30 research outputs found
Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
No full textLow muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. © 2021, The Author(s)
Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
No full textGenome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women [Elektronisk resurs]
No full textLow muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10−17), arthritis (GDF5p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, includingseveral pathways considered to be hallmarks of ageing. © 2021, The Author(s)
The Analysis of Architecture Image of Anande Temple - The Value and Protection of Gude Temple in Wuhan City
No full textAnande Temple originated from Myanmar, which belongs to Theravada Buddhism. Anande was the son of the Sakyamuni’s uncle, Hufan, and he finally became one of the Ten Great Disciples of Sakyamuni. Dedicated to the Buddhist temple, AnandeTemple is the most important Theravada Buddhist temple. According to literature, this kind of architectural style has only two buildings: one is AnandeTemple in Myanmar, the other is Gude Temple in Wuhan.This article mainly discusses the idea of restoration programming system of Gude Temple, one of the four jungles in Wuhan city. From the different characteristics in cultural value and architectural space layout represented by “Tianzhu standard” and “Garan seven standard”, the author explains the overall cultural understanding of Gude Temple and program the system with the consideration of cultural and environmental factors.</jats:p
Sarcopenia and variation in the Human Leukocyte Antigen complex.
No full textThis is the author accepted manuscript. The final version is available
from Oxford University Press via the DOI in this record.BACKGROUND: Aging is characterized by chronic inflammation plus muscle mass and strength loss, termed sarcopenia. Human Leukocyte Antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants associate with sarcopenia in autoimmune disease free older people. METHODS: Data from 181,301 UK Biobank European descent volunteers aged 60 - 70 with measured hand-grip strength and impedance. Logistic regression analysis estimated HLA types sarcopenia associations, adjusted for confounders and multiple testing. RESULTS: Having any autoimmune diagnosis was associated with sarcopenia (Odds Ratio 1.83, 95% Confidence Intervals 1.74-1.92, p=4.0*10-125). After excluding autoimmune diagnoses, six of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p=2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23 CI 1.12-1.35, p=7.28*10-6).Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (ORs 1.08, CI 1.05-1.11, p=1.06*10-8 and 1.07, CI 1.04-1.09 p=1.5*10-6, respectively). Some HLAs associations with sarcopenia were greater in female participants. CONCLUSION: Autoimmune diagnoses are strongly associated with sarcopenia in 60 to 70 year olds. Variation in specific HLA types and non-coding SNPs are also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.Medical Research Council (MRC)IPA Assignment Agreement (National Institute of Aging
Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations
No full textPLIN1 haploinsufficiency is not associated with lipodystrophy
No full textThis is the final version of the article. Available from OUP via the DOI in this record.Context: Monogenic partial lipodystrophy is a genetically heterogenous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance. Objective: We investigated if null variants in PLIN1 cause lipodystrophy. Methods: As part of a targeted sequencing panel test we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal. Results: We identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632 - 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. Conclusions: Our study suggests that heterozygous variants which are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy.KAP has a postdoctoral fellowship funded by the Wellcome Trust (110082/Z/15/Z). DBS is supported by the Wellcome Trust (WT107064), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5), and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z). ATH and SE are Wellcome Trust Senior Investigators (WT098395/Z/12/Z). ATH is also supported by a National Institute for Health Research Senior Investigator award. MNW is supported by Medical Research Council grant MR/M005070/1. The authors thank Garan Jones, Andrew Parrish, Anna Bussell and Jessica Settle (Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK) and Matthew Johnson (University of Exeter) for their technical assistance
An enhanced method for targeted next generation sequencing copy number variant detection using ExomeDepth [version 1; peer review: 1 approved, 1 approved with reservations]
No full textCopy number variants (CNV) are a major cause of disease, with over 30,000 reported in the DECIPHER database. To use read depth data from targeted Next Generation Sequencing (NGS) panels to identify CNVs with the highest degree of sensitivity, it is necessary to account for biases inherent in the data. GC content and ambiguous mapping due to repetitive sequence elements and pseudogenes are the principal components of technical variability. In addition, the algorithms used favour the detection of multi-exon CNVs, and rely on suitably matched normal dosage samples for comparison. We developed a calling strategy that subdivides target intervals, and uses pools of historical control samples to overcome these limitations in a clinical diagnostic laboratory. We compared our enhanced strategy with an unmodified pipeline using the R software package ExomeDepth, using a cohort of 109 heterozygous CNVs (91 deletions, 18 duplications in 26 genes), including 25 single exon CNVs. The unmodified pipeline detected 104/109 CNVs, giving a sensitivity of 89.62% to 98.49% at the 95% confidence interval. The detection of all 109 CNVs by our enhanced method demonstrates 95% confidence the sensitivity is ≥96.67%, allowing NGS read depth analysis to be used for CNV detection in a clinical diagnostic setting
