacement therapy. Modifications to the computer version of the McCance and Widdowson nutrient database, which differed from the published version, were noted. These changes altered the original baseline values for our study. CONCLUSIONS: The menopause per se is not a period of marked change in nutrient intake. Caution is advised when using computer databases of food compositions for longitudinal studies.

Basal Metabolism↗
PubMed2005

Low dietary potassium intakes and high dietary estimates of net endogenous acid production are associated with low bone mineral density in premenopausal women and increased markers of bone resorption in postmenopausal women.

BACKGROUND: The Western diet may be a risk factor for osteoporosis. Excess acid generated from high protein intakes increases calcium excretion and bone resorption. Fruit and vegetable intake could balance this excess acidity by providing alkaline salts of potassium. Algorithms based on dietary intakes of key nutrients can be used to approximate net endogenous acid production (NEAP) and to explore the association between dietary acidity and bone health. OBJECTIVE: We investigated the relation between dietary potassium and protein, NEAP (with an algorithm including the ratio of protein to potassium intake), and potential renal acid load (with an algorithm including dietary protein, phosphorous, potassium, magnesium, and calcium) and markers of bone health. DESIGN: Measurements of bone mineral density (BMD) (n = 3226) and urinary bone resorption markers (n = 2929) at the lumbar spine and femoral neck were performed in perimenopausal and early postmenopausal women aged 54.9 +/- 2.2 y (x +/- SD) in 1997-1999. BMD (g/cm(2)), free pyridinoline (fPYD), and free deoxypyridinoline (fDPD) were expressed relative to creatinine. Dietary intake was assessed with a food-frequency questionnaire. RESULTS: Comparison of the highest with the lowest quartile of potassium intake or the lowest with the highest NEAP showed a 6-8% increase in fPYD/creatinine and fDPD/creatinine. A difference of 8% in BMD was observed between the highest and lowest quartiles of potassium intake in the premenopausal group (n = 337). CONCLUSIONS: Dietary potassium, an indicator of NEAP and fruit and vegetable intake, may exert a modest influence on markers of bone health, which over a lifetime may contribute to a decreased risk of osteoporosis.

Acid-Base Equilibrium↗
PubMed2005

Bone shape, structure, and density as determinants of osteoporotic hip fracture: a pilot study investigating the combination of risk factors.

OBJECTIVES: This article compares and combines methods for examining the external shape and the internal structure of the proximal femur with bone mineral density (BMD) to provide a classifier for hip fracture. MATERIALS AND METHODS: Fifty standard pelvic radiographs were available from age-matched fracture and control groups of postmenopausal women. Femoral shape was measured using an active shape model, the trabecular structure by means of a Fourier transform. RESULTS: Both the shape and various structure measures were independent of BMD (P=0.16 and >0.50, respectively). Calculating the area under the receiver operator characteristic (ROC) curve (Az), each of shape (Az=0.81), the best structure measure (Az=0.79-0.93), and BMD (Az=0.79), could partially classify the fracture and control groups. However, the combination achieved almost perfect separation (Az=0.99). CONCLUSIONS: This pilot study shows how bone shape and structure can complement BMD measurements for investigations of fracture risk.

Absorptiometry, Photon↗