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Sökning: WFRF:(Ebeling Peter R.)

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1.
  • Graff, M., et al. (författare)
  • Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
  • 2017
  • Ingår i: PLoS Genet. - : Public library service. - 1553-7404 .- 1553-7390. ; 13:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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  • Marouli, Eirini, et al. (författare)
  • Rare and low-frequency coding variants alter human adult height
  • 2017
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
  • Tidskriftsartikel (refereegranskat)abstract
    • Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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4.
  • Graff, Mariaelisa, et al. (författare)
  • Genome-wide physical activity interactions in adiposity : A meta-analysis of 200,452 adults.
  • 2017
  • Ingår i: PLoS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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5.
  • Liu, Dajiang J., et al. (författare)
  • Exome-wide association study of plasma lipids in > 300,000 individuals
  • 2017
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 49:12, s. 1758-1766
  • Tidskriftsartikel (refereegranskat)abstract
    • We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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6.
  • Jamal, Sophie A., et al. (författare)
  • Effects of Denosumab on Fracture and Bone Mineral Density by Level of Kidney Function
  • 2011
  • Ingår i: Journal of Bone and Mineral Research. - 0884-0431 .- 1523-4681. ; 26:8, s. 1829-1835
  • Tidskriftsartikel (refereegranskat)abstract
    • The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 +/- 5.2 years; 73 women had an eGFR of 15 to 29mL/min; 2817, between 30 to 59mL/min; 4069, between 60 to 89mL/min, and 842 had an eGFR of 90mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.
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7.
  • Scott, David, et al. (författare)
  • Adiposity Without Obesity : Associations with Osteoporosis, Sarcopenia, and Falls in the Healthy Ageing Initiative Cohort Study
  • 2020
  • Ingår i: ; 28:11, s. 2232-2241
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Obesity is commonly defined by BMI rather than adiposity, which may have differential effects on musculoskeletal health. Musculoskeletal outcomes were compared in older adults with normal adiposity and normal BMI (NA‐NBMI), those with high adiposity but normal BMI (HA‐NBMI), and those with high adiposity and high BMI (HA‐HBMI).Methods: In 3,411 70‐year‐olds, obesity was defined as BMI ≥ 30 kg/m2 and adiposity as body fat percentage ≥ 25% (men) or ≥ 35% (women) from dual‐energy x‐ray absorptiometry. Bone parameters were measured by dual‐energy x‐ray absorptiometry and peripheral quantitative computed tomography. Sarcopenia was defined as low handgrip strength with or without low appendicular lean mass. Falls were self‐reported 6 and 12 months later.Results: Prevalence of NA‐NBMI, HA‐NBMI, and HA‐HBMI was 14.2%, 68.1%, and 17.7%, respectively. Compared with HA‐HBMI, HA‐NBMI had increased likelihood for sarcopenia (adjusted odds ratio: 3.99; 95% CI: 1.41‐11.32) and osteoporosis (2.91; 95% CI: 2.35‐3.61) but similar likelihood of falls (P > 0.05). HA‐NBMI had lower values for bone geometry parameters, as well as grip strength, than both NA‐NBMI and HA‐HBMI (all P < 0.05).Conclusions: High adiposity without high BMI is more common than BMI‐defined obesity in older Swedish adults but does not provide similar protection from osteoporosis and sarcopenia.
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8.
  • Scott, David, et al. (författare)
  • Associations of Sarcopenia and Its Components with Bone Structure and Incident Falls in Swedish Older Adults
  • 2019
  • Ingår i: ; 105:1, s. 26-36
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to compare bone structure parameters and likelihood of falls across European Working Group on Sarcopenia in Older People (EWGSOP2) sarcopenia categories. 3334 Swedish 70-year olds had appendicular lean mass (normalized to height; ALMHt), lumbar spine and total hip areal BMD (aBMD) estimated by dual-energy X-ray absorptiometry. Volumetric BMD (vBMD) and structure at the distal and proximal tibia and radius were estimated by peripheral quantitative computed tomography. Hand grip strength and timed up-and-go were assessed, and sarcopenia was defined according to EWGSOP2 criteria. Incident falls were self-reported 6 and 12 months after baseline. Only 0.8% and 1.0% of participants had probable and confirmed sarcopenia, respectively. Almost one-third of participants with confirmed sarcopenia reported incident falls, compared with 20% for probable sarcopenia and 14% without sarcopenia (P = 0.025). Participants with confirmed sarcopenia had poorer bone parameters (all P < 0.05) except endosteal circumference at the proximal radius and tibia, while those with probable sarcopenia had lower cortical area at the proximal radius (B = - 5.9; 95% CI - 11.7, - 0.1 mm2) and periosteal and endosteal circumferences at the proximal tibia (- 3.3; - 6.4, - 0.3 and - 3.8; - 7.5, - 0.1 mm2, respectively), compared with those without sarcopenia. Compared with probable sarcopenia, confirmed sarcopenic participants had significantly lower lumbar spine and total hip aBMD, distal radius and tibia total vBMD, and proximal radius and tibia cortical vBMD, area and thickness (all P < 0.05). Swedish 70-year olds with confirmed sarcopenia demonstrate poorer BMD and bone architecture than those with probable and no sarcopenia, and have increased likelihood of incident falls.
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9.
  • Scott, David, et al. (författare)
  • Mid-calf skeletal muscle density and its associations with physical activity, bone health and incident 12-month falls in older adults : The Healthy Ageing Initiative
  • 2019
  • Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 120, s. 446-451
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Lower skeletal muscle density, indicating greater infiltration of adipose tissue into muscles, is associated with higher fracture risk in older adults. We aimed to determine whether mid-calf muscle density is associated with falls risk and bone health in community-dwelling older adults.METHODS: 2214 community-dwelling men and women who participated in the Healthy Ageing Initiative (Sweden) study at age 70 were included in this analysis. Mid-calf muscle density (mg/cm3) at the proximal tibia, and volumetric bone mineral density (vBMD) and architecture at the distal and proximal tibia and radius, were assessed by peripheral quantitative computed tomography. Whole-body lean and fat mass, lumbar spine and total hip areal bone mineral density (aBMD) were assessed by dual-energy X-ray absorptiometry. Participants completed seven-day accelerometer measurements of physical activity intensity, and self-reported falls data were collected 6 and 12 months later.RESULTS: 302 (13.5%) participants reported a fall at the 6- or 12-month interview, and 29 (1.3%) reported a fall at both interviews. After adjustment for confounders, each standard deviation decrease in mid-calf muscle density was associated with a trend towards greater likelihood of experiencing a fall (OR 1.13; 95% CI 1.00, 1.29 per SD lower) and significantly greater likelihood of multiple falls (1.61; 1.16, 2.23). Higher muscle density was not associated with total hip aBMD, and was associated with lower lumbar spine aBMD (B = -0.003; 95% CI -0.005, -0.001 per mg/cm3) and higher proximal cortical vBMD (0.74; 0.20, 1.28) at the radius. At the tibia, muscle density was positively associated with distal total and trabecular vBMD, and proximal total and cortical vBMD, cortical thickness, cortical area and stress-strain index (all P < 0.05). Only moderate/vigorous (%) intensity physical activity, not sedentary time or light activity, was associated with higher mid-calf muscle density (0.086; 0.034, 0.138).CONCLUSIONS: Lower mid-calf muscle density is independently associated with higher likelihood for multiple incident falls and appears to have localised negative effects on bone structure in older adults.
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