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7. Population scale whole genome sequencing provides novel insights into cardiometabolic health

Author

Zhao, Yajie, primary, Lockhart, Sam, additional, Liu, Jimmy, additional, Li, Xihao, additional, Cortes, Adrian, additional, Hua, Xing, additional, Gardner, Eugene J., additional, Kentistou, Katherine A., additional, Lo, Yancy, additional, Davitte, Jonathan, additional, Savage, David B., additional, Buser-Doepner, Carolyn, additional, Ong, Ken K., additional, Zhang, Haoyu, additional, Scott, Robert, additional, O'Rahilly, Stephen, additional, and Perry, John R.B., additional

Published
2024
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8. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Author

Ellinghaus, David, Jostins, Luke, Spain, Sarah L, Cortes, Adrian, Bethune, Jörn, Han, Buhm, Park, Yu Rang, Raychaudhuri, Soumya, Pouget, Jennie G, Hübenthal, Matthias, Folseraas, Trine, Wang, Yunpeng, Esko, Tonu, Metspalu, Andres, Westra, Harm-Jan, Franke, Lude, Pers, Tune H, Weersma, Rinse K, Collij, Valerie, D'Amato, Mauro, Halfvarson, Jonas, Jensen, Anders Boeck, Lieb, Wolfgang, Degenhardt, Franziska, Forstner, Andreas J, Hofmann, Andrea, Schreiber, Stefan, Mrowietz, Ulrich, Juran, Brian D, Lazaridis, Konstantinos N, Brunak, Søren, Dale, Anders M, Trembath, Richard C, Weidinger, Stephan, Weichenthal, Michael, Ellinghaus, Eva, Elder, James T, Barker, Jonathan NWN, Andreassen, Ole A, McGovern, Dermot P, Karlsen, Tom H, Barrett, Jeffrey C, Parkes, Miles, Brown, Matthew A, and Franke, Andre

Subjects
Biological Sciences, Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Bayes Theorem, Cholangitis, Sclerosing, Chronic Disease, Colitis, Ulcerative, Comorbidity, Crohn Disease, Genetic Heterogeneity, Genetic Pleiotropy, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Inflammation, Psoriasis, Quantitative Trait Loci, Spondylitis, Ankylosing, International IBD Genetics Consortium, International Genetics of Ankylosing Spondylitis Consortium, International PSC Study Group, Genetic Analysis of Psoriasis Consortium, Psoriasis Association Genetics Extension, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

Published
2016

9. HLA and KIR Associations of Cervical Neoplasia

Author

Bao, Xiao, Hanson, Aimee L., Madeleine, Margaret M., Wang, Sophia S., Schwartz, Stephen M., Newell, Felicity, Pettersson-Kymmer, Ulrika, Hemminki, Kari, Tiews, Sven, Steinberg, Winfried, Rader, Janet S., Castro, Felipe, Safaeian, Mahboobeh, Franco, Eduardo L., Coutlée, François, Ohlsson, Claes, Cortes, Adrian, Marshall, Mhairi, Mukhopadhyay, Pamela, Cremin, Katie, Johnson, Lisa G., Garland, Suzanne M., Tabrizi, Sepehr N., Wentzensen, Nicolas, Sitas, Freddy, Trimble, Cornelia, Little, Julian, Cruickshank, Maggie, Frazer, Ian H., Hildesheim, Allan, Brown, Matthew A., Duncan, Emma L., Sun, YingPu, and Leo, Paul J.

Published
2018

10. Kansas City Chiefs: A Potential Dynasty

Author

Cortes, Adrian

Subjects
Football teams, Football (Professional), News, opinion and commentary, Sports and fitness, Kansas City Chiefs -- Officials and employees
Abstract

Byline: Adrian Cortes IMAGE| The Kansas City Chiefs won the 2024 Super Bowl by beating the San Francisco 49ers in a riveting game of back-and-forth at the Allegiant Stadium in [...]

Published
2024

12. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

Author

Cortes, Adrian, Pulit, Sara L, Leo, Paul J, Pointon, Jenny J, Robinson, Philip C, Weisman, Michael H, Ward, Michael, Gensler, Lianne S, Zhou, Xiaodong, Garchon, Henri-Jean, Chiocchia, Gilles, Nossent, Johannes, Lie, Benedicte A, Førre, Øystein, Tuomilehto, Jaakko, Laiho, Kari, Bradbury, Linda A, Elewaut, Dirk, Burgos-Vargas, Ruben, Stebbings, Simon, Appleton, Louise, Farrah, Claire, Lau, Jonathan, Haroon, Nigil, Mulero, Juan, Blanco, Francisco J, Gonzalez-Gay, Miguel A, Lopez-Larrea, C, Bowness, Paul, Gaffney, Karl, Gaston, Hill, Gladman, Dafna D, Rahman, Proton, Maksymowych, Walter P, Crusius, J Bart A, van der Horst-Bruinsma, Irene E, Valle-Oñate, Raphael, Romero-Sánchez, Consuelo, Hansen, Inger Myrnes, Pimentel-Santos, Fernando M, Inman, Robert D, Martin, Javier, Breban, Maxime, Wordsworth, Bryan Paul, Reveille, John D, Evans, David M, de Bakker, Paul IW, and Brown, Matthew A

Subjects
Humans, Spondylitis, Ankylosing, Genetic Predisposition to Disease, Aminopeptidases, HLA-B27 Antigen, Minor Histocompatibility Antigens, Case-Control Studies, Major Histocompatibility Complex, Epistasis, Genetic, Polymorphism, Single Nucleotide, HLA-B40 Antigen, Epistasis, Genetic, Polymorphism, Single Nucleotide, Spondylitis, Ankylosing
Abstract

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Published
2015

13. Genetic Dissection of Acute Anterior Uveitis Reveals Similarities and Differences in Associations Observed With Ankylosing Spondylitis

Author

Robinson, Philip C, Claushuis, Theodora AM, Cortes, Adrian, Martin, Tammy M, Evans, David M, Leo, Paul, Mukhopadhyay, Pamela, Bradbury, Linda A, Cremin, Katie, Harris, Jessica, Maksymowych, Walter P, Inman, Robert D, Rahman, Proton, Haroon, Nigil, Gensler, Lianne, Powell, Joseph E, Horst‐Bruinsma, Irene E, Hewitt, Alex W, Craig, Jamie E, Lim, Lyndell L, Wakefield, Denis, McCluskey, Peter, Voigt, Valentina, Fleming, Peter, Spondyloarthritis Research Consortium of Canada, Australio-Anglo-American Spondylitis Consortium, Degli‐Esposti, Mariapia, Pointon, Jennifer J, Weisman, Michael H, Wordsworth, B Paul, Reveille, John D, Rosenbaum, James T, and Brown, Matthew A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Genetics, Clinical Research, Human Genome, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Aminopeptidases, Case-Control Studies, Genome-Wide Association Study, Genotype, HLA-B27 Antigen, Humans, Interleukin-10, Interleukin-18 Receptor alpha Subunit, Minor Histocompatibility Antigens, Receptors, Interleukin, Receptors, Peptide, Spondylitis, Ankylosing, Uveitis, Anterior, Spondyloarthritis Research Consortium of Canada, Australio-Anglo-American Spondylitis Consortium, International Genetics of Ankylosing Spondylitis Consortium, Wellcome Trust Case Control Study 2, Mariapia Degli-Esposti, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveTo use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS).MethodsWe genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription-polymerase chain reaction.ResultsA comparison between all patients with AAU and healthy control subjects showed strong association over HLA-B, corresponding to the HLA-B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non-major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10(-8)). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10(-6)). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments.ConclusionThese findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

Published
2015

16. The UK Biobank resource with deep phenotyping and genomic data

Author

Bycroft, Clare, Freeman, Colin, Petkova, Desislava, Band, Gavin, Elliott, Lloyd T., Sharp, Kevin, Motyer, Allan, Vukcevic, Damjan, Delaneau, Olivier, O’Connell, Jared, Cortes, Adrian, Welsh, Samantha, Young, Alan, Effingham, Mark, McVean, Gil, Leslie, Stephen, Allen, Naomi, Donnelly, Peter, and Marchini, Jonathan

Published
2018
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17. Mapping the functional impact of non-coding regulatory elements in primary T cells through single-cell CRISPR screens

Author

Alda-Catalinas, Celia, primary, Ibarra-Soria, Ximena, additional, Flouri, Christina, additional, Esparza-Gordillo, Jorge, additional, Cousminer, Diana, additional, Hutchinson, Anna, additional, Krejci, Adam, additional, Cortes, Adrian, additional, Acevedo, Alison, additional, Malla, Sunir, additional, Fishwick, Carl, additional, Drewes, Gerard, additional, and Rapiteanu, Radu, additional

Published
2023
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19. Nationwide genomic biobank in Mexico unravels demographic history and complex trait architecture from 6,057 individuals

Author

Sohail, Mashaal, primary, Chong, Amanda Y, additional, Quinto-Cortes, Consuelo D, additional, Palma-Martinez, Maria J, additional, Ragsdale, Aaron, additional, Medina-Munoz, Santiago G, additional, Barberena-Jonas, Carmina, additional, Delgado-Sanchez, Guadalupe, additional, Cruz-Hervert, Luis Pablo, additional, Ferreyra-Reyes, Leticia, additional, Ferreira-Guerrero, Elizabeth, additional, Mongua-Rodriguez, Norma, additional, Jimenez-Kaufmann, Andres, additional, Moreno-Macias, Hortensia, additional, Aguilar-Salinas, Carlos A, additional, Auckland, Kathryn, additional, Cortes, Adrian, additional, Acuna-Alonzo, Victor, additional, Ioannidis, Alexander G, additional, Gignoux, Christopher R, additional, Wojcik, Genevieve L, additional, Fernandez-Valverde, Selene L, additional, Hill, Adrian V.S., additional, Tusie-Luna, Maria Teresa, additional, Mentzer, Alexander J, additional, Novembre, John, additional, Garcia-Garcia, Lourdes, additional, and Moreno-Estrada, Andres, additional

Published
2022
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20. Mapping the proteo-genomic convergence of human diseases

Author

Pietzner, Maik, primary, Wheeler, Eleanor, additional, Carrasco-Zanini, Julia, additional, Cortes, Adrian, additional, Koprulu, Mine, additional, Wörheide, Maria A., additional, Oerton, Erin, additional, Cook, James, additional, Stewart, Isobel D., additional, Kerrison, Nicola D., additional, Luan, Jian’an, additional, Raffler, Johannes, additional, Arnold, Matthias, additional, Arlt, Wiebke, additional, O’Rahilly, Stephen, additional, Kastenmüller, Gabi, additional, Gamazon, Eric R., additional, Hingorani, Aroon D., additional, Scott, Robert A., additional, Wareham, Nicholas J., additional, and Langenberg, Claudia, additional

Published
2021
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21. ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients

Author

Robinson, Philip C, Costello, Mary-Ellen, Leo, Paul, Bradbury, Linda A, Hollis, Kelly, Cortes, Adrian, Lee, Seunghun, Joo, Kyung Bin, Shim, Seung-Cheol, Weisman, Michael, Ward, Michael, Zhou, Xiaodong, Garchon, Henri-Jean, Chiocchia, Gilles, Nossent, Johannes, Lie, Benedicte A, Førre, Øystein, Tuomilehto, Jaakko, Laiho, Kari, Jiang, Lei, Liu, Yu, Wu, Xin, Elewaut, Dirk, Burgos-Vargas, Ruben, Gensler, Lianne S, Stebbings, Simon, Haroon, Nigil, Mulero, Juan, Fernandez-Sueiro, Jose Luis, Gonzalez-Gay, Miguel A, Lopez-Larrea, Carlos, Bowness, Paul, Gafney, Karl, Gaston, John S Hill, Gladman, Dafna D, Rahman, Proton, Maksymowych, Walter P, Xu, Huji, van der Horst-Bruinsma, Irene E, Chou, Chung-Tei, Valle-Oñate, Raphael, Romero-Sánchez, María Consuelo, Hansen, Inger Myrnes, Pimentel-Santos, Fernando M, Inman, Robert D, Martin, Javier, Breban, Maxime, Evans, David, Reveille, John D, Kim, Tae-Hwan, Wordsworth, B Paul, and Brown, Matthew A

Published
2015
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25. Fine-mapping inflammatory bowel disease loci to single-variant resolution

Author

Huang, Hailiang, Fang, Ming, Jostins, Luke, Umievi Mirkov, Maa, Boucher, Gabrielle, Anderson, Carl A., Andersen, Vibeke, Cleynen, Isabelle, Cortes, Adrian, Crins, Franois, DAmato, Mauro, Deffontaine, Valrie, Dmitrieva, Julia, Docampo, Elisa, Elansary, Mahmoud, Farh, Kyle Kai-How, Franke, Andre, Gori, Ann-Stephan, Goyette, Philippe, Halfvarson, Jonas, Haritunians, Talin, Knight, Jo, Lawrance, Ian C., Lees, Charlie W., Louis, Edouard, Mariman, Rob, Meuwissen, Theo, Mni, Myriam, Momozawa, Yukihide, Parkes, Miles, Spain, Sarah L., Thtre, Emilie, Trynka, Gosia, Satsangi, Jack, van Sommeren, Suzanne, Vermeire, Severine, Xavier, Ramnik J., Weersma, Rinse K., Duerr, Richard H., Mathew, Christopher G., Rioux, John D., McGovern, Dermot P. B., Cho, Judy H., Georges, Michel, Daly, Mark J., and Barrett, Jeffrey C.

Subjects
Inflammatory bowel diseases -- Genetic aspects, Quantitative trait loci -- Health aspects, Genetic variation -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription-factor binding sites (n=3), and tissue-specific epigenetic marks (n=10), with the last category showing enrichment in specific immune cells among associations stronger in Crohns disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms., Author(s): Hailiang Huang (corresponding author) [1, 2]; Ming Fang [3, 4]; Luke Jostins [5, 6]; Maa Umievi Mirkov [7]; Gabrielle Boucher [8]; Carl A. Anderson [7]; Vibeke Andersen [9, 10]; [...]

Published
2017
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29. Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes

Author

Cortes, Adrian, Field, Judith, Glazov, Evgeny A., Hadler, Johanna, Stankovich, Jim, Brown, Matthew A., Baxter, Alan, Kermode, Allan G, Taylor, Bruce, Booth, David R, Mason, Deborah, Stewart, Graeme J, Butzkueven, Helmut, Charlesworth, Jac, Wiley, James, Lechner-Scott, Jeannette, Field, Judith, Tajouri, Lotti, Griffiths, Lyn, Slee, Mark, Brown, Matthew A, Moscato, Pablo, Scott, Rodney J, Broadley, Simon, Vucic, Steve, Kilpatrick, Trevor J, and Carroll, William M

Published
2013
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31. Emerging trends of the illegal wildlife trade in Mesoamerica

Author

Gluszek, Sarah, primary, Ariano-Sánchez, Daniel, additional, Cremona, Patricia, additional, Goyenechea, Alejandra, additional, Luque Vergara, Darío Antonio, additional, Mcloughlin, Lee, additional, Morales, Alejandro, additional, Reuter Cortes, Adrian, additional, Rodríguez Fonseca, Javier, additional, Radachowsky, Jeremy, additional, and Knight, Andrew, additional

Published
2020
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34. Emerging trends of the illegal wildlife trade in Mesoamerica.

Author

Gluszek, Sarah, Ariano-Sánchez, Daniel, Cremona, Patricia, Goyenechea, Alejandra, Luque Vergara, Darío Antonio, Mcloughlin, Lee, Morales, Alejandro, Reuter Cortes, Adrian, Rodríguez Fonseca, Javier, Radachowsky, Jeremy, and Knight, Andrew

Subjects
WILD animal trade, BIODIVERSITY, WILDLIFE crimes, ANIMAL populations
Abstract

Mesoamerica is the world's third largest biodiversity hotspot and has c. 4,000 wildlife species protected under CITES. Despite the high biodiversity in the region, there is limited global attention, data and funding for conservation. The continued exploitation of wildlife species for the trade requires a more proactive approach to address emerging trends, and low-cost and effective solutions to prevent species decline. Over a 5-month period in 2017, we used expert-driven horizon scanning, facilitated online, to identify emerging trends of the illegal wildlife trade in Mesoamerica. We found that the main emerging trends included digital and technological advancements, greater regional access to the global community, developments in trafficking techniques and growing demand for certain species. Our findings demonstrate that horizon scanning can be used as a tool for identifying emerging trends of illegal wildlife trade in data-poor contexts. We recommend that horizon scanning is used regularly for systematic monitoring of trends and to prioritize resources for immediate and emerging trends in illegal wildlife trade. [ABSTRACT FROM AUTHOR]

Published
2021
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35. Systematic classification of shared components of genetic risk for common human diseases

Author

Cortes, Adrian, Dendrou, Calliope A., Fugger, Lars, and McVean, Gil

Subjects
0303 health sciences, Disease Association, Disease classification, Disease, Computational biology, Biology, Biobank, Genetic architecture, 3. Good health, Clinical Practice, 03 medical and health sciences, 0302 clinical medicine, Genetic risk, Healthcare data, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Disease classification is fundamental to clinical practice, but current taxonomies do not necessarily reflect the pathophysiological processes that are common or unique to different disorders, such as those determined by genetic risk factors. Here, we use routine healthcare data from the 500,000 participants in the UK Biobank to map genome-wide associations across 19,628 diagnostic terms. We find that 3,510 independent genetic risk loci affect multiple clinical phenotypes, which we cluster into 629 distinct disease association profiles. We use multiple approaches to link clusters to different underlying biological pathways and show how these clusters define the genetic architecture of common medical conditions, including hypertension and immune-mediated diseases. Finally, we demonstrate how clusters can be utilised to re-define disease relationships and to inform therapeutic strategies.One sentence summarySystematic classification of genetic risk factors reveals molecular connectivity of human diseases with clinical implications

Published
2018

36. A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells

Author

Vecellio, Matteo, primary, Cortes, Adrian, additional, Bonham, Sarah, additional, Selmi, Carlo, additional, Knight, Julian C, additional, Fischer, Roman, additional, Brown, Matthew A, additional, Wordsworth, B Paul, additional, and Cohen, Carla J, additional

Published
2019
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39. HLA and KIR Associations of Cervical Neoplasia

Author

Pettersson-Kymmer, Ulrika, Hanson, Aimee L, Madeleine, Margaret M, Wang, Sophia S, Schwartz, Stephen M, Newell, Felicity, Hemminki, Kari, Tiews, Sven, Steinberg, Winfried, Rader, Janet S, Castro, Felipe, Safaeian, Mahboobeh, Franco, Eduardo L, Coutlée, François, Ohlsson, Claes, Cortes, Adrian, Marshall, Mhairi, Mukhopadhyay, Pamela, Cremin, Katie, Johnson, Lisa G, Garland, Suzanne M, Tabrizi, Sepehr N, Wentzensen, Nicolas, Sitas, Freddy, Trimble, Cornelia, Little, Julian, Cruickshank, Maggie, Frazer, Ian H, Hildesheim, Allan, Brown, Matthew A, Duncan, Emma L, Sun, YingPu, Leo, Paul J, Pettersson-Kymmer, Ulrika, Hanson, Aimee L, Madeleine, Margaret M, Wang, Sophia S, Schwartz, Stephen M, Newell, Felicity, Hemminki, Kari, Tiews, Sven, Steinberg, Winfried, Rader, Janet S, Castro, Felipe, Safaeian, Mahboobeh, Franco, Eduardo L, Coutlée, François, Ohlsson, Claes, Cortes, Adrian, Marshall, Mhairi, Mukhopadhyay, Pamela, Cremin, Katie, Johnson, Lisa G, Garland, Suzanne M, Tabrizi, Sepehr N, Wentzensen, Nicolas, Sitas, Freddy, Trimble, Cornelia, Little, Julian, Cruickshank, Maggie, Frazer, Ian H, Hildesheim, Allan, Brown, Matthew A, Duncan, Emma L, Sun, YingPu, and Leo, Paul J

Abstract

Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Methods: Here, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent. Results: Four novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (OR=1.24, P=2.49×10-9), HLA-DRB5*0101 (OR=1.29, P=2.26×10-8), HLA-DRB5*9901 (OR=0.77, P=1.90×10-9) and HLA-DRB3*0301 (OR=0.63, P=4.06×10-5), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006). Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

Published
2018
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40. Imputation-based analysis of MICA alleles in the susceptibility to ankylosing spondylitis (Letter)

Author

Cortes, Adrian, Gladman, Dafna, Raychaudhuri, Soumya, Cui, Jing, Wheeler, Lawrie, Brown, Matt, Cortes, Adrian, Gladman, Dafna, Raychaudhuri, Soumya, Cui, Jing, Wheeler, Lawrie, and Brown, Matt

Abstract

Ankylosing spondylitis (AS) susceptibility is strongly correlated with genetic variation within the major histocompatibility complex (MHC), and the class I HLA-B*27 allele confers the major genetic risk factor to AS. Furthermore, strong evidence for additional alleles in the MHC has been observed which affect susceptibility independently from the HLA-B*27 allele, either by direct genotyping in candidate gene studies or through large-scale imputation-driven association studies. We have previously identified variants in both class I and II which affect susceptibility to AS through imputation of classical HLA alleles...

Published
2018

41. Evidence for a second ankylosing spondylitis-associated RUNX3 regulatory polymorphism

Author

Vecellio, Matteo, Cortes, Adrian, Roberts, Amity, Ellis, Jonathan, Cohen, Carla, Knight, Julian, Brown, Matt, Bowness, Paul, Wordsworth, Paul (B.P.), Vecellio, Matteo, Cortes, Adrian, Roberts, Amity, Ellis, Jonathan, Cohen, Carla, Knight, Julian, Brown, Matt, Bowness, Paul, and Wordsworth, Paul (B.P.)

Abstract

Objectives To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS).

Published
2018

44. HLAandKIRAssociations of Cervical Neoplasia

Author

Bao, Xiao, primary, Hanson, Aimee L, additional, Madeleine, Margaret M, additional, Wang, Sophia S, additional, Schwartz, Stephen M, additional, Newell, Felicity, additional, Pettersson-Kymmer, Ulrika, additional, Hemminki, Kari, additional, Tiews, Sven, additional, Steinberg, Winfried, additional, Rader, Janet S, additional, Castro, Felipe, additional, Safaeian, Mahboobeh, additional, Franco, Eduardo L, additional, Coutlée, François, additional, Ohlsson, Claes, additional, Cortes, Adrian, additional, Marshall, Mhairi, additional, Mukhopadhyay, Pamela, additional, Cremin, Katie, additional, Johnson, Lisa G, additional, Garland, Suzanne M, additional, Tabrizi, Sepehr N, additional, Wentzensen, Nicolas, additional, Sitas, Freddy, additional, Trimble, Cornelia, additional, Little, Julian, additional, Cruickshank, Maggie, additional, Frazer, Ian H, additional, Hildesheim, Allan, additional, Brown, Matthew A, additional, Duncan, Emma L, additional, Sun, Ying Pu, additional, and Leo, Paul J, additional

Published
2018
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47. Correction: Defining the genetic susceptibility to cervical neoplasia—A genome-wide association study

Author

Leo, Paul J., primary, Madeleine, Margaret M., additional, Wang, Sophia, additional, Schwartz, Stephen M., additional, Newell, Felicity, additional, Pettersson-Kymmer, Ulrika, additional, Hemminki, Kari, additional, Hallmans, Goran, additional, Tiews, Sven, additional, Steinberg, Winfried, additional, Rader, Janet S., additional, Castro, Felipe, additional, Safaeian, Mahboobeh, additional, Franco, Eduardo L., additional, Coutlée, François, additional, Ohlsson, Claes, additional, Cortes, Adrian, additional, Marshall, Mhairi, additional, Mukhopadhyay, Pamela, additional, Cremin, Katie, additional, Johnson, Lisa G., additional, Trimble, Cornelia L., additional, Garland, Suzanne, additional, Tabrizi, Sepehr N., additional, Wentzensen, Nicolas, additional, Sitas, Freddy, additional, Little, Julian, additional, Cruickshank, Maggie, additional, Frazer, Ian H., additional, Hildesheim, Allan, additional, and Brown, Matthew A., additional

Published
2018
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49. Defining the genetic susceptibility to cervical neoplasia : A genome-wide association study

Author

Leo, Paul J, Madeleine, Margaret M, Wang, Sophia, Schwartz, Stephen M, Newell, Felicity, Pettersson-Kymmer, Ulrika, Hemminki, Kari, Hallmans, Göran, Tiews, Sven, Steinberg, Winfried, Rader, Janet S, Castro, Felipe, Safaeian, Mahboobeh, Franco, Eduardo L, Coutlée, François, Ohlsson, Claes, Cortes, Adrian, Marshall, Mhairi, Mukhopadhyay, Pamela, Cremin, Katie, Johnson, Lisa G, Garland, Suzanne, Tabrizi, Sepehr N, Wentzensen, Nicolas, Sitas, Freddy, Little, Julian, Cruickshank, Maggie, Frazer, Ian H, Hildesheim, Allan, Brown, Matthew A, Leo, Paul J, Madeleine, Margaret M, Wang, Sophia, Schwartz, Stephen M, Newell, Felicity, Pettersson-Kymmer, Ulrika, Hemminki, Kari, Hallmans, Göran, Tiews, Sven, Steinberg, Winfried, Rader, Janet S, Castro, Felipe, Safaeian, Mahboobeh, Franco, Eduardo L, Coutlée, François, Ohlsson, Claes, Cortes, Adrian, Marshall, Mhairi, Mukhopadhyay, Pamela, Cremin, Katie, Johnson, Lisa G, Garland, Suzanne, Tabrizi, Sepehr N, Wentzensen, Nicolas, Sitas, Freddy, Little, Julian, Cruickshank, Maggie, Frazer, Ian H, Hildesheim, Allan, and Brown, Matthew A

Abstract

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

Published
2017
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50. ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

Author

Roberts, Amity, Appleton, Louise, Cortes, Adrian, Vecellio, Matteo, Lau, Jonathan, Watts, Laura, Brown, Matt, Wordsworth, Paul (B.P.), Roberts, Amity, Appleton, Louise, Cortes, Adrian, Vecellio, Matteo, Lau, Jonathan, Watts, Laura, Brown, Matt, and Wordsworth, Paul (B.P.)

Abstract

Free to read at publisher's site. We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)—rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher’s exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes (“VRNQE,” “MKDRQ,” “MRDRE,” and “MKDRE”) in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination (“*001/*005”) previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10–24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.

Published
2017

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