| 1. |
- Loth, Daan W, et al.
(author)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Journal article (peer-reviewed)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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| 2. |
- Artigas Soler, María, et al.
(author)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Journal article (peer-reviewed)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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| 3. |
- Repapi, Emmanouela, et al.
(author)
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Genome-wide association study identifies five loci associated with lung function.
- 2010
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:1, s. 36-44
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Journal article (peer-reviewed)abstract
- Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
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| 4. |
- Demirkan, Ayse, et al.
(author)
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Genetic architecture of circulating lipid levels
- 2011
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 19:7, s. 813-819
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Journal article (peer-reviewed)abstract
- Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
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| 5. |
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| 6. |
- Obeidat, Ma'en, et al.
(author)
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A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5, s. e19382-
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Journal article (peer-reviewed)abstract
- Rationale: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives: To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods: We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results: The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3 x 10(-5). The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81 x 10(-5)), CNTN5 (P = 4.37 x 10(-4)), and TRPV4 (P = 1.58 x 10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41 x 10(-5)), followed by PDE4D (P = 1.22 x 10(-4)). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38 x 10(-4)), and ESR1 (P = 5.42 x 10(-4)) among ever-smokers. Conclusions: Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.
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| 7. |
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| 8. |
- Spets, J-P, et al.
(author)
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Bioorganic materials as a fuel source for low-temperature direct-mode fuel cells
- 2010
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In: Electrochimica Acta. - : Elsevier BV. - 0013-4686 .- 1873-3859. ; 55:26, s. 7706-7709
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Journal article (peer-reviewed)abstract
- In this study a direct-mode fuel cell in which the fuel and electrolyte are mixed with each other is tested. An alkaline electrolyte is used. The aim was to develop a fuel cell which operates directly by mixing the fuel with the electrolyte. The target is to create a fuel cell with a capacity of a few mW cm(-2) with starch as a fuel source. Starch, glucose, and sorbitol were tested as fuels for the fuel cell. With the selected fuel cell type and with glucose as the fuel, a maximum current density of 8 mA cm(-2) with a voltage of 0.5 V was obtained.
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| 9. |
- Spets, J. -P, et al.
(author)
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Direct glucose fuel cell with the anion exchange membrane in the near-neutral-state electrolyte
- 2012
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In: International Journal of Electrochemical Science. - 1452-3981. ; 7:12, s. 11696-11705
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Journal article (peer-reviewed)abstract
- This paper deals with the direct glucose fuel cell with an electrolyte at near-neutral-state pH value at room temperature by incorporating an anion exchange membrane (AEM) that was directly attached to a cathode. The wetted surface of the cathode was exposed to the AEM without implementing hot-pressing. The current-voltage curves were measured and the specific energy values for glucose were calculated for every test. Different concentrations of glucose were used and the results show that the lower the concentration of glucose, the higher is the specific energy, apparently showing higher utilization of the fuel with high Coulombic efficiency.
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| 10. |
- Spets, J. -P, et al.
(author)
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Effect of temperature on a direct glucose anion exchange membrane fuel cell in a near-neutral-state electrolyte
- 2013
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In: International Journal of Electrochemical Science. - 1452-3981. ; 8:1, s. 1226-1236
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Journal article (peer-reviewed)abstract
- A direct glucose anion exchange membrane fuel cell (AEMFC) with a near-neutral-state electrolyte was studied at varying temperatures of 20, 30 and 37 ° C at two different concentrations of glucose of 0.1 and 0.3 M and with three concentrations of electrolyte of 0.1, 0.2 and 0.3 M [PO4]tot. The prime objective was to show how specific energy (W kg-1 glucose) of the direct glucose AEMFC is related to the operation temperature and concentrations of the species. Current and voltage values were measured together with the pHs and conductivities of the electrolytes. No component analysis of the final products after the fuel cell operation were done as the oxidation products of glucose is believed to be mainly gluconic acid and unreacted glucose as shown in the low Coulombic efficiency based on the exchange of 24 e-. Temperature, electrolyte and glucose concentrations have shown to have pronounced effect for the achievement of the highest energy capacity of 5.15 Wh kg-1 glucose.
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| 11. |
- Spets, J. P., et al.
(author)
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Enhancement of glucose electro-oxidation by an external electromagnetic field in direct-mode fuel cells
- 2010
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In: Journal of Power Sources. - : Elsevier BV. - 0378-7753 .- 1873-2755. ; 195:2, s. 475-479
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Journal article (peer-reviewed)abstract
- In this study a direct-mode fuel cell in which the fuel and electrolyte are mixed with each other is tested. An alkaline electrolyte is used. The direct-mode fuel cell is exposed to an externally generated electromagnetic field between electrodes to cause both the splitting of the fuel molecule into smaller units (i.e. electrochemical reforming) and an increase in the activity of catalyst materials on the fuel before electrochemical oxidation. The target is to create a fuel cell with a capacity range of a few mW cm(-2) with glucose as a fuel. In the selected fuel cell type with glucose as the fuel, a maximum current density of 13 mA cm(-2) was obtained. On the basis of the tests it seems to be possible to use the glucose-fuelled cell in small-scale applications, e. g. in small electronic devices.
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| 12. |
- Spets, J. -P., et al.
(author)
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Production of glucose by starch and cellulose acid hydrolysis and its use as a fuel in low-temperature direct-mode fuel cells
- 2010
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In: THERMEC 2009, PTS 1-4. - Berlin. ; , s. 1164-1169
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Conference paper (other academic/artistic)abstract
- The use of glucose, which is produced from the acid hydrolysis of starch and cellulose, is studied as a fuel in a low-temperature direct-mode fuel cell (LTDMFC) with an alkaline electrolyte. Glucose is regarded as being as good a fuel as bioethanol, because both the fuels give 2 electrons per molecule in the fuel cell without carbonisation problems. However, glucose can be produced with fewer processing stages from starch and cellulose than can bioethanol. In the LTDMFC the fuel and the electrolyte are mixed with each other and the fuel cell is equipped only with metal catalysts. Cellulose as a fuel is of great importance because the fuel for the energy production is not taken from food production. A description of an acid hydrolysis method for starch and cellulose is presented. Values for glucose concentrations in each hydrolysate are analysed by means of a chromatographic method. Each glucose hydrolysate was made alkaline by adding of potassium hydroxide before feed in the fuel cell. Polarisation curves were measured, and they were found to produce lower current density values when compared to earlier tests with pure glucose. The Coulombic efficiency of pure glucose electrochemical oxidation in LTDMFC, which was calculated from a ratio of detected current capacity (As) to the maximum current capacity with the release of two electrons per molecule, was also found to be very low. Concerning the hydrolysates, the glucose concentrations were found to have values that were too low when compared to the earlier tests with pure glucose in a concentration of 1 M. The further development demands for the system under consideration are indicated. The concentration of glucose in the hydrolysate is essential to achieve high enough current density values in the LTDMFC.
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| 13. |
- Spets, J. -P, et al.
(author)
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The Simultaneous Uses of the Direct-Mode Bioorganic Fuel Cell and the Function Generator for the Enhancement of the Glucose Electro-chemical Oxidation
- 2010
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In: International Journal of Electrochemical Science. - 1452-3981. ; 5:4, s. 547-555
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Journal article (peer-reviewed)abstract
- In this study a test of the direct-mode bioorganic fuel cell (DMBFC) in which the fuel and the alkaline electrolyte are mixed with each other at two temperatures of 20 and 35 degrees C are carried out. The direct-mode bioorganic fuel cell is exposed to an externally generated electromagnetic field with simultaneous discharging in order to split the fuel molecule before the electrochemical oxidation at the two operation temperatures. The current-voltage characteristics are measured and analyzed. The liquid phase of the fuel-electrolyte concentration of the glucose was analysed both before and after the electrochemical tests at the operation temperature 20 degrees C. The aim is to continue with the development of the direct-mode glucose fuel cell by increasing the power density range by several mWcm(-2). This type of the fuel cell with glucose as a fuel has increased to the specific capacity levels of 120.8 and 132.7 Ah / kg glucose at the temperatures of 20 degrees C and 35 degrees C, respectively.
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| 14. |
- Albrecht, Eva, et al.
(author)
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Telomere length in circulating leukocytes is associated with lung function and disease
- 2014
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In: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 43:4, s. 983-992
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Journal article (peer-reviewed)abstract
- Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
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| 15. |
- Kulmala, J., et al.
(author)
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Association between mid- to late life physical fitness and dementia : evidence from the CAIDE study
- 2014
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 276:3, s. 296-307
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Journal article (peer-reviewed)abstract
- Objectives. This study investigated the association between perceived physical fitness at midlife, changes in perceived fitness during the three decades from mid-to late life and dementia risk. Design. Prospective cohort study. Setting. Cardiovascular risk factors, ageing and incidence of dementia (CAIDE) study. Subjects. Subjects were selected from four independent, random samples of population-based cardiovascular surveys and were first examined in 1972, 1977, 1982 or 1987, when they were on average 50 years old. The CAIDE target population included 3559 individuals. A random sample of 2000 individuals still alive in 1997 was drawn for re-examinations (performed in 1998 and 2005-2008) that consisted of cognitive assessments, with 1511 subjects participating in at least one re-examination. Dementia diagnoses were also confirmed from national registers for the entire target population. Main outcome measure. All-cause dementia. Results. Poor physical fitness at midlife was associated with increased dementia risk in the entire target population [hazard ratio (HR), 1.5; 95% confidence interval (CI), 1.1-2.0]. In participants, odds ratio (OR) was 2.0 (95% CI, 0.9-4.0). This association was significant in apolipoprotein E epsilon 4 allele (APO epsilon 4) noncarriers (OR, 4.3; 95% CI, 1.4-13.3), men (HR, 1.8; 95% CI, 1.1-3.0) and people with chronic conditions (HR, 2.9; 95% CI, 1.3-6.6). A decline in fitness after midlife was also associated with dementia (OR, 3.0; 95% CI, 1.7-5.1), which was significant amongst both men and women and more pronounced in APOE epsilon 4 carriers (OR, 4.4; 95% CI, 2.1-9.1). Conclusions. Perceived poor physical fitness reflects a combination of biological and lifestyle-related factors that can increase dementia risk. A simple question about perceived physical fitness may reveal at-risk individuals who could benefit from preventive interventions.
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| 16. |
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| 17. |
- Mikkola, T. M., et al.
(author)
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Influence of long-term postmenopausal hormone-replacement therapy on estimated structural bone strength: A study in discordant monozygotic twins
- 2011
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In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 26:3, s. 546-52
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Journal article (peer-reviewed)abstract
- Although postmenopausal hormone-replacement therapy (HRT) is known to prevent fractures, knowledge on the influence of long-term HRT on bone strength and its determinants other than areal bone mineral density is scarce. This study used a genetically controlled design with 24 monozygotic female twin pairs aged 54 to 72 years in which one cotwin was using HRT (mean duration 8 years) and the other had never used HRT. Estimated bone strength, cross-sectional area, volumetric bone mineral density, bone mineral mass, and cross-sectional density and mass distributions were assessed in the tibial shaft, distal tibia, and distal radius with peripheral computed tomography (pQCT). In the tibial shaft, HRT users had 9% [95% confidence interval (CI) 3%-15%] higher estimated bending strength than their nonusing cotwins. Larger cortical area and higher cortical bone mineral density accounted for this difference. The cortex was larger in the HRT users in the endocortical region. In the distal tibia, estimated compressive strength was 24% (95% CI 9%-40%) higher and in the distal radius 26% (95% CI 11%-41%) higher in the HRT users than in their nonusing cotwins owing to higher volumetric bone mineral density. No difference between users and nonusers was observed in total bone cross-sectional area in any measured bone site. The added mineral mass in the HRT users was distributed evenly within and between bone sites. In postmenopausal women, long-term HRT preserves estimated bone strength systemically by preventing bone mineral loss similarly in body weight-loaded and non-weight-loaded bone. (c) 2011 American Society for Bone and Mineral Research.
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| 18. |
- Surakka, Ida, et al.
(author)
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A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol
- 2011
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:10, s. e1002333-
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Journal article (peer-reviewed)abstract
- Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
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| 19. |
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| 20. |
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| 21. |
- Surakka, Ida, et al.
(author)
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A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol
- 2012
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In: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 15:6, s. 691-699
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Journal article (peer-reviewed)abstract
- Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene-environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10-8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10-8).
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| 22. |
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