| 1. |
- Teslovich, Tanya M., et al.
(författare)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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| 2. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 3. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 4. |
- Stoett, Peter, et al.
(författare)
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Avoiding catastrophes : seeking synergies among the public health, environmental protection, and human security sectors
- 2016
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Ingår i: The Lancet Global Health. - 2214-109X. ; 4:10, s. e680-e681
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Tidskriftsartikel (refereegranskat)abstract
- Global health catastrophes have complex origins, often rooted in social disruption, poverty, conflict, and environmental collapse. Avoiding them will require a new integrative analysis of the links between disease, armed conflict, and environmental degradation within a socioecological vulnerability and human security context. Exploring these connections was the aim of Avoiding Catastrophe: Linking Armed Conflict, Harm to Ecosystems, and Public Health, an expert workshop held in May 4–6, 2016, at Concordia University in Montreal, QC, Canada.
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| 5. |
- Welch, Vivian, et al.
(författare)
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Health, social care and technological interventions to improve functional ability of older adults living at home : An evidence and gap map
- 2021
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Ingår i: Campbell Systematic Reviews. - : Wiley. - 1891-1803. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: By 2030, the global population of people older than 60 years is expected to be higher than the number of children under 10 years, resulting in major health and social care system implications worldwide. Without a supportive environment, whether social or built, diminished functional ability may arise in older people. Functional ability comprises an individual's intrinsic capacity and people's interaction with their environment enabling them to be and do what they value. Objectives: This evidence and gap map aims to identify primary studies and systematic reviews of health and social support services as well as assistive devices designed to support functional ability among older adults living at home or in other places of residence. Search Methods: We systematically searched from inception to August 2018 in: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, CINAHL, PsycINFO, AgeLine, Campbell Library, ASSIA, Social Science Citation Index and Social Policy & Practice. We conducted a focused search for grey literature and protocols of studies (e.g., ProQuest Theses and Dissertation Global, conference abstract databases, Help Age, PROSPERO, Cochrane and Campbell libraries and ClinicalTrials.gov). Selection Criteria: Screening and data extraction were performed independently in duplicate according to our intervention and outcome framework. We included completed and on-going systematic reviews and randomized controlled trials of effectiveness on health and social support services provided at home, assistive products and technology for personal indoor and outdoor mobility and transportation as well as design, construction and building products and technology of buildings for private use such as wheelchairs, and ramps. Data Collection and Analysis: We coded interventions and outcomes, and the number of studies that assessed health inequities across equity factors. We mapped outcomes based on the International Classification of Function, Disability and Health (ICF) adapted categories: intrinsic capacities (body function and structures) and functional abilities (activities). We assessed methodological quality of systematic reviews using the AMSTAR II checklist. Main Results: After de-duplication, 10,783 records were screened. The map includes 548 studies (120 systematic reviews and 428 randomized controlled trials). Interventions and outcomes were classified using domains from the International Classification of Function, Disability and Health (ICF) framework. Most systematic reviews (n = 71, 59%) were rated low or critically low for methodological quality. The most common interventions were home-based rehabilitation for older adults (n = 276) and home-based health services for disease prevention (n = 233), mostly delivered by visiting healthcare professionals (n = 474). There was a relative paucity of studies on personal mobility, building adaptations, family support, personal support and befriending or friendly visits. The most measured intrinsic capacity domains were mental function (n = 269) and neuromusculoskeletal function (n = 164). The most measured outcomes for functional ability were basic needs (n = 277) and mobility (n = 160). There were few studies which evaluated outcome domains of social participation, financial security, ability to maintain relationships and communication. There was a lack of studies in low- and middle-income countries (LMICs) and a gap in the assessment of health equity issues. Authors' Conclusions: There is substantial evidence for interventions to promote functional ability in older adults at home including mostly home-based rehabilitation for older adults and home-based health services for disease prevention. Remotely delivered home-based services are of greater importance to policy-makers and practitioners in the context of the COVID-19 pandemic. This map of studies published prior to the pandemic provides an initial resource to identify relevant home-based services which may be of interest for policy-makers and practitioners, such as home-based rehabilitation and social support, although these interventions would likely require further adaptation for online delivery during the COVID-19 pandemic. There is a need to strengthen assessment of social support and mobility interventions and outcomes related to making decisions, building relationships, financial security, and communication in future studies. More studies are needed to assess LMIC contexts and health equity issues.
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| 6. |
- Lange, Leslie A, et al.
(författare)
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
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Tidskriftsartikel (refereegranskat)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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| 7. |
- Tait, Brian D, et al.
(författare)
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Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation.
- 2013
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Ingår i: Transplantation. - 1534-6080. ; 95:1, s. 19-47
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS: With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS: A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS: A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.
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