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Effect of the inclusion of Bacillus spp. in growing–finishing pigs’ diets: a meta-analysis
This meta-analysis determined the effect of Bacillus spp. on growth performance of growing–finishing pigs and then assessed causes for the heterogeneity of responses detected using meta-regression. A database of 22 articles published from 2000 to 2020 was identified, and 9 articles fitted the selection criteria and were integrated in the final database. Statistical analysis was performed to analyze the effect size for ADG, average daily feed intake (ADFI), and F:G ratio using a standardized means difference (SMD) at a 95% confidence interval. A meta-regression analysis was used to investigate the cause of heterogeneity, using the individual SMD for each study assessment as the outcome and the associated SE as the measure of variance. Dietary Bacillus spp. supplementation had no effect on ADFI (SMD: −0.052, p = 0.138) and numerically increased ADG (SMD: 0.113, p = 0.081) and reduced the F:G ratio SMD: −0.127, p < 0.001). Meta-regression outcomes suggested that the number of animals per group was an essential component promoting heterogeneity in ADG. Overall, the inclusion of Bacillus spp. (median 486 mg/d) in growing–finishing pigs can increase ADG and can decrease the F:G ratio
Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study
Summary: Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with those who had stopped bisphosphonate (BP) therapy for more than 1 year.Introduction: Bisphosphonates are widely used to prevent bone fractures. Controversial findings regarding the association between bisphosphonate use and the risk of atrial fibrillation (AF) have been reported. The aim of this study was to evaluate the risk of AF in association with BP exposure.Methods: We performed a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions. The data cover a period ranging from July 1, 2003 to December 31, 2006. The study population comprised new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an AF diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. A conditional logistic regression was performed to obtain the odds ratio with 95 % confidence intervals (CI). The BP exposure was classified into current (<90 days prior to ID), recent (91–180), past (181–364), and distant past (≥365) use, with the latter category being used as a reference point. A subgroup analysis by individual BP was then carried out.Results: In comparison with distant past users of BP, current users of BP showed an almost twofold increased risk of AF: odds ratio (OR) = 1.78 and 95 % CI = 1.46–2.16. Specifically, alendronate users were mostly associated with AF as compared with distant past use of BP (OR, 1.97; 95 % CI, 1.59–2.43).Conclusion: In our nested case-control study, current users of BP are associated with a higher risk of atrial fibrillation as compared with those who had stopped BP treatment for more than 1 year
Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density
OBJECTIVES:
To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis.
METHODS:
Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies.
RESULTS:
A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures.
CONCLUSION:
We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.Funding: ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework programme 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the
invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. CABRIO was supported by the Instituto de Salud Carlos III and Fondos FEDER from the EU (PI 11/1092 and PI12/615). The AOGC study was funded by the Australian National Health and Medical Research Council (Project grant 511132). Lothian Birth Cohort 1921 phenotype collection was
supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping of the cohorts was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Research work on Slovenian case and control samples was funded by Slovenian Research Agency (project no. P3-0298 and J3-2330). The Danish National Birth
Cohort (DNBC) is a result of major grants from the Danish National Research Foundation, the Danish Pharmacists’Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. The DNBC biobank is a part of the Danish National Biobank
resource, which is supported by the Novo Nordisk Foundation. Dr Bjarke Feenstra is supported by an Oak Foundation Fellowship. The Framingham Study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and R01 AR061162; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the
National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was performed within the Genetic Factors for Osteoporosis (GEFOS) consortium, funded by the European Commission (HEALTH-F2-2008-201865-GEFOS).Acknowledgments: The authors are grateful to the patients and controls from the different centres who agreed to participate in this study. We would like to thank Ms Dilruba Kabir at the Rheumatology and Bone Disease Unit, CGEM-IGMM, Edinburgh, UK; Mr Matt Sims at the MRC Epidemiology Unit, University of Cambridge, UK; Ms Mila Jhamai and
Ms Sarah Higgins at the Genetics Laboratory of Erasmus MC, Rotterdam, The Netherlands; Ms Johanna Hadler, Ms Kathryn A Addison and Ms Karena Pryce of the University of Queensland Centre for Clinical Genomics, Brisbane, Australia, for technical support on the genotyping stage; and Mr Marijn Verkerk and Dr Anis Abuseiris at the Genetics Laboratory of Erasmus MC, Rotterdam, for assistance on the data analysis. We would like to
acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. We would also like to thank Professor Nick Gilbert and Dr Giovanny Rodriguez-Blanco for their comments and advice on the manuscript preparation. This study makes use
of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk
Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the Generation R Study
Genome-wide association studies (GWAS) have been successful in identifying loci associated with a wide range of complex human traits and diseases. Up to now, the majority of GWAS have focused on European populations. However, the inclusion of other ethnic groups as well as admixed populations in GWAS studies is rapidly rising following the pressing need to extrapolate findings to non-European populations and to increase statistical power. In this paper, we describe the methodological steps surrounding genetic data generation, quality control, study design and analytical procedures needed to run GWAS in the multiethnic and highly admixed Generation R Study, a large prospective birth cohort in Rotterdam, the Netherlands. Furthermore, we highlight a number of practical considerations and alternatives pertinent to the quality control and analysis of admixed GWAS data
Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.
OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism
Assessment of gene-by-sex interaction effect on bone mineral density
To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.Medtronic
NIH R01 AG18728
R01HL088119
R01AR046838
U01 HL084756
R01 AR43351
P01-HL45522
R01-MH-078111
R01-MH-083824
Nutrition and Obesity Research Center of Maryland P30DK072488
NIAMS/NIH F32AR059469
Instituto de Salud Carlos III-FIS (Spanish Health Ministry) PI 06/0034
PI08/0183
Canadian Institutes of Health Research (CIHR)
NHLBI HHSN268201200036C
N01-HC-85239
N01-HC-85079
N01-HC-85086
N01-HC-35129
N01 HC15103
N01 HC-55222
N01-HC-75150
N01-HC-45133
HL080295
HL087652
HL105756
NIA AG-023629
AG-15928
AG-20098
AG-027058
N01AG62101
N01AG62103
N01AG62106
1R01AG032098-01A1
National Center of Advancing Translational Technologies CTSI UL1TR000124
National Institute of Diabetes and Digestive and Kidney Diseases DK063491
EUROSPAN (European Special Populations Research Network)
European Commission FP6 STRP grant 018947
LSHG-CT-2006-01947
Netherlands Organisation for Scientific Research
Erasmus MC
Centre for Medical Systems Biology (CMSB)
Netherlands Brain Foundation (HersenStichting Nederland)
US National Institute for Arthritis, Musculoskeletal and Skin Diseases
National Institute on Aging R01 AR/AG41398
R01 AR050066
R21 AR056405
National Heart, Lung, and Blood Institute's Framingham Heart Study N01-HC-25195
Affymetrix, Inc. N02-HL-6-4278
Canadian Institutes of Health Research from Institute of Aging 165446
Institute of Genetics 179433
Institute of Musculoskeletal health 221765
Intramural Research Program of the NIH, National Institute on Aging
National Institutes of Health HHSN268200782096C
Hong Kong Research Grant Council HKU 768610M
Bone Health Fund of HKU Foundation
KC Wong Education Foundation
Small Project Funding 201007176237
Matching Grant
CRCG Grant
Osteoporosis and Endocrine Research Fund
Genomics Strategic Research Theme of The University of Hong Kong
Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011
911-03-012
Research Institute for Diseases in the Elderly 014-93-015
Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810
Erasmus Medical Center and Erasmus University, Rotterdam
Netherlands Organization for the Health Research and Development (ZonMw)
Research Institute for Diseases in the Elderly (RIDE)
Ministry of Education, Culture and Science
Ministry for Health, Welfare and Sports
European Commission (DG XII)
Municipality of Rotterdam
German Bundesministerium fur Forschung und Technology 01 AK 803 A-H
01 IG 07015
Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus
To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1×10-11 observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ±500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6×10-31 and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42×10-10) for rs4609139 and mapping to C7orf58. We a
Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.
Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity
New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms