{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:09:58Z","timestamp":1784873398635,"version":"3.55.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T00:00:00Z","timestamp":1731456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008413","name":"Instrumentariumin Tiedes\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["230041"],"award-info":[{"award-number":["230041"]}],"id":[{"id":"10.13039\/501100008413","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014438","name":"Business Finland","doi-asserted-by":"publisher","award":["UH 4386\/31\/2016"],"award-info":[{"award-number":["UH 4386\/31\/2016"]}],"id":[{"id":"10.13039\/501100014438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014438","name":"Business Finland","doi-asserted-by":"publisher","award":["HUS 4685\/31\/2016"],"award-info":[{"award-number":["HUS 4685\/31\/2016"]}],"id":[{"id":"10.13039\/501100014438","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Puumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to PUUV infections. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus and ERAP1 with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response. ERAP1 facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR\u2009=\u20090.84, P\u2009=\u20092.9\u2009\u00d7\u200910\u20138) in the ERAP1 gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with four HLA alleles with severe PUUV infection using conditional HLA fine mapping. The strongest association was found with the HLA-C*07:01 allele (OR\u2009=\u20091.54, P\u2009=\u20094.0\u2009\u00d7\u200910\u221224) followed by signals at HLA-B*13:02, HLA-DRB1*01:01, and HLA-DRB1*11:01 alleles (P\u2009&amp;lt;\u20095\u2009\u00d7\u200910\u22128). Our findings suggest an association of viral peptide processing with ERAP1 and antigen presentation through HLA alleles that may contribute to the development of severe PUUV disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddae158","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T15:23:40Z","timestamp":1730993020000},"page":"77-84","source":"Crossref","is-referenced-by-count":3,"title":["Genetic analysis implicates\n                    <i>ERAP1<\/i>\n                    and HLA as risk factors for severe Puumala virus infection"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4887-7739","authenticated-orcid":false,"given":"Hele","family":"Haapaniemi","sequence":"first","affiliation":[{"name":"Institute for Molecular Medicine Finland , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"University of Helsinki , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satu","family":"Strausz","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"University of Helsinki , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki , Haartmaninkatu 1, 00290 Helsinki ,","place":["Finland"]},{"name":"Department of Plastic Surgery , Cleft Palate and Craniofacial Center, , Stenb\u00e4ckinkatu 11, 00290 Helsinki ,","place":["Finland"]},{"name":"Helsinki University Hospital and University of Helsinki , Cleft Palate and Craniofacial Center, , Stenb\u00e4ckinkatu 11, 00290 Helsinki ,","place":["Finland"]},{"name":"Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, MA 02142 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9857-2132","authenticated-orcid":false,"given":"Anniina","family":"Tervi","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"University of Helsinki , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel E","family":"Jones","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"University of Helsinki , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Kanerva","sequence":"additional","affiliation":[{"name":"Department of Hospital Hygiene and Infection Control, TYKS Turku University Hospital , Kiinamyllynkatu 4-8, 20521 Turku ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"FinnGen, Estonian Biobank Research Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Abner","sequence":"additional","affiliation":[{"name":"Estonian Genome Centre , Institute of Genomics, , Riia tn 23b, 51010 Tartu ,","place":["Estonia"]},{"name":"University of Tartu , Institute of Genomics, , Riia tn 23b, 51010 Tartu ,","place":["Estonia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Fors Connolly","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Ume\u00e5 University , Biologihuset, 90187 Ume\u00e5 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna M","family":"Ollila","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"University of Helsinki , FIMM, HiLIFE, , Tukholmankatu 8, 00290 Helsinki ,","place":["Finland"]},{"name":"Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, MA 02142 ,","place":["United States"]},{"name":"Department of Anesthesia , Critical Care and Pain Medicine, , 55 Fruit Street, GRB 444 Boston, MA ,","place":["United States"]},{"name":"Massachusetts General Hospital and Harvard Medical School , Critical Care and Pain Medicine, , 55 Fruit Street, GRB 444 Boston, MA ,","place":["United States"]},{"name":"Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School , 185 Cambridge Street, Boston, MA 02114 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,13]]},"reference":[{"key":"2026032005013269600_ref1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/rmv.1722","article-title":"Hantavirus infections in Europe and their impact on public health","volume":"23","author":"Vaheri","year":"2013","journal-title":"Rev Med Virol"},{"key":"2026032005013269600_ref2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/(SICI)1099-1654(199804\/06)8:2<67::AID-RMV217>3.0.CO;2-U","article-title":"Pathogenesis of Puumala and other hantavirus infections","volume":"8","author":"Kanerva","year":"1998","journal-title":"Rev Med Virol"},{"key":"2026032005013269600_ref3","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.3390\/v13081452","article-title":"Hantavirus research in Finland: highlights and 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First of two parts","volume":"343","author":"Klein","year":"2000","journal-title":"N Engl J Med"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/1\/77\/60642718\/ddae158.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/1\/77\/60642718\/ddae158.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:01:40Z","timestamp":1773997300000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/34\/1\/77\/7899376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,13]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,23]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddae158","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,1,1]]},"published":{"date-parts":[[2024,11,13]]}}}