{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:47:09Z","timestamp":1773326829070,"version":"3.50.1"},"reference-count":69,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI20\/01845, PI12\/02688 and PI17\/02276"],"award-info":[{"award-number":["PI20\/01845, PI12\/02688 and PI17\/02276"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The ERA-NET PathoGenoMics","award":["PIM2010EPA-00756 (0315900A)"],"award-info":[{"award-number":["PIM2010EPA-00756 (0315900A)"]}]},{"name":"The Collaborative Research Center \/ Transregio 124 FungiNet","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"The Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["PTDC\/SAU-SER\/29635\/2017, PTDC\/MED-GEN\/28778\/2017, CEECIND\/03628\/2017,and CEECIND\/04058\/2018"],"award-info":[{"award-number":["PTDC\/SAU-SER\/29635\/2017, PTDC\/MED-GEN\/28778\/2017, CEECIND\/03628\/2017,and CEECIND\/04058\/2018"]}]},{"name":"The Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia (FCT)","award":["LCF\/PR\/HP17\/52190003"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190003"]}]},{"name":"the European Union\u2019s Horizon 2020 research and innovation programme","award":["grant agreement no. 847507"],"award-info":[{"award-number":["grant agreement no. 847507"]}]},{"name":"The \u201cla Caixa\u201d Foundation","award":["ID 100010434"],"award-info":[{"award-number":["ID 100010434"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T\/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.<\/jats:p>","DOI":"10.3390\/jof7010004","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T12:19:51Z","timestamp":1608725991000},"page":"4","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium"],"prefix":"10.3390","volume":"7","author":[{"given":"Jose Manuel","family":"S\u00e1nchez-Maldonado","sequence":"first","affiliation":[{"name":"Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"},{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Mo\u00f1iz-D\u00edez","sequence":"additional","affiliation":[{"name":"Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"},{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"ter Horst","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Campa","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Pisa, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Jos\u00e9","family":"Cabrera-Serrano","sequence":"additional","affiliation":[{"name":"Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4333-4487","authenticated-orcid":false,"given":"Manuel","family":"Mart\u00ednez-Bueno","sequence":"additional","affiliation":[{"name":"Genomic Medicine Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda del Pilar","family":"Garrido-Collado","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisca","family":"Hern\u00e1ndez-Mohedo","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Fern\u00e1ndez-Puerta","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel \u00c1ngel","family":"L\u00f3pez-Nevot","sequence":"additional","affiliation":[{"name":"Immunology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Cunha","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s-PT Government Associate Laboratory, 4710-057 Braga\/Guimar\u00e3es, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Antonio","family":"Gonz\u00e1lez-Sierra","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Springer","sequence":"additional","affiliation":[{"name":"Hematology Department, Universit\u00e4tsklinikum W\u00fcrzburg, Medizinische Klinik II, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9073-2886","authenticated-orcid":false,"given":"Michaela","family":"Lackner","sequence":"additional","affiliation":[{"name":"Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Alcazar-Fuoli","sequence":"additional","affiliation":[{"name":"Mycology Reference Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, 28222 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luana","family":"Fianchi","sequence":"additional","affiliation":[{"name":"Istituto di Ematologia, Universit\u00e0 Cattolica del S. Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9520-8255","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Aguado","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Hospital Universitario \u201c12 de Octubre\u201d, Instituto de Investigaci\u00f3n Hospital \u201c12 de Octubre\u201d (i+12), 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-928X","authenticated-orcid":false,"given":"Livio","family":"Pagano","sequence":"additional","affiliation":[{"name":"Istituto di Ematologia, Universit\u00e0 Cattolica del S. Cuore, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"L\u00f3pez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Clavero","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Potenza","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Luppi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Moratalla","sequence":"additional","affiliation":[{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Solano","sequence":"additional","affiliation":[{"name":"Hematology Department, Hospital Cl\u00ednico Universitario-INCLIVA, University of Valencia, 46010 Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Sampedro","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Virgen de las Nieves University Hospital, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Cuenca-Estrella","sequence":"additional","affiliation":[{"name":"Mycology Reference Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, 28222 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-7785","authenticated-orcid":false,"given":"Cornelia","family":"Lass-Fl\u00f6rl","sequence":"additional","affiliation":[{"name":"Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"PCRAGA Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4261-4583","authenticated-orcid":false,"given":"Federico","family":"Canzian","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juergen","family":"Loeffler","sequence":"additional","affiliation":[{"name":"Hematology Department, Universit\u00e4tsklinikum W\u00fcrzburg, Medizinische Klinik II, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4022-7341","authenticated-orcid":false,"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands"},{"name":"Centre for Individualised Infection Medicine (CiiM) &amp; TWINCORE, Joint Ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hermann","family":"Einsele","sequence":"additional","affiliation":[{"name":"Hematology Department, Universit\u00e4tsklinikum W\u00fcrzburg, Medizinische Klinik II, 97080 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, 6500HB Nijmegen, The Netherlands"},{"name":"Department for Immunology &amp; Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8191-0046","authenticated-orcid":false,"given":"Lourdes","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Hematology Department, University Hospital of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8935-8030","authenticated-orcid":false,"given":"Agostinho","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s-PT Government Associate Laboratory, 4710-057 Braga\/Guimar\u00e3es, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Jurado","sequence":"additional","affiliation":[{"name":"Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"},{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9355-2423","authenticated-orcid":false,"given":"Juan","family":"Sainz","sequence":"additional","affiliation":[{"name":"Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer\/University of Granada\/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"},{"name":"Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada\/Universidad de Granada, 18016 Granada, Spain"},{"name":"Department of Medicine, University of Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1086\/652768","article-title":"Factors associated with mortality in transplant patients with invasive aspergillosis","volume":"50","author":"Baddley","year":"2010","journal-title":"Clin. 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