| 1. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 2. |
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| 3. |
- Zhang, Tongwu, et al.
(författare)
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Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
- 2018
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 28:11, s. 1621-1635
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Tidskriftsartikel (refereegranskat)abstract
- Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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| 4. |
- Budtz-Lilly, Jacob, et al.
(författare)
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Editor's Choice - Assessment of International Outcomes of Intact Abdominal Aortic Aneurysm Repair over 9 Years
- 2017
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 54:1, s. 13-20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Case mix and outcomes of complex surgical procedures vary over time and between regions. This study analyses peri-operative mortality after intact abdominal aortic aneurysm (AAA) repair in 11 countries over 9 years. Methods: Data on primary AAA repair from vascular surgery registries in 11 countries for the years 2005-2009 and 2010-2013 were analysed. Multivariate adjusted logistic regression analyses were carried out to adjust for variations in case mix. Results: A total of 83,253 patients were included. Over the two periods, the proportion of patients >= 80 years old increased (18.5% vs. 23.1%; p < .0001) as did the proportion of endovascular repair (EVAR) (44.3% vs. 60.6; p < .0001). In the latter period, 25.8% of AAAs were less than 5.5 cm. The mean annual volume of open repairs per centre decreased from 12.9 to 10.6 between the two periods (p < .0001), and it increased for EVAR from 10.0 to 17.1 (p < .0001). Overall, peri-operative mortality fell from 3.0% to 2.4% (p < .0001). Mortality for EVAR decreased from 1.5% to 1.1% (p < .0001), but the outcome worsened for open repair from 3.9% to 4.4% (p = .008). The peri-operative risk was greater for octogenarians (overall, 3.6% vs. 2.1%, p < .0001; open, 9.5% vs. 3.6%, p < .0001; EVAR, 1.8% vs. 0.7%, p < .0001), and women (overall, 3.8% vs. 2.2%, p < .0001; open, 6.0% vs. 4.0%, p < .0001; EVAR, 1.9% vs. 0.9%, p < .0001). Peri-operative mortality after repair of AAAs <5.5 cm was 4.4% with open repair and 1.0% with EVAR, p < .0001. Conclusions: In this large international cohort, total peri-operative mortality continues to fall for the treatment of intact AAAs. The number of EVAR procedures now exceeds open procedures. Mortality after EVAR has decreased, but mortality for open operations has increased. The peri-operative mortality for small AM treatment, particularly open surgical repair, is still considerable and should be weighed against the risk of rupture.
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| 5. |
- Lanigan, Fiona, et al.
(författare)
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Delineating Transcriptional Networks of Prognostic Gene Signatures Refines Treatment Recommendations for Lymph Node-negative Breast Cancer Patients.
- 2015
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X. ; 282:18, s. 3455-3473
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Tidskriftsartikel (refereegranskat)abstract
- The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics following surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. Here, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multi-gene prognostic assays, particularly in lymph node-negative, estrogen receptor-positive patients. Simultaneous examination of p16(INK) (4A ) expression, which predicts tumors that have bypassed cellular senescence, revealed that intermediate levels of p16(INK) (4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK) (4A) , termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, this study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline breast cancer prognosis. This article is protected by copyright. All rights reserved.
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| 6. |
- Mani, Kevin, et al.
(författare)
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Regional Differences in Case Mix and Peri-operative Outcome After Elective Abdominal Aortic Aneurysm Repair in the Vascunet Database
- 2015
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 49:6, s. 646-652
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Tidskriftsartikel (refereegranskat)abstract
- Objective/background: National differences exist in the outcome of elective abdominal aortic aneurysm (AAA) repair. The role of case mix variation was assessed based on an international vascular registry collaboration. Methods: All elective AAA repairs with aneurysm size data in the Vascunet database in the period 2005-09 were included. AAA size and pen-operative outcome (crude and age adjusted mortality) were analysed overall and in risk cohorts, as well as per country. Glasgow Aneurysm Score (GAS) was calculated as risk score, and patients were stratified in three equal sized risk cohorts based on GAS. Predictors of pen-operative mortality were analysed with multiple regression. Missing data were handled with multiple imputation. Results: Patients from Australia, Finland, Hungary, Norway, Sweden and the UK (n = 5,895) were analysed; mean age was 72.7 years and 54% had endovascular repair (EVAR). There were significant variations in GAS (lowest = Finland [75.7], highest = UK [79.4], p for comparison of all regions < .001), proportion of AAA < 5.5 cm (lowest = UK [6.4%], highest = Hungary [29.0%]; p < .001), proportion undergoing EVAR (lowest = Finland [10.1%], highest = Australia [58.9%]; p < .001), crude mortality (lowest = Norway [2.0%], highest = Finland [5.0%]; p = .006), and age adjusted mortality (lowest = Norway [2.5%], highest = Finland [6.0%]; p = .048). Both aneurysm size and pen-operative mortality were highest among patients with a GAS >82. Of those with a GAS >82, 8.4% of men and 20.8% of women had an AAA <5.5 cm. Conclusion: Important regional differences exist in case selection for elective AAA repair, including variations in AAA size and patient risk profile. These differences partly explain the variations in pen-operative mortality. Further audit is warranted to assess the underlying reasons for the regional variation in case-mix.
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| 8. |
- Loftus, Christian, et al.
(författare)
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Activation of Human Natural Killer Cells by Graphene Oxide-Templated Antibody Nanoclusters
- 2018
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 18:5, s. 3282-3289
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Tidskriftsartikel (refereegranskat)abstract
- An emerging new paradigm is that immune cell activation is controlled by transient interactions between supramolecular assemblies of receptors and ligands. Current immunotherapy biologic pharmaceuticals that activate or desensitize NK cells are, however, individual molecules that do not replicate this nanoscale organization of proteins. Here, we use nanoscale graphene oxide (NGO) as a template to generate soluble nanoscale clusters of Natural Killer cell-activating antibodies. We control nanocluster size and molecular number to mimic reported values for cell surface proteins. These NGO-templated molecular nanoclusters, used to stimulate NK cells via the CD16 receptor, successfully induced cellular activation, indicated by degranulation of cytolytic granules and IFN-γ secretion. Importantly, activation significantly exceeded that induced by the same antibodies applied as a solution of individual molecules. These results demonstrate that future immunotherapies could be enhanced by assembling immunomodulatory drugs into nanoclusters and establish NGO-templating as a candidate technology.
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| 9. |
- Lona-Durazo, Frida, et al.
(författare)
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Meta-analysis of GWA studies provides new insights on the genetic architecture of skin pigmentation in recently admixed populations
- 2019
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Ingår i: BMC Genetics. - : BMC. - 1471-2156. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations.Results: We present a GWAS of skin pigmentation in an admixed sample from Cuba (N=762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N=2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response.Conclusions: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.
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