F. McGuigan - Academia.edu (original) (raw)

Papers by F. McGuigan

Journal of Bone and Mineral Research, 2007

Calcified Tissue International, 2003

The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has ... more The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant association between the G-1102A genotype and BMD at the lumbar spine ( P = 0.01) and femoral neck ( P = 0.03). The association remained significant after correcting for age, weight, height, menopausal status/HRT use and smoking ( P = 0.008 for spine BMD and P = 0.03 for hip BMD), and homozygotes for the -1100 "G" allele had BMD values significantly higher than individuals who carried the -1100 "A" allele at both spine ( P = 0.007) and hip ( P = 0.047). Subgroup analysis showed that the association between G-1102A and BMD was restricted to premenopausal women who comprised 50.6% of the study group. None of the other polymorphisms or haplotypes were significantly associated with BMD in the study group as a whole or in any subgroup. Functional studies will need to be performed to determine the mechanisms that underlie this association, but we conclude that, in this relatively large population, allelic variation at the G-1102A site of TCIRG1 accounts for part of the heritable component of BMD in Scottish women, possibly by affecting peak bone mass.

Bone, 1997

Genetic factors play an important role in determining bone mass and several genes probably act as... more Genetic factors play an important role in determining bone mass and several genes probably act as regulators of this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone density, since it has stimulatory effects on cells of the osteoclast lineage and has been implicated in the pathogenesis of bone loss associated with estrogen deficiency. Here we studied the relationship between bone mineral density (BMD) and a polymorphic AT rich minisatelite repeat in the 3' flank of the IL-6 gene in a cohort of 200 women. Six length variants were identified (designated A-F), but four of these were rare such that the vast majority of individuals fell into one of two common genotypes: F/F (58.5%) and C/F (27.5%). There was a significant relationship between IL-6 genotype and bone mass at the lumbar spine as determined by analysis of variance (p = 0.04) and a similar trend for bone mass at the femoral neck (p = 0.11). When BMD values were compared in the two common genotypes, we found that spine BMD values were significantly higher in the C/F genotype (mean + SEM = 0.94 + 0.04 g/cm2) as compared with the F/F genotype (0.81-C 0.02 g/cm'; p = 0.012). A similar trend was seen for hip BMD values, but here, the difference failed to reach statistical significance (p = 0.06). Further analysis showed that genotype-specific effects on bone mass were observed in both premenopausal and postmenopausal women and did not increase with age, sugggesting that the association between IL-6 polymorphisms and bone density may be mediated by an effect on peak bone mass, rather than rate of bone loss. We conclude that bone mass is associated with two common polymorphisms of the IL-6 gene. Although the mechanisms that underlie this association will require further research, our data suggest that polymorphic variation at the IL-6 gene locus may contribute to the genetic regulation of bone mass.

Bone, 2011

expression. Our data also imply that the joint pathology caused by loss of ANK function initiates... more expression. Our data also imply that the joint pathology caused by loss of ANK function initiates in the ligaments. The spatial-temporal correlation between changes in joints and trabecular bone indicates that the osteopenia observed in murine and human ankylosis is a secondary event. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.

European Journal of Immunology, 1992

Nitric oxide responses in mediates suppression of T cell murine Trypanosoma brucei infection* Afr... more Nitric oxide responses in mediates suppression of T cell murine Trypanosoma brucei infection* African trypanosomes induce a generalized state of immunosuppression in their mammalian hosts. One characteristic of this is a suppression of lymphocyte responses to mitogen, which is mediated by suppressor macrophages. We investigated the involvement of nitric oxide in this phenomenon. Both peritoneal and splenic cell cultures from infected mice released nitrite and this was inhibitable by NG-monomethyl L-arginine (L-NMMA). The release of nitrite correlated with suppressed splenic T cell proliferative responses to concanavalin A. It was shown that adherent spleen cells from infected mice mediate suppression, which could be abrogated by L-NMMA. These results suggest that in 7: brucei infection, the activation of macrophages to produce nitric oxide leads to impaired lymphocyte responses and immunosuppression.

Osteoporosis International, 2017

Kidney function decreases with age; however, the long-term influence on bone density (BMD) in old... more Kidney function decreases with age; however, the long-term influence on bone density (BMD) in older women already at risk of osteoporosis is unknown. We followed kidney function and bone loss for 10 years. Declining kidney function was adversely associated with bone loss and mineral homeostasis in old women, though it attenuated with advanced aging. Introduction Existing studies do not fully address the relationship between kidney function and bone metabolism with advanced aging in Caucasian women. This study describes the association between kidney function, BMD, bone loss and bone metabolism in older women and provides a review of the available literature for context. Methods We studied participants from the OPRA cohort with follow-up after 5 and 10 years. Using plasma cystatin C (cysC), estimated glomerular function rate (eGFR) was evaluated at age 75 (n = 981), 80 (n = 685) and 85 (n = 365). Women were stratified into Bnormal^function (CKD stages 1-2), Bintermediate^(stage 3a) and Bpoor^(stages 3b-5), and outcome measures-BMD, bone loss and markers of mineral homeostasis-were compared. Results Femoral neck (FN) BMD positively associated with kidney function at 75 years old (β = 0.001, p = 0.028) and 80 years old (β = 0.001, p = 0.001), although with small effect size. Prevalence of osteoporosis (FN T-score ≤ − 2.5) did not differ with kidney function. Measured at age 75, women with poor kidney function had higher annual percentage bone loss over 5 years compared to those with normal function (2.3%, 95% CI 1.8-2.8 versus 1.3%, 95% CI 1.1-1.5, p = 0.007), although not when measured from age 80 or 85. Additionally, markers of mineral homeostasis (PTH, phosphate, vitamin D, calcium), CRP and osteocalcin differed by kidney function. Conclusions In old women, kidney function is associated with BMD, bone loss and altered mineral homeostasis; probably, a relationship attenuated in the very elderly.

The American Journal of Clinical Nutrition, 2018

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We pr... more Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age 2 , and height with or without fat mass adjustments (Model 1 no fat adjustment; Model Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2015

This longitudinal study investigates the association between C-reactive protein (CRP), osteoporos... more This longitudinal study investigates the association between C-reactive protein (CRP), osteoporosis, fractures, and mortality in 1044 elderly women. CRP was not an indicator for low bone mineral density (BMD), bone loss, or fracture in elderly women; however, women with elevated CRP levels over a prolonged period lost more bone over the 10-year follow-up, although fracture risk was not increased. Inflammation may contribute to the pathophysiology underlying impaired bone metabolism. This study investigates the association between CRP, BMD, bone loss, fracture risk, and mortality in women aged 75 and above. This longitudinal study is based on 1044 women, all age 75 at inclusion, reassessed at ages 80 and 85, with a mean follow-up time of 11.6 years (maximum 16.9 years). Women in the lowest CRP quartile (mean 0.63 mg/L) had lower BMD compared to those in the highest CRP quartile (mean 5.74 mg/L) at total hip (TH) (0.809 vs. 0.871 g/cm2, p<0.001) and femoral neck (FN) (0.737 vs. 0.7...

Murray, LJ, Boreham, CAG, Neville, CE, Gallagher, Alison, McGuigan, F, Ralston, SH, McGuinness, M... more Murray, LJ, Boreham, CAG, Neville, CE, Gallagher, Alison, McGuigan, F, Ralston, SH, McGuinness, M, Strain, JJ, Robson, PJ, Cran, GW and Savage, JM (2000) Birthweight and bone health in young adults: The Young Hearts project. Calcified Tissue International, 66 ( ...

Osteoporos Int, 2014

Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational ... more Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational cohort study of elderly women.

PloS one, 2014

Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. ... more Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to ...

Osteoporosis International, 2009

Fall prevention is a key strategy for reducing osteoporotic fractures. We investigated the associ... more Fall prevention is a key strategy for reducing osteoporotic fractures. We investigated the association between vitamin D receptor (VDR) polymorphisms and reported falls in postmenopausal women. Bsm1 polymorphisms were associated with falls, balance and muscle power measurements. These results may explain some of the excess fracture risk associated with VDR in some studies. Fall prevention is a key strategy for reducing osteoporotic fractures. It has been suggested that vitamin D supplementation may reduce the incidence of falls by reducing body sway and increasing muscle power. The vitamin D receptor gene is a well-studied candidate gene for osteoporosis. We investigated the association between VDR polymorphisms and reported falls in postmenopausal women. Falls data were collected in two separate population cohorts. Five polymorphisms of the VDR gene were analysed (Cdx-2, Fok-1, BsmI, Taq1 and Apa1) in the Aberdeen Prospective Osteoporosis Screening Study (APOSS) cohort. Results found in APOSS were then validated in an independent cohort--the Osteoporosis and Ultrasound (OPUS) study (Bsm1 and Fok1 only), where muscle power and balance were also measured. Carriers of the &#39;B&#39; allele (Bsm1) showed an increased risk for falls. In APOSS, this was statistically significant for visit 3 multiple falls (p = 0.047) and for recurrent falls (p = 0.043). Similar results were found in OPUS for visit 1 falls (p = 0.025) and visit 1 multiple falls (p = 0.015). Bsm1 polymorphisms were also associated with balance and muscle power measurements. In conclusion, these results demonstrate an association between the Bsm1 polymorphism and risk of falling that may explain some of the excess fracture risk associated with VDR in some studies.

Osteoporosis International, 2012

In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated bo... more In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated bone mineral density (BMD) values, consequently missing a large proportion of those with osteoporosis. Our aim was to determine the distribution and impact of degenerative changes on lumbar spine DXA over time and its clinical implications. Methods: Participants were 1044 women from the population-based OPRA-cohort. All women were 75 years old at invitation and followed up after 5 years (n=715) and 10 years (n=382). Degenerative changes were evaluated visually on the DXA image for each vertebra L1 to L4 (intra-observer precision kappa values 0.66-0.70). Results: At baseline, apparent degenerative changes were more frequent in the inferior segments of the lumbar spine: 5% (L1), 15% (L2), 26% (L3), 36% (L4) and increased over time. At 10-years the prevalence was: 20% (L1), 39% (L2), 59% (L3), 72% (L4), resulting in a significant increase in overall BMD. In women without apparent degenerative changes, BMD remained stable between 75-85 rather than an expected bone loss. At baseline, 37% had osteoporosis (BMD<-2.5) at L1-L4; exclusion of women with apparent degenerative changes increased this proportion to 47%. Using L1-L2, which was less prone to degenerative changes, 46% of women were classified as osteoporotic regardless of degenerative changes. Conclusion: Degenerative changes were very common in elderly women, accelerated disproportionately over time, were increasingly frequent from vertebrae L1-L4 and had significant impact on diagnosing osteoporosis. This suggests that routine reporting of spine BMD at L1-L2 would add valuable information for re-assessment and monitoring.

Osteoporosis International, 2012

Birth weight is more important for peak bone mineral content than for bone density: the PEAK-25 s... more Birth weight is more important for peak bone mineral content than for bone density: the PEAK-25 study of 1,061 young adult women.

Osteoporosis International, 2012

Self-reported recreational exercise combining regularity and impact is necessary to maximize bone... more Self-reported recreational exercise combining regularity and impact is necessary to maximize bone mineral density in young adult women : A population-based study of 1,061 women 25 years of age.

Journal of Bone and Mineral Research, 2010

Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, t... more Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (S-TotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC (p ¼ .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures (p ¼ .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture (p ¼ .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis.

Journal of Bone and Mineral Research, 2013

Previous genome-wide association studies (GWAS) have identified common variants in genes associat... more Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n ¼ 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age-and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p ¼ 1.7 Â 10 À9) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p ¼ 1.3 Â 10 À8) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n ¼ 5597 for femoral neck; n ¼ 4744 for lumbar spine). When

Human Molecular Genetics, 2014

Journal of Bone and Mineral Research, 2007

Calcified Tissue International, 2003

The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has ... more The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant association between the G-1102A genotype and BMD at the lumbar spine ( P = 0.01) and femoral neck ( P = 0.03). The association remained significant after correcting for age, weight, height, menopausal status/HRT use and smoking ( P = 0.008 for spine BMD and P = 0.03 for hip BMD), and homozygotes for the -1100 &amp;amp;quot;G&amp;amp;quot; allele had BMD values significantly higher than individuals who carried the -1100 &amp;amp;quot;A&amp;amp;quot; allele at both spine ( P = 0.007) and hip ( P = 0.047). Subgroup analysis showed that the association between G-1102A and BMD was restricted to premenopausal women who comprised 50.6% of the study group. None of the other polymorphisms or haplotypes were significantly associated with BMD in the study group as a whole or in any subgroup. Functional studies will need to be performed to determine the mechanisms that underlie this association, but we conclude that, in this relatively large population, allelic variation at the G-1102A site of TCIRG1 accounts for part of the heritable component of BMD in Scottish women, possibly by affecting peak bone mass.

Bone, 1997

Genetic factors play an important role in determining bone mass and several genes probably act as... more Genetic factors play an important role in determining bone mass and several genes probably act as regulators of this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone density, since it has stimulatory effects on cells of the osteoclast lineage and has been implicated in the pathogenesis of bone loss associated with estrogen deficiency. Here we studied the relationship between bone mineral density (BMD) and a polymorphic AT rich minisatelite repeat in the 3' flank of the IL-6 gene in a cohort of 200 women. Six length variants were identified (designated A-F), but four of these were rare such that the vast majority of individuals fell into one of two common genotypes: F/F (58.5%) and C/F (27.5%). There was a significant relationship between IL-6 genotype and bone mass at the lumbar spine as determined by analysis of variance (p = 0.04) and a similar trend for bone mass at the femoral neck (p = 0.11). When BMD values were compared in the two common genotypes, we found that spine BMD values were significantly higher in the C/F genotype (mean + SEM = 0.94 + 0.04 g/cm2) as compared with the F/F genotype (0.81-C 0.02 g/cm'; p = 0.012). A similar trend was seen for hip BMD values, but here, the difference failed to reach statistical significance (p = 0.06). Further analysis showed that genotype-specific effects on bone mass were observed in both premenopausal and postmenopausal women and did not increase with age, sugggesting that the association between IL-6 polymorphisms and bone density may be mediated by an effect on peak bone mass, rather than rate of bone loss. We conclude that bone mass is associated with two common polymorphisms of the IL-6 gene. Although the mechanisms that underlie this association will require further research, our data suggest that polymorphic variation at the IL-6 gene locus may contribute to the genetic regulation of bone mass.

Bone, 2011

expression. Our data also imply that the joint pathology caused by loss of ANK function initiates... more expression. Our data also imply that the joint pathology caused by loss of ANK function initiates in the ligaments. The spatial-temporal correlation between changes in joints and trabecular bone indicates that the osteopenia observed in murine and human ankylosis is a secondary event. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.

European Journal of Immunology, 1992

Nitric oxide responses in mediates suppression of T cell murine Trypanosoma brucei infection* Afr... more Nitric oxide responses in mediates suppression of T cell murine Trypanosoma brucei infection* African trypanosomes induce a generalized state of immunosuppression in their mammalian hosts. One characteristic of this is a suppression of lymphocyte responses to mitogen, which is mediated by suppressor macrophages. We investigated the involvement of nitric oxide in this phenomenon. Both peritoneal and splenic cell cultures from infected mice released nitrite and this was inhibitable by NG-monomethyl L-arginine (L-NMMA). The release of nitrite correlated with suppressed splenic T cell proliferative responses to concanavalin A. It was shown that adherent spleen cells from infected mice mediate suppression, which could be abrogated by L-NMMA. These results suggest that in 7: brucei infection, the activation of macrophages to produce nitric oxide leads to impaired lymphocyte responses and immunosuppression.

Osteoporosis International, 2017

Kidney function decreases with age; however, the long-term influence on bone density (BMD) in old... more Kidney function decreases with age; however, the long-term influence on bone density (BMD) in older women already at risk of osteoporosis is unknown. We followed kidney function and bone loss for 10 years. Declining kidney function was adversely associated with bone loss and mineral homeostasis in old women, though it attenuated with advanced aging. Introduction Existing studies do not fully address the relationship between kidney function and bone metabolism with advanced aging in Caucasian women. This study describes the association between kidney function, BMD, bone loss and bone metabolism in older women and provides a review of the available literature for context. Methods We studied participants from the OPRA cohort with follow-up after 5 and 10 years. Using plasma cystatin C (cysC), estimated glomerular function rate (eGFR) was evaluated at age 75 (n = 981), 80 (n = 685) and 85 (n = 365). Women were stratified into Bnormal^function (CKD stages 1-2), Bintermediate^(stage 3a) and Bpoor^(stages 3b-5), and outcome measures-BMD, bone loss and markers of mineral homeostasis-were compared. Results Femoral neck (FN) BMD positively associated with kidney function at 75 years old (β = 0.001, p = 0.028) and 80 years old (β = 0.001, p = 0.001), although with small effect size. Prevalence of osteoporosis (FN T-score ≤ − 2.5) did not differ with kidney function. Measured at age 75, women with poor kidney function had higher annual percentage bone loss over 5 years compared to those with normal function (2.3%, 95% CI 1.8-2.8 versus 1.3%, 95% CI 1.1-1.5, p = 0.007), although not when measured from age 80 or 85. Additionally, markers of mineral homeostasis (PTH, phosphate, vitamin D, calcium), CRP and osteocalcin differed by kidney function. Conclusions In old women, kidney function is associated with BMD, bone loss and altered mineral homeostasis; probably, a relationship attenuated in the very elderly.

The American Journal of Clinical Nutrition, 2018

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We pr... more Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age 2 , and height with or without fat mass adjustments (Model 1 no fat adjustment; Model Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2015

This longitudinal study investigates the association between C-reactive protein (CRP), osteoporos... more This longitudinal study investigates the association between C-reactive protein (CRP), osteoporosis, fractures, and mortality in 1044 elderly women. CRP was not an indicator for low bone mineral density (BMD), bone loss, or fracture in elderly women; however, women with elevated CRP levels over a prolonged period lost more bone over the 10-year follow-up, although fracture risk was not increased. Inflammation may contribute to the pathophysiology underlying impaired bone metabolism. This study investigates the association between CRP, BMD, bone loss, fracture risk, and mortality in women aged 75 and above. This longitudinal study is based on 1044 women, all age 75 at inclusion, reassessed at ages 80 and 85, with a mean follow-up time of 11.6 years (maximum 16.9 years). Women in the lowest CRP quartile (mean 0.63 mg/L) had lower BMD compared to those in the highest CRP quartile (mean 5.74 mg/L) at total hip (TH) (0.809 vs. 0.871 g/cm2, p<0.001) and femoral neck (FN) (0.737 vs. 0.7...

Murray, LJ, Boreham, CAG, Neville, CE, Gallagher, Alison, McGuigan, F, Ralston, SH, McGuinness, M... more Murray, LJ, Boreham, CAG, Neville, CE, Gallagher, Alison, McGuigan, F, Ralston, SH, McGuinness, M, Strain, JJ, Robson, PJ, Cran, GW and Savage, JM (2000) Birthweight and bone health in young adults: The Young Hearts project. Calcified Tissue International, 66 ( ...

Osteoporos Int, 2014

Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational ... more Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational cohort study of elderly women.

PloS one, 2014

Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. ... more Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to ...

Osteoporosis International, 2009

Fall prevention is a key strategy for reducing osteoporotic fractures. We investigated the associ... more Fall prevention is a key strategy for reducing osteoporotic fractures. We investigated the association between vitamin D receptor (VDR) polymorphisms and reported falls in postmenopausal women. Bsm1 polymorphisms were associated with falls, balance and muscle power measurements. These results may explain some of the excess fracture risk associated with VDR in some studies. Fall prevention is a key strategy for reducing osteoporotic fractures. It has been suggested that vitamin D supplementation may reduce the incidence of falls by reducing body sway and increasing muscle power. The vitamin D receptor gene is a well-studied candidate gene for osteoporosis. We investigated the association between VDR polymorphisms and reported falls in postmenopausal women. Falls data were collected in two separate population cohorts. Five polymorphisms of the VDR gene were analysed (Cdx-2, Fok-1, BsmI, Taq1 and Apa1) in the Aberdeen Prospective Osteoporosis Screening Study (APOSS) cohort. Results found in APOSS were then validated in an independent cohort--the Osteoporosis and Ultrasound (OPUS) study (Bsm1 and Fok1 only), where muscle power and balance were also measured. Carriers of the &#39;B&#39; allele (Bsm1) showed an increased risk for falls. In APOSS, this was statistically significant for visit 3 multiple falls (p = 0.047) and for recurrent falls (p = 0.043). Similar results were found in OPUS for visit 1 falls (p = 0.025) and visit 1 multiple falls (p = 0.015). Bsm1 polymorphisms were also associated with balance and muscle power measurements. In conclusion, these results demonstrate an association between the Bsm1 polymorphism and risk of falling that may explain some of the excess fracture risk associated with VDR in some studies.

Osteoporosis International, 2012

In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated bo... more In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated bone mineral density (BMD) values, consequently missing a large proportion of those with osteoporosis. Our aim was to determine the distribution and impact of degenerative changes on lumbar spine DXA over time and its clinical implications. Methods: Participants were 1044 women from the population-based OPRA-cohort. All women were 75 years old at invitation and followed up after 5 years (n=715) and 10 years (n=382). Degenerative changes were evaluated visually on the DXA image for each vertebra L1 to L4 (intra-observer precision kappa values 0.66-0.70). Results: At baseline, apparent degenerative changes were more frequent in the inferior segments of the lumbar spine: 5% (L1), 15% (L2), 26% (L3), 36% (L4) and increased over time. At 10-years the prevalence was: 20% (L1), 39% (L2), 59% (L3), 72% (L4), resulting in a significant increase in overall BMD. In women without apparent degenerative changes, BMD remained stable between 75-85 rather than an expected bone loss. At baseline, 37% had osteoporosis (BMD<-2.5) at L1-L4; exclusion of women with apparent degenerative changes increased this proportion to 47%. Using L1-L2, which was less prone to degenerative changes, 46% of women were classified as osteoporotic regardless of degenerative changes. Conclusion: Degenerative changes were very common in elderly women, accelerated disproportionately over time, were increasingly frequent from vertebrae L1-L4 and had significant impact on diagnosing osteoporosis. This suggests that routine reporting of spine BMD at L1-L2 would add valuable information for re-assessment and monitoring.

Osteoporosis International, 2012

Birth weight is more important for peak bone mineral content than for bone density: the PEAK-25 s... more Birth weight is more important for peak bone mineral content than for bone density: the PEAK-25 study of 1,061 young adult women.

Osteoporosis International, 2012

Self-reported recreational exercise combining regularity and impact is necessary to maximize bone... more Self-reported recreational exercise combining regularity and impact is necessary to maximize bone mineral density in young adult women : A population-based study of 1,061 women 25 years of age.

Journal of Bone and Mineral Research, 2010

Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, t... more Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (S-TotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC (p ¼ .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures (p ¼ .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture (p ¼ .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis.

Journal of Bone and Mineral Research, 2013

Previous genome-wide association studies (GWAS) have identified common variants in genes associat... more Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n ¼ 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age-and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p ¼ 1.7 Â 10 À9) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p ¼ 1.3 Â 10 À8) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n ¼ 5597 for femoral neck; n ¼ 4744 for lumbar spine). When

Human Molecular Genetics, 2014