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1. Educational intervention for the awareness improvement and control programme design on Echinococcosis in Izmir, Turkey

Author

Altintas NA., Altintas NU., Sarica Yilmaz O., Akil M., Akdur Ozturk E., and Unver A.

Subjects
cystic echinococcosis, cyst hydatid disease, creating awareness, prevention, Microbiology, QR1-502
Abstract

In Turkey, cyst hydatid disease (CHD) or cystic echinococcosis (CE) is publicly known as “dog cyst”, a fatal and serious disease not only affects livestock husbandry and human health but also brings about economic loss to our country. According to the data of the Ministry of Health; number of annual cases was 408 in 2008, and this number reached 1,867 by the end of 2019. Cystic echinococcosis is especially taken up during childhood and emerged at an older age. They become exposed to the eggs of the tapeworm after close contact with an infected dog or its contaminated environment. The infected dogs also pass in their feces E. granulosus eggs that adhere to the dogs’ hairs, and pass on to the children who are in the course of playful and intimate contact with the infected dogs. This study was to create the awareness of risk factors of CE among 10 different districts of Izmir province. Awareness raising seminars are essential component of this study because local people living in CE endemic areas, are crucial to continue and sustain the long-time effort that is needed to tackle this disease. In each district, 3 awareness raising seminars were held to the target groups: (a) in schools for students, teachers, administrators, (b) for general public, (c) for healthcare professionals. 4090 students attended to the trainings, 242 administrators and teachers who attended to the presentations together with the students, 524 people were attended to the trainings and 327 health workers attended to the trainings from different institutions. This study helped improving this situation by organising educational events for the rural populations for preventing transmission of the disease. This is the first educational intervention study regarding creating awareness on CE in Izmir Province which includes 10 districts between January 2019 to January 2020.

Published
2021
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2. A pilot comparative study between serological and genetic investigations in relationship to clinical outcomes on patients with cystic echinococcosis

Author

Altintas Nu., Karamil S. A., Turkum O., Akil M., Sakarya A., Bozkaya H., Šoltys J., and Altintas Na.

Subjects
cystic echinococcosis, elisa, western blotting, serology, sequence analysis, Microbiology, QR1-502
Abstract

The aim of this study was to investigate whether Enzyme-Linked Immunosorbent Assays (ELISA) and Western Blotting (WB) methods could contribute to the assessment of clinical outcomes in genotype-defined cystic echinococcosis (CE) patients. Twenty-nine human isolates and blood samples have been taken from patients who underwent surgery or percutaneous aspiration (PAIR) for therapeutic purposes at Ege University and Manisa Celal Bayar University Hospitals. All sera of patients were screened for the presence of E. granulosus IgG antibodies using in-house approved ELISA and WB methods. According to the ELISA results, five patients had high, thirteen patients had medium and eight patients had low specific antibody level response which ranged 1/640 -1/5000. Despite confirmed WB positivity three patients were found to be negative by ELISA. Immunoblot analysis of EgAg showed many protein bands with size of 8, 12, 20, 22, 24, 36, 75 and 90 kDa. Among of them, 8 – 12 kDa bands (90 %), 20 – 22 kDa and 36 kDa bands presented strong reactivity against human serum specimens. No serum samples from healthy control reacted with EgAg. Phylogenetic analysis of resulting COX1 and NAD1sequences has revealed that all patients in our study were infected with the E. granulosus G1-G3 genotype. There was no consistent correlation between results of ELISA and WB, the number or size of cysts and genotype. Our study brings a unique contribution in terms of relationship between serological investigation, disease genotypes and clinical outcomes.

Published
2020
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6. Applications of TE and TM Modes in Advanced Optical Systems and Communications.

Author

Ayari, Mohamed, Klai, Zeineb, Elkamel, Akil M., and Hammami, Mohamed Ali

Subjects
OPTICAL communications, OPTICAL devices, FIBER optics, OPTICAL sensors, FIBER lasers
Abstract

This study investigates the use of Transverse Electric (TE) and Transverse Magnetic (TM) modes in sophisticated optical systems, with a specific emphasis on their influence on fiber optic communications, laser technology, optical sensors, and photonics. Through the use of intricate simulations, we demonstrate how these modes increase transmission efficiency, improve the quality of laser beams, and augment sensor precision. The research emphasizes the crucial significance of TE and TM modes in enhancing the efficiency of optical devices and offers valuable insights for future advancements in optical systems. [ABSTRACT FROM AUTHOR]

Published
2024

10. Maskeringsmaterial med multi-axial varptrikå

Author

Hagman, Anton, Angelbratt, Simon, Akil, M Said, Hagman, Anton, Angelbratt, Simon, and Akil, M Said

Abstract

Kamouflagenät är ett viktigt verktyg inom försvarsindustrin där det används för att maskera eller dölja objekt från att bli visuellt upptäckta. Kamouflagenät är utformade för att efterlikna den omgivande miljön eller terräng som den appliceras vid. Traditionellt tillverkas kamouflagesystemen genom virkningsstekniken bi-axial varptrikå med två system inslagstrådar i 0° respektive 90°. För produktutvecklingens syfte att tillverka ett lätt kamouflagenät med lämpliga hållfasthetsegenskaper, undersöks tekniken multi-axial varptrikå med fyra system inslagstrådar i 0°, 90° och ±45°. Genom semi-strukturerade intervjuer med experter inom bi- och multi-axial varptrikå samlas det in information och fakta om multi-axial teknik. Detta fungerar som en grund för att avgöra om det är en möjlig teknik för den befintliga produkten. En teoretisk modellering utförs sedan för att undersöka, förutsäga samt jämföra beteenden och egenskaper hos de bi- och multi-axiella strukturerna. De semi-strukturerade intervjuerna resulterade i en omfattande och informativ faktainsamling om multi-axial teknik. Det inhämtades underlag gällande hur tillämpbar den multi-axiella tekniken är för kamouflagenät, samt information om maskinens begränsningar och trådorientering. Den teoretiska modelleringen innebär tillämpning av kända matematiska och fysikaliska begrepp, modelleringen lägger således en grund för att förstå mekaniska beteenden hos bi -och multi-axiella strukturer då de utsätts för små deformationer. Den teoretiska modelleringen resulterade i värden som beskriver styvheten hos de båda strukturerna vid deformationer på =0,01 i fyra riktningar. Kunskapen om lämpliga styvhetsegenskaper för kamouflagenät i kombination med resultatet från den teoretiska modelleringen lade en grund för att dra slutsatser om ifall multi-axiella strukturer, som är lika lätta som motsvarande bi-axiella strukturer vilka idag används i kamouflagenät, är lämpliga för att användas i kamouflagenät. Resultaten från modelleringen, Camouflage net is an essential device in the arms industry, where it is utilized to camouflage and hide objects from being visually detected. The camouflage net is designed to imitate the surrounding environment or terrain in which it is being applied. Traditionally, camouflage systems are manufactured using a knitting technique called bi-axial warp knitting with two systems of inlay yarns in 0° and 90° angles relative to the fabrics warp direction. To enhance the current product and produce light camouflage net with suitable strength properties, the multi-axial warp knitting technique with four systems of inlay yarns at 0°, 90° and ±45° angles is investigated. By utilizing semi-structured interviews with experts in the area of bi- and multi-axial warp knitting, can information and facts about multi-axial be collected and be used as a basis for concluding whether multi-axial is a suitable technique for the existing product. A theoretical modeling is then performed to examine, predict and compare the behaviors and properties of the bi- and multi-axial structures. The semi-structured interviews resulted in a comprehensive and informative collection of data about multi-axial technique. It also gathered information about the suitability and application of the technique to camouflage nets, as well as information regarding the machine’s limitations and thread orientation. The theoretical modeling involves the application of known mathematical and physical concepts, thus providing a foundation for understanding the mechanical behavior of bi- and multi-axial structures under small deformations. The theoretical modeling resulted in values that describe the stiffness of both structures at deformations of =0,01 in four directions. The knowledge of appropriate stiffness properties for camouflage nets, combined with the results from the theoretical modeling, laid the groundwork for drawing conclusions about the suitability of using multi-axial structures, which are as lightweigh

Published
2023

15. Parallel Algorithm for Concurrent Computation of Connected Component Tree

Author

Matas, P., Dokládalová, E., Akil, M., Grandpierre, T., Najman, L., Poupa, M., Georgiev, V., Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Nierstrasz, Oscar, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Sudan, Madhu, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Vardi, Moshe Y., Series editor, Weikum, Gerhard, Series editor, Blanc-Talon, Jacques, editor, Bourennane, Salah, editor, Philips, Wilfried, editor, Popescu, Dan, editor, and Scheunders, Paul, editor

Published
2008
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18. Outcomes of children born to mothers with systemic lupus erythematosus exposed to hydroxychloroquine or azathioprine

Author

Reynolds, J.A., Gayed, M., Khamashta, M.A., Leone, F., Toescu, V., Bruce, I.N., Giles, I., Teh, L.-S., McHugh, N., Akil, M., Edwards, C.J., and Gordon, C.

Abstract

Objectives\ud \ud HCQ and AZA are used to control disease activity and reduce risk of flare during pregnancy in patients with SLE. The aim of this study was to determine the outcomes of children born to mothers with SLE exposed to HCQ or AZA during pregnancy and breast-feeding.\ud \ud \ud \ud Methods\ud \ud Women attending UK specialist lupus clinics with children ≤17 years old, born after SLE diagnosis, were recruited to this retrospective study. Data were collected using questionnaires and from clinical record review. Factors associated with the outcomes of low birth weight and childhood infection were determined using multivariable mixed-effects logistic regression models.\ud \ud \ud \ud Results\ud \ud We analysed 284 live births of 199 mothers from 10 UK centres. The first pregnancies of 73.9% of mothers (147/199) were captured in the study; (60.4%) (150/248) and 31.1% (87/280) children were exposed to HCQ and AZA, respectively. There were no significant differences in the frequency of congenital malformations or intrauterine growth restriction between children exposed or not to HCQ or AZA. AZA use was increased in women with a history of hypertension or renal disease. Although AZA was associated with low birth weight in univariate models, there was no significant association in multivariable models. In adjusted models, exposure to AZA was associated with increased reports of childhood infection requiring hospital management [odds ratio 2.283 (1.003, 5.198), P = 0.049].\ud \ud \ud \ud Conclusions\ud \ud There were no significant negative outcomes in children exposed to HCQ in pregnancy. AZA use was associated with increased reporting of childhood infection, which warrants further study.

Published
2022

22. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Author

Lyons, P. A., Peters, J. E., Alberici, F., Liley, J., Coulson, R. M. R., Astle, W., Baldini, C., Bonatti, F., Cid, María Cinta, Elding, H., Emmi, G., Epplen, J., Guillevin, L., Jayne, D. R. W., Jiang, T., Gunnarsson, I., Lamprecht, P., Leslie, S., Little, M. A., Martorana, D., Moosig, F., Neumann, T., Ohlsson, S., Quickert, S., Ramirez, G. A., Rewerska, B., Schett, George, Sinico, R. A., Szczeklik, W., Tesar, Vladimir, Vukcevic, D., Akil, M., Barratt, J., Basu, N., Butterworth, A. S., Bruce, I., Clarkson, M., Conlon, N., DasGupta, B., Doulton, T. W. R., Espígol-Frigolé, Georgina, Flossmann, O., Gabrielli, A., Gasior, J., Gregorini, G., Guida, G., Hernández Rodríguez, José, Hruskova, Z., Hudson, A., Knight, A., Lanyon, P., Luqmani, R., Magliano, M., Manfredi, A. A., Marguerie, C., Maritati, F., Marvisi, C., McHugh, N. J., Molloy, E., Motyer, A., Mukhtyar, C., Padyukov, Leonid, Pesci, Alberto, Prieto-Gonzalez, S., Ramentol-Sintas, Marc, Reis, P., Roccatello, D., Rovere-Querini, P., Salvarani, C., Santarsia, F., Solans, Roser, Soranzo, N., Taylor, J., Wessels, J., Zwerina, J., Terrier, B., Watts, R. A., Vaglio, A., Holle, J. U., Wallace, C., Smith, K. G. C., Universitat Autònoma de Barcelona, Lyons, P. A., Peters, J. E., Alberici, F., Liley, J., Coulson, R. M. R., Astle, W., Baldini, C., Bonatti, F., Cid, M. C., Elding, H., Emmi, G., Epplen, J., Guillevin, L., Jayne, D. R. W., Jiang, T., Gunnarsson, I., Lamprecht, P., Leslie, S., Little, M. A., Martorana, D., Moosig, F., Neumann, T., Ohlsson, S., Quickert, S., Ramirez, G. A., Rewerska, B., Schett, G., Sinico, R. A., Szczeklik, W., Tesar, V., Vukcevic, D., Akil, M., Barratt, J., Basu, N., Butterworth, A. S., Bruce, I., Clarkson, M., Conlon, N., Dasgupta, B., Doulton, T. W. R., Espigol-Frigole, G., Flossmann, O., Gabrielli, A., Gasior, J., Gregorini, G., Guida, G., Hernandez-Rodriguez, J., Hruskova, Z., Hudson, A., Knight, A., Lanyon, P., Luqmani, R., Magliano, M., Manfredi, A. A., Marguerie, C., Maritati, F., Marvisi, C., Mchugh, N. J., Molloy, E., Motyer, A., Mukhtyar, C., Padyukov, L., Pesci, A., Prieto-Gonzalez, S., Ramentol-Sintas, M., Reis, P., Roccatello, D., Rovere-Querini, P., Salvarani, C., Santarsia, F., Solans-Laque, R., Soranzo, N., Taylor, J., Wessels, J., Zwerina, J., Terrier, B., Watts, R. A., Vaglio, A., Holle, J. U., Wallace, C., Smith, K. G. C., Lyons, P, Peters, J, Alberici, F, Liley, J, Coulson, R, Astle, W, Baldini, C, Bonatti, F, Cid, M, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, D, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, M, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramierez, G, Rewerska, B, Schett, G, Sinico, R, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, A, Bruce, I, Clarkson, M, Conlon, N, Dasgupta, B, Doulton, T, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, A, Marguerie, C, Maritati, F, Marvisi, C, Mchugh, N, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, R, Vaglio, A, Holle, J, Wallace, C, Smith, K, and United Kingdom Research and Innovation

Subjects
0301 basic medicine, Candidate gene, Antineutrophil Cytoplasmic, General Physics and Astronomy, Genome-wide association study, Autoimmunity, Genome-wide association studies, 0302 clinical medicine, Rheumatic diseases, immune system diseases, Eosinophilic, Eosinophilia, lcsh:Science, education.field_of_study, Multidisciplinary, Genome-wide association, eosinophilic granulomatosis with polyangiitis, ANCA status, 3. Good health, medicine.symptom, Vasculitis, Granulomatosis with polyangiitis, Antibodies, Antineutrophil Cytoplasmic, Eosinophils, Genetic Association Studies, Granulomatosis with Polyangiitis, Humans, Mendelian Randomization Analysis, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, European Vasculitis Genetics Consortium, Science, Population, General Biochemistry, Genetics and Molecular Biology, Article, Antibodies, 03 medical and health sciences, medicine, Immunogenetics, education, Rheumatology and Autoimmunity, Anti-neutrophil cytoplasmic antibody, 030203 arthritis & rheumatology, Reumatologi och inflammation, business.industry, General Chemistry, medicine.disease, respiratory tract diseases, 030104 developmental biology, Immunology, EGPA, HLA, ANCA, genetics, lcsh:Q, business
Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA., Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).

Published
2019
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23. Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Author

Jani, Meghna, Chinoy, Hector, Warren, Richard B., Griffiths, Christopher E. M., Plant, Darren, Fu, Bo, Morgan, Ann W., Wilson, Anthony G., Isaacs, John D., Hyrich, Kimme L., Barton, Anne, Prouse, P. J., Moitra, R. K., Shawe, D. J., Nisar, M., Fairburn, K., Nixon, J., Barnes, T., Hui, M., Coady, D., Wright, D., Morley, C., Raftery, G., Bracewell, C., Bridges, M., Armstrong, D., Chuck, A. J., Hailwood, S., Kumar, N., Ashok, D., Reece, R., OʼReilly, S. C., Ding, T., Badcock, L. J., Deighton, C. M., Raj, N., Regan, M. R., Summers, G. D., Williams, R. A., Lambert, J. R., Stevens, R., Wilkinson, C., Kelly, C. A., Hamilton, J., Heycock, C. R., Saravanan, V., Cope, A., Garrood, T., Ng, N., Kirkham, B., Green, M., Gough, A., Lawson, C., Das, D., Borbas, E., Wazir, T., Emery, P., Bingham, S., Bird, H. A., Conaghan, P. G., Pease, C. T., Wakefield, R. J., Buch, M., Bruce, I., Gorodkin, R., Ho, P., Parker, B., Smith, W., Jenkins, E., Mukhtyar, C., Gaffney, K., Macgregor, A. J., Marshall, T., Merry, P., DeSilva, C., Birrell, F. N., Crook, P. R., Szebenyi, B., Bates, D., James, D., Gillott, T., Alvi, A., Grey, C., Browning, J., McHale, J. F., Gaywood, I. C., Jones, A. C., Lanyon, P., Pande, I., Doherty, M., Gupta, A., Courtney, P. A., Srikanth, A., Abhishek, A., Das, L., Pattrick, M., Snowden, H. N., Bowden, A. P., Smith, E. E., Klimiuk, P., Speden, D. J., Naz, S., Ledingham, J. M., Hull, R. G., McCrae, F., Cooper, A., Young-Min, S. A., Wong, E., Shaban, R., Woolf, A. D., Davis, M., Hutchinson, D., Endean, A., Mewar, D., Tunn, E. J., Nelson, K., Kennedy, T. D., Dubois, C., Pauling, J., Korendowych, E., Jenkinson, T., Sengupta, R., Bhalla, A., McHugh, N., OʼNeil, T., Herrick, A. L., Jones, A. K., Cooper, R. G., Dixon, W. G., Harrison, B., Buckley, C. D., Carruthers, D. C., Elamanchi, R., Gordon, P. C., Grindulis, K. A., Khattak, F., Raza, K., Situnayake, K., Akil, M., Till, S., Dunkley, L., Tattersall, R., Kilding, R., Tait, T., Maxwell, J., Kuet, K.-P., Plant, M. J., Clarke, F., Fordham, J. N., Tuck, S., Pathare, S. K., Paul, A., Marguerie, C. P., Rigby, S. P., Dunn, N., Abbas, I., Filer, C., Abernethy, V. E., Clewes, A. R., Dawson, J. K., Kitas, G., Erb, N., Klocke, R., Whallett, A. J., Douglas, K., Pace, A., Sandhu, R., John, H., Shand, L., Lane, S., Foster, H., Griffiths, B., Griffiths, I., Kay, L., Ng, W.-F., Platt, P. N., Walker, D. J., Peterson, P., Lorenzi, A., Friswell, M., Thompson, B., Lee, M., Pratt, A., Hopkinson, N. D., Dunne, C. A., Quilty, B., Marks, J., Mukherjee, S., Mulherin, D., Chalam, S. V., Price, T., Sheeran, T., Venkatachalam, S., Baskar, S., Al-Allaf, W., McKenna, F., Shah, P., Filer, A., Bowman, S. J., Jobanputra, P., Rankin, E. C., Allen, M., Chaudhuri, K., Dubey, S., Price-Forbes, A., Ravindran, J., Samanta, A., Sheldon, P., Hassan, W., Francis, J., Kinder, A., Neame, R., Moorthy, A., Bukhari, M., Ottewell, L., Palkonyai, E., Hider, S., Hassell, A., Menon, A., Dowson, C., Kamath, S., Packham, J., Dutta, S., Price, S., Roddy, E., Paskins, Z., OʼReilly, D. T., Rajagopal, V., Bhagat, S., Chattopadhyay, C. B., Quinn, D., Isdale, A., Brown, A., Saleem, B., Foo, B., Al Saffar, Z., and Koduri, G.

Published
2015
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26. Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors

Author

Layla Shojaie, Jacob M. Bogdanov, Helia Alavifard, Mahmoud G. Mohamed, Aria Baktash, Myra Ali, Simeon Mahov, Sue Murray, Gary C. Kanel, Zhang-Xu Liu, Fumito Ito, Gino K. In, Akil Merchant, William Stohl, and Lily Dara

Subjects
Cytology, QH573-671
Abstract

Abstract Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these checkpoints to avoid immune destruction. Immune checkpoint inhibitors (ICIs) activate immune cells and restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on these tolerogenic mechanisms, and their disruption with ICI use can trigger the unintended side effect of hepatotoxicity termed immune-mediated liver injury from ICIs (ILICI). Learning how to uncouple ILICI from ICI anti-tumor activity is of paramount clinical importance. We developed a murine model to recapitulate human ILICI using CTLA4+/- mice treated with either combined anti-CTLA4 + anti-PDL1 or IgG1 + IgG2. We tested two forms of antisense oligonucleotides to knockdown caspase-3 in a total liver (parenchymal and non-parenchymal cells) or in a hepatocyte-specific manner. We also employed imaging mass cytometry (IMC), a powerful multiplex modality for immunophenotyping and cell interaction analysis in our model. ICI-treated mice had significant evidence of liver injury. We detected cleaved caspase-3 (cC3), indicating apoptosis was occurring, as well as Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total liver knockdown of caspase-3 worsened liver injury, and induced further inflammasome activation, and Gasdermin-D-mediated pyroptosis. Hepatocyte-specific knockdown of caspase-3 reduced liver injury and NLRP3 inflammasome activation. IMC-generated single-cell data for 77,692 cells was used to identify 22 unique phenotypic clusters. Spatial analysis revealed that cC3+ hepatocytes had significantly closer interactions with macrophages, Kupffer cells, and NLRP3hi myeloid cells than other cell types. We also observed zones of three-way interaction between cC3+ hepatocytes, CD8 + T-cells, and macrophages. Our work is the first to identify hepatocyte apoptosis and NLRP3 inflammasome activation as drivers of ILICI. Furthermore, we report that the interplay between adaptive and innate immune cells is critical to hepatocyte apoptosis and ILICI.

Published
2024
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27. Testing the role of vitamin D in response to antitumour necrosis factor α therapy in a UK cohort: a Mendelian randomisation approach

Author

Yarwood, Annie, Viatte, Sebastien, Plant, Darren, Morgan, Ann W, Isaacs, John, Wilson, Anthony G, Hyrich, Kimme, Eyre, Steve, Barton, Anne, Gaston, H, Mulherin, D, Price, T, Sheeran, T, Chalam, V, Baskar, S, Emery, P, Morgan, A W, Buch, M, Bingham, S, O’Reilly, S, Badcock, L, Regan, M, Ding, T, Deighton, C, Summers, G, Raj, N, Stevens, R, Williams, N, Isaacs, J, Platt, P, Walker, D, Kay, L, Griffiths, B, Ng, W-F, Peterson, P, Lorenzi, A, Foster, H, Friswell, M, Thompson, B, Lee, M, Griffiths, I, Hassell, A, Dawes, P, Dowson, C, Kamath, S, Packham, J, Shadforth, M, Williams, R, Mukhtyar, C, Harrison, B, Snowden, N, Naz, S, Ledingham, J, Hull, R, McCrae, F, Thomas, A, Young Min, S, Shaban, R, Wong, E, Kelly, C, Heycock, C, Hamilton, J, Saravanan, V, Wilson, G, Bax, D, Dunkley, L, Akil, M, Tattersall, R, Kilding, R, Till, S, Boulton, J, Tait, T, Bukhari, M, Halsey, J, Ottewell, L, Buckley, C, Situnayake, D, Carruthers, D, Grindulis, K, Khatack, F, Elamanchi, S, Raza, K, Filer, A, Jubb, R, Abernathy, R, Plant, M, Pathare, S, Clarke, F, Tuck, S, Fordham, J, Paul, A, Bridges, M, Hakim, A, O’Reilly, D, Rajagopal, V, Bhagat, S, Edwards, C, Prouse, P, Moitra, R, Shawe, D, Bamji, A, Klimiuk, P, Bowden, A, Mitchell, W, Bruce, I, Barton, A, Gorodkin, R, Ho, P, Hyrich, K, Dixon, W, Rai, A, Kitas, G, Erb, N, Klocke, R, Douglas, K, Pace, A, Sandhu, R, Whallett, A, Birrell, F, Allen, M, Chaudhuri, K, Chattopadhyay, C, McHale, J, Jones, A, Gupta, A, Pande, I, Gaywood, I, Lanyon, P, Courtney, P, Doherty, M, Chinoy, H, O’Neill, T, Herrick, A, Jones, A, Cooper, R, Bucknall, R, Marguerie, C, Rigby, S, Dunn, N, Green, S, Al-Ansari, A, Webber, S, Hopkinson, N, Dunne, C, Quilty, B, Szebenyi, B, Green, M, Quinn, M, Isdale, A, Brown, A, Saleem, B, Samanta, A, Sheldon, P, Hassan, W, Francis, J, Kinder, A, Neame, R, Moorthy, A, Al-Allaf, W, Taggart, A, Fairburn, K, McKenna, F, Green, M, Gough, A, Lawson, C, Piper, M, Korendowych, E, Jenkinson, T, Sengupta, R, Bhalla, A, McHugh, N, Bond, Debbie, Luqmani, R, Bowness, B, Wordsworth, P, David, J, Smith, W, Mewar, D, Tunn, E, Nelson, K, Kennedy, T, Nixon, J, Woolf, A, Davis, M, Hutchinson, D, Endean, A, Coady, D, Wright, D, Morley, C, Raftery, G, Bracewell, C, Kidd, L, Abbas, I, Filer, C, and Kallarackal, G

Published
2014
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28. POS0106 BILAG-2004 LDA AND BST LDA ARE VALID TREAT TO TARGET IN SLE

Author

Yee, C. S., primary, Gordon, C., additional, Akil, M., additional, Lanyon, P., additional, Edwards, C. J., additional, Isenberg, D., additional, Rahman, A., additional, Teh, L. S., additional, Tosounidou, S., additional, Stevens, R., additional, Prabu, A., additional, Griffiths, B., additional, Mchugh, N., additional, Bruce, I. N., additional, Ahmad, Y., additional, Khamashta, M., additional, and Farewell, V., additional

Published
2021
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29. POS0705 BILAG-2004 INDEX ACTIVE DISEASE PREDICTS DEVELOPMENT OF DAMAGE

Author

Yee, C. S., primary, Farewell, V., additional, Akil, M., additional, Lanyon, P., additional, Edwards, C. J., additional, Isenberg, D., additional, Rahman, A., additional, Teh, L. S., additional, Tosounidou, S., additional, Stevens, R., additional, Prabu, A., additional, Griffiths, B., additional, Mchugh, N., additional, Bruce, I. N., additional, Ahmad, Y., additional, Khamashta, M., additional, and Gordon, C., additional

Published
2021
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30. POS0111 DEVELOPMENT OF DAMAGE AND MORTALITY IN AN INCEPTION COHORT OF SLE PATIENTS

Author

Yee, C. S., primary, Farewell, V., additional, Akil, M., additional, Lanyon, P., additional, Edwards, C. J., additional, Isenberg, D., additional, Rahman, A., additional, Teh, L. S., additional, Tosounidou, S., additional, Stevens, R., additional, Prabu, A., additional, Griffiths, B., additional, Mchugh, N., additional, Bruce, I. N., additional, Ahmad, Y., additional, Khamashta, M., additional, and Gordon, C., additional

Published
2021
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35. Predictive value of lymphocyte to monocyte ratio for cardiac syndrome X.

Author

AKIL, M. A., OYLUMLU, M., DEMIR, M., OZBEK, M., POLAT, N., ACET, H., and BILIK, M. Z.

Abstract

OBJECTIVE: Cardiac syndrome X (CSX) is typically described with ischemia in stress tests in addition to angina-like chest pain and without stenosis in coronary angiography. We aimed at determining the relationship between LMR and CSX. PATIENTS AND METHODS: We retrospectively collected patients with CSX between January 2016 and December 2019. Patients with typical angina-like chest pain, normal 12-lead electrocardiography at rest, a positive response to the exercise test (> 0.1 mV ST-segment depression at 80 ms after the J point in two or more contiguous leads) or ischemia on myocardial perfusion scintigraphy and normal coronary angiography were included in the study as CSX patients. RESULTS: This study consisted of 116 patients with CSX and 153 control groups. The mean age of the patients with CSX was 52.7±9.7 years, and the mean age of the control group was 53.7±10.6 years (p= 0.416). The patients with CSX were more likely to have higher monocyte counts and LMR. According to the Pearson correlation test, the CRP value negatively correlated with the LMR. In multivariate logistic regression analysis, LMR remained a significant predictor of CSX. In ROC analysis, LMR < 4.1 had 64% sensitivity and 50% specificity (ROC area under curve: 0.587, 95% CI: 0.519-0.655, p=0.015) in accurately predicting a CSX diagnosis. CONCLUSIONS: We showed that lower LMR levels were associated with the presence of CSX. [ABSTRACT FROM AUTHOR]

Published
2022

38. Bakti Sosial di Lembang Marinding dan Kelurahan Lemo, Kecamatan Mengkendek, Tana Toraja

Author

Mappaware, Nasrudin Andi, primary, Rijal, Syamsu, primary, Akil, M., primary, Harahap, Wirawan, primary, Makmun, Armanto, primary, Latief, Shofiyah, primary, Arfah, Arni Isnaini, primary, Khalid, Nurfadhillah, primary, L.B, Rezky Pratiwi, primary, P, Utomo Andi, primary, Masdipa, Andi, primary, Pratama, Ryan Charmy, primary, Takdir, Andi Dirhan, primary, Kurnia, Rahmawaty, primary, Alamsyah, Muh. Fuad, primary, Irsan, Muhammad, primary, and Pratama, Asro Akjuma, primary

Published
2020
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43. TIESTO: Tested Intelligent Systems For Traffic Operations

Author

D. Ezhilarasi, Srinivasa Karthik, Joel Antony Joseph, and Akil M

Subjects
Traffic congestion, Computer science, Game engine, Control (management), Intelligent decision support system, Self adaptive, Automotive engineering
Abstract

The paper describes real-time traffic problems and proposes a feasible solution to curb pollution due to traffic idling and congestion. The aim is to decrease wait times at traffic lights in turn decreasing pollution due to less traffic congestion. This would have the additional advantage of economic improvement due to curtailed fuel consumption.fuel loss is directly proportional to the idling time of vehicles in traffic junctions. The proposed model aims at reducing the idling time of any vehicle at traffic junctions and thereby significantly reducing the fuel loss incurred. This model would also prioritize passage of Emergency Service Vehicles. This is attained by implementing a self-adaptive traffic control switching mechanism according to a devised algorithm. The model uses RSSI values to calculate the vehicle density in each lane. A Unity Game Engine simulation is used to demonstrate the idea. A small scale physical representation of the same has been done as well.

Published
2019
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44. Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Author

Tarn, JR, Howard-Tripp, N, Lendrem, DW, Mariette, X, Saraux, A, Devauchelle-Pensec, V, Seror, R, Skelton, AJ, James, K, McMeekin, P, Al-Ali, S, Hackett, KL, Lendrem, BC, Hargreaves, B, Casement, J, Mitchell, S, Bowman, SJ, Price, E, Pease, CT, Emery, P, Lanyon, P, Hunter, J, Gupta, M, Bombardieri, M, Sutcliffe, N, Pitzalis, C, McLaren, J, Cooper, A, Regan, M, Giles, I, Isenberg, D, Saravanan, V, Coady, D, Dasgupta, B, McHugh, N, Young-Min, S, Moots, R, Gendi, N, Akil, M, Griffiths, B, Johnsen, SJA, Norheim, KB, Omdal, R, Stocken, D, Everett, C, Fernandez, C, Isaacs, JD, Gottenberg, J-E, Ng, W-F, French ASSESS cohort, and UK Primary Sjögren's Syndrome Registry

Abstract

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology.

Published
2019

45. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Author

Lyons, P.A., Peters, J.E., Alberici, F., Liley, J., Coulson, R.M.R., Astle, W., Baldini, C., Bonatti, F., Cid, M.C., Elding, H., Emmi, G., Epplen, J., Guillevin, L., Jayne, D.R.W., Jiang, T., Gunnarsson, I., Lamprecht, P., Leslie, S., Little, M.A., Martorana, D., Moosig, F., Neumann, T., Ohlsson, S., Quickert, S., Ramirez, G.A., Rewerska, B., Schett, G., Sinico, R.A., Szczeklik, W., Tesar, V., Vukcevic, D., Akil, M., Barratt, J., Basu, N., Butterworth, A.S., Bruce, I., Clarkson, M., Conlon, N., DasGupta, B., Doulton, T.W.R., Espígol-Frigolé, Georgina, Flossmann, O., Gabrielli, A., Gasior, J., Gregorini, G., Guida, G., Hernández Rodríguez, José, Hruskova, Z., Hudson, A., Knight, A., Lanyon, P., Luqmani, R., Magliano, M., Manfredi, A.A., Marguerie, C., Maritati, F., Marvisi, C., McHugh, N.J., Molloy, E., Motyer, A., Mukhtyar, C., Padyukov, L., Pesci, A., Prieto-Gonzalez, S., Ramentol-Sintas, Marc, Reis, P., Roccatello, D., Rovere-Querini, P., Salvarani, C., Santarsia, F., Solans-Laque, R., Soranzo, N., Taylor, J., Wessels, J., Zwerina, J., Terrier, B., Watts, R.A., Vaglio, A., Holle, J.U., Wallace, C., Smith, K.G.C., and Universitat Autònoma de Barcelona

Subjects
Eosinophils, Genetic Loci, Granulomatosis with Polyangiitis, Humans, Genetic Predisposition to Disease, Mendelian Randomization Analysis, Genetic Association Studies, Antibodies, Antineutrophil Cytoplasmic, Genome-Wide Association Study
Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Published
2019

47. Irish society for rheumatology: Proceedings of annual general meeting held in Beaumont Hospital on Friday 22nd October, 1993

Author

Mulherin, Diarmuid, FitzGerald, Oliver, Bresnihan, Barry, Bruce, I. N., McNally, J. A., Bell, A. L., Yanni, G., Cauli, A., Challacombe, S., Panayi, G. S., Foley-Nolan, D., Akil, M., Anthony, M., Cundall, D., Bourne, J., Arthur, R., Chamberlain, M. A., Byrne, P., Mahon, N., Robinson, H., Sant, S. M., Donnelly, S., Barnes, L., Watson, R., Casey, E. B., Donnelly, S., Casey, E. B., Bruce, I. N., Edgar, D. E., McMillan, S. A., Conlan, S. K., McNeill, T. A., Bell, A. L., Robinson, H., Byrne, P., Mahon, N., Sant, S. M., Abuzakouk, M., Feighery, C., Jones, E., O’Briain, S., Goggins, M., Weir, D. G., Casey, E., O’Farrelly, C., Kelleher, D., Murphy, A., Casey, E. B., Veale, D. J., Kirk, G., McLaren, M., Belch, J. J. F., Byrne, P., Mahon, N., Robinson, H., Sant, S. M., Foley-Nolan, D., Daly, M. J., Mahon, N., Robinson, H., Byrne, P., Sant, S. M., Donnelly, S., Murphy, J., Lynch, M., Casey, E. B., McKernan, S., Donnelly, S., Casey, E. B., Sothinathan, R., Donnelly, S., Casey, E. B., Blake, C., Garrett, M., Robinson, H., Byrne, P., Mahon, N., Sant, S. M., Gourley, I. S., Bell, A. L., Bresnihan, B., FitzGerald, O., Cunnane, G., Abuzakouk, M., Feighery, C., Bergin, C., Cherukuri, A., Weir, D. G., Casey, E., O’Farrelly, C., Mulherin, D., Kirk, G., Veale, D. J., Belch, J. J. F., Bresnihan, B., FitzGerald, O., Kelleher, D., Hall, N., Murphy, A., Casey, E. B., Mulcahy, B., Molloy, M., Phelan, M., O’Gara, F., McConnell, F., Shanahan, F., FitzGerald, O., Heffernan, M., Mulcahy, B., Neary, P., and Molloy, M.

Published
1994
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49. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Author

Lyons, P, Peters, J, Alberici, F, Liley, J, Coulson, R, Astle, W, Baldini, C, Bonatti, F, Cid, M, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, D, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, M, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramierez, G, Rewerska, B, Schett, G, Sinico, R, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, A, Bruce, I, Clarkson, M, Conlon, N, Dasgupta, B, Doulton, T, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, A, Marguerie, C, Maritati, F, Marvisi, C, Mchugh, N, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, R, Vaglio, A, Holle, J, Wallace, C, Smith, K, Lyons, PA, Peters, JE, Cid, MC, Little, MA, Ramierez, GA, Butterworth, AS, DasGupta, B, Doulton, TWR, Manfredi, AA, McHugh, NJ, Watts, RA, Holle, JU, Smith, KGC, Lyons, P, Peters, J, Alberici, F, Liley, J, Coulson, R, Astle, W, Baldini, C, Bonatti, F, Cid, M, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, D, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, M, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramierez, G, Rewerska, B, Schett, G, Sinico, R, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, A, Bruce, I, Clarkson, M, Conlon, N, Dasgupta, B, Doulton, T, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, A, Marguerie, C, Maritati, F, Marvisi, C, Mchugh, N, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, R, Vaglio, A, Holle, J, Wallace, C, Smith, K, Lyons, PA, Peters, JE, Cid, MC, Little, MA, Ramierez, GA, Butterworth, AS, DasGupta, B, Doulton, TWR, Manfredi, AA, McHugh, NJ, Watts, RA, Holle, JU, and Smith, KGC

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Published
2019

50. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Author

Lyons, PA, Peters, JE, Alberici, F, Liley, J, Coulson, RMR, Astle, W, Baldini, C, Bonatti, F, Cid, MC, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, DRW, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, MA, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramirez, GA, Rewerska, B, Schett, G, Sinico, RA, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, AS, Bruce, I, Clarkson, M, Conlon, N, DasGupta, B, Doulton, TWR, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, AA, Marguerie, C, Maritati, F, Marvisi, C, McHugh, NJ, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, RA, Vaglio, A, Holle, JU, Wallace, C, Smith, KGC, Lyons, PA, Peters, JE, Alberici, F, Liley, J, Coulson, RMR, Astle, W, Baldini, C, Bonatti, F, Cid, MC, Elding, H, Emmi, G, Epplen, J, Guillevin, L, Jayne, DRW, Jiang, T, Gunnarsson, I, Lamprecht, P, Leslie, S, Little, MA, Martorana, D, Moosig, F, Neumann, T, Ohlsson, S, Quickert, S, Ramirez, GA, Rewerska, B, Schett, G, Sinico, RA, Szczeklik, W, Tesar, V, Vukcevic, D, Akil, M, Barratt, J, Basu, N, Butterworth, AS, Bruce, I, Clarkson, M, Conlon, N, DasGupta, B, Doulton, TWR, Espigol-Frigole, G, Flossmann, O, Gabrielli, A, Gasior, J, Gregorini, G, Guida, G, Hernandez-Rodriguez, J, Hruskova, Z, Hudson, A, Knight, A, Lanyon, P, Luqmani, R, Magliano, M, Manfredi, AA, Marguerie, C, Maritati, F, Marvisi, C, McHugh, NJ, Molloy, E, Motyer, A, Mukhtyar, C, Padyukov, L, Pesci, A, Prieto-Gonzalez, S, Ramentol-Sintas, M, Reis, P, Roccatello, D, Rovere-Querini, P, Salvarani, C, Santarsia, F, Solans-Laque, R, Soranzo, N, Taylor, J, Wessels, J, Zwerina, J, Terrier, B, Watts, RA, Vaglio, A, Holle, JU, Wallace, C, and Smith, KGC

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Published
2019

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