{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T15:52:49Z","timestamp":1768837969872,"version":"3.49.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["320030-153389"],"award-info":[{"award-number":["320030-153389"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001275","name":"Oak Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001275","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CANSESARCH Foundation, Oak Foundation"},{"name":"CANSEARCH Foundation"},{"name":"CANSEARCH Foundation, Oak Foundation"},{"name":"CANSEARCH FOUNDATION"},{"name":"The Leukaemia Research and Support Fund"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharmacogenomics J"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Acute Graft versus Host Disease (aGvHD) grades 2\u20134 occurs in 15\u201360% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and\/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2\u20134 in 60 pediatric patients. The cumulative incidence of aGvHD 2\u20134 was 12% (<jats:italic>n<\/jats:italic>\u2009=\u20097) in the exploratory cohort. <jats:italic>MGMT<\/jats:italic> rs10764881 (G&gt;A) and <jats:italic>EXO<\/jats:italic> rs9350 (c.2270C&gt;T) variants were associated with aGvHD 2\u20134 [Odds ratios\u2009=\u200914.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3\u2013191.8), respectively, multiple testing corrected <jats:italic>p<\/jats:italic>\u2009\u2264\u20090.001]. Upon evaluation in an extended cohort (<jats:italic>n<\/jats:italic>\u2009=\u2009182) with an incidence of aGvHD 2\u20134 of 22% (<jats:italic>n<\/jats:italic>\u2009=\u200940), only <jats:italic>MGMT<\/jats:italic> rs10764881 (G&gt;A) remained significant (adjusted HR\u2009=\u20092.05 [95% CI: 1.06\u20133.94]; <jats:italic>p<\/jats:italic>\u2009=\u20090.03) in the presence of other clinical risk factors. Higher <jats:italic>MGMT<\/jats:italic> expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. <jats:italic>MGMT<\/jats:italic> rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.<\/jats:p>","DOI":"10.1038\/s41397-021-00251-7","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T11:03:05Z","timestamp":1635418985000},"page":"9-18","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation"],"prefix":"10.1038","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-7049","authenticated-orcid":false,"given":"C. R. S.","family":"Uppugunduri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6949-5185","authenticated-orcid":false,"given":"P.","family":"Huezo-Diaz Curtis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Nava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. A.","family":"Rezgui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4968-5592","authenticated-orcid":false,"given":"V.","family":"Mlakar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2552-456X","authenticated-orcid":false,"given":"S. Jurkovic","family":"Mlakar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2271-8959","authenticated-orcid":false,"given":"N.","family":"Waespe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y.","family":"Th\u00e9oret","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Gumy-Pause","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Bernard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-8104","authenticated-orcid":false,"given":"Y.","family":"Chalandon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. J.","family":"Boelens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. G. M.","family":"Bredius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. H.","family":"Dalle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1013-3646","authenticated-orcid":false,"given":"C.","family":"Nath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Corbacioglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0369-8515","authenticated-orcid":false,"given":"C.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Bader","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-8310","authenticated-orcid":false,"given":"H.","family":"Bittencourt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4772-7031","authenticated-orcid":false,"given":"M.","family":"Krajinovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9649-6498","authenticated-orcid":false,"given":"M.","family":"Ansari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"251_CR1","doi-asserted-by":"publisher","first-page":"4007","DOI":"10.1182\/blood-2010-01-261958","volume":"116","author":"PJ Shaw","year":"2010","unstructured":"Shaw PJ, Kan F, Woo Ahn K, Spellman SR, Aljurf M, Ayas M, et al. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood. 2010;116:4007\u201315.","journal-title":"Blood"},{"key":"251_CR2","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1182\/blood-2004-11-4557","volume":"106","author":"JY Cahn","year":"2005","unstructured":"Cahn JY, Klein JP, Lee SJ, Milpied N, Blaise D, Antin JH, et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood. 2005;106:1495\u2013500.","journal-title":"Blood"},{"key":"251_CR3","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1056\/NEJMra1609337","volume":"377","author":"R Zeiser","year":"2017","unstructured":"Zeiser R, Blazar BR. Acute Graft-versus-host disease\u2014biologic process, prevention, and therapy. N Engl J Med. 2017;377:2167\u201379.","journal-title":"N Engl J Med"},{"key":"251_CR4","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/sj.bmt.1705885","volume":"41","author":"DA Jacobsohn","year":"2008","unstructured":"Jacobsohn DA. Acute graft-versus-host disease in children. Bone Marrow Transplant. 2008;41:215\u201321.","journal-title":"Bone Marrow Transplant"},{"key":"251_CR5","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.2165\/00003088-200645110-00003","volume":"45","author":"IH Bartelink","year":"2006","unstructured":"Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45:1077\u201397.","journal-title":"Clin Pharmacokinet"},{"key":"251_CR6","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.bbmt.2008.12.489","volume":"15","author":"SO Ciurea","year":"2009","unstructured":"Ciurea SO, Andersson BS. Busulfan in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:523\u201336.","journal-title":"Biol Blood Marrow Transplant"},{"key":"251_CR7","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1182\/blood-2004-02-0414","volume":"104","author":"M de Lima","year":"2004","unstructured":"de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857\u201364.","journal-title":"Blood"},{"key":"251_CR8","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.3390\/ijerph9082636","volume":"9","author":"I Casorelli","year":"2012","unstructured":"Casorelli I, Bossa C, Bignami M. DNA damage and repair in human cancer: molecular mechanisms and contribution to therapy-related leukemias. Int J Environ Res Public Health. 2012;9:2636\u201357.","journal-title":"Int J Environ Res Public Health"},{"key":"251_CR9","doi-asserted-by":"publisher","first-page":"90852","DOI":"10.18632\/oncotarget.20310","volume":"8","author":"M Ansari","year":"2017","unstructured":"Ansari M, Curtis PH, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget. 2017;8:90852\u201367.","journal-title":"Oncotarget"},{"key":"251_CR10","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1182\/blood-2003-11-3778","volume":"104","author":"A Srivastava","year":"2004","unstructured":"Srivastava A, Poonkuzhali B, Shaji RV, George B, Mathews V, Chandy M, et al. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104:1574\u20137.","journal-title":"Blood"},{"key":"251_CR11","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1182\/bloodadvances.2017011502","volume":"2","author":"C Martinez-Laperche","year":"2018","unstructured":"Martinez-Laperche C, Buces E, Aguilera-Morillo MC, Picornell A, Gonzalez-Rivera M, Lillo R, et al. A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms. Blood Adv. 2018;2:1719\u201337.","journal-title":"Blood Adv"},{"key":"251_CR12","doi-asserted-by":"publisher","first-page":"248264","DOI":"10.1155\/2015\/248264","volume":"2015","author":"R Masetti","year":"2015","unstructured":"Masetti R, Zama D, Urbini M, Astolfi A, Libri V, Vendemini F, et al. Impact of inflammatory cytokine gene polymorphisms on developing acute graft-versus-host disease in children undergoing allogeneic hematopoietic stem cell transplantation. J Immunol Res. 2015;2015:248264.","journal-title":"J Immunol Res"},{"key":"251_CR13","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1007\/s10555-010-9258-8","volume":"29","author":"AG Pallis","year":"2010","unstructured":"Pallis AG, Karamouzis MV. DNA repair pathways and their implication in cancer treatment. Cancer Metastasis Rev. 2010;29:677\u201385.","journal-title":"Cancer Metastasis Rev"},{"key":"251_CR14","doi-asserted-by":"publisher","first-page":"543531","DOI":"10.4061\/2010\/543531","volume":"2010","author":"N Kondo","year":"2010","unstructured":"Kondo N, Takahashi A, Ono K, Ohnishi T. DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids. 2010;2010:543531.","journal-title":"J Nucleic Acids"},{"key":"251_CR15","doi-asserted-by":"publisher","first-page":"2621","DOI":"10.1101\/gad.1688508","volume":"22","author":"RC Fry","year":"2008","unstructured":"Fry RC, Svensson JP, Valiathan C, Wang E, Hogan BJ, Bhattacharya S, et al. Genomic predictors of interindividual differences in response to DNA damaging agents. Genes Dev. 2008;22:2621\u20136.","journal-title":"Genes Dev"},{"key":"251_CR16","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1038\/leu.2010.139","volume":"24","author":"M Arora","year":"2010","unstructured":"Arora M, Lindgren B, Basu S, Nagaraj S, Gross M, Weisdorf D, et al. Polymorphisms in the base excision repair pathway and graft-versus-host disease. Leukemia. 2010;24:1470\u20135.","journal-title":"Leukemia"},{"key":"251_CR17","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1038\/bmt.2014.20","volume":"49","author":"D Kim","year":"2014","unstructured":"Kim D, Won HH, Su S, Cheng L, Xu W, Hamad N, et al. Risk stratification of organ-specific GVHD can be improved by single-nucleotide polymorphism-based risk models. Bone Marrow Transplant. 2014;49:649\u201356.","journal-title":"Bone Marrow Transplant"},{"key":"251_CR18","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/nrc1319","volume":"4","author":"SL Gerson","year":"2004","unstructured":"Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4:296\u2013307.","journal-title":"Nat Rev Cancer"},{"key":"251_CR19","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1200\/JCO.1995.13.9.2301","volume":"13","author":"JK Willson","year":"1995","unstructured":"Willson JK, Haaga JR, Trey JE, Stellato TA, Gordon NH, Gerson SL. Modulation of O6-alkylguanine alkyltransferase-directed DNA repair in metastatic colon cancers. J Clin Oncol. 1995;13:2301\u20138.","journal-title":"J Clin Oncol"},{"key":"251_CR20","doi-asserted-by":"publisher","first-page":"e0186430","DOI":"10.1371\/journal.pone.0186430","volume":"12","author":"CY Hsu","year":"2017","unstructured":"Hsu CY, Ho HL, Lin SC, Ho TD, Ho DM. The MGMT promoter single-nucleotide polymorphism rs1625649 had prognostic impact on patients with MGMT methylated glioblastoma. PLoS ONE. 2017;12:e0186430.","journal-title":"PLoS ONE"},{"key":"251_CR21","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1093\/carcin\/bgt355","volume":"35","author":"M Xu","year":"2014","unstructured":"Xu M, Nekhayeva I, Cross CE, Rondelli CM, Wickliffe JK, Abdel-Rahman SZ. Influence of promoter\/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents. Carcinogenesis. 2014;35:564\u201371.","journal-title":"Carcinogenesis"},{"key":"251_CR22","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1007\/s002800051106","volume":"43","author":"HS Friedman","year":"1999","unstructured":"Friedman HS, Pegg AE, Johnson SP, Loktionova NA, Dolan ME, Modrich P, et al. Modulation of cyclophosphamide activity by O6-alkylguanine-DNA alkyltransferase. Cancer Chemother Pharmacol. 1999;43:80\u20135.","journal-title":"Cancer Chemother Pharmacol"},{"key":"251_CR23","doi-asserted-by":"publisher","first-page":"7369","DOI":"10.1038\/sj.onc.1206940","volume":"22","author":"DM Townsend","year":"2003","unstructured":"Townsend DM, Tew KD. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 2003;22:7369\u201375.","journal-title":"Oncogene"},{"key":"251_CR24","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1093\/carcin\/bgl155","volume":"28","author":"SK Niture","year":"2007","unstructured":"Niture SK, Velu CS, Smith QR, Bhat GJ, Srivenugopal KS. Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines. Carcinogenesis. 2007;28:378\u201389.","journal-title":"Carcinogenesis"},{"key":"251_CR25","first-page":"5815","volume":"60","author":"K Ochs","year":"2000","unstructured":"Ochs K, Kaina B. Apoptosis induced by DNA damage O6-methylguanine is Bcl-2 and caspase-9\/3 regulated and Fas\/caspase-8 independent. Cancer Res. 2000;60:5815\u201324.","journal-title":"Cancer Res"},{"key":"251_CR26","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1126\/science.1262110","volume":"348","author":"GT Consortium","year":"2015","unstructured":"Consortium GT. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648\u201360.","journal-title":"Science"},{"key":"251_CR27","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1093\/carcin\/17.11.2329","volume":"17","author":"T Grombacher","year":"1996","unstructured":"Grombacher T, Mitra S, Kaina B. Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes. Carcinogenesis. 1996;17:2329\u201336.","journal-title":"Carcinogenesis"},{"key":"251_CR28","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/s41409-018-0221-6","volume":"54","author":"M Kato","year":"2019","unstructured":"Kato M, Kurata M, Kanda J, Kato K, Tomizawa D, Kudo K, et al. Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia. Bone Marrow Transplant. 2019;54:68\u201375.","journal-title":"Bone Marrow Transplant"},{"key":"251_CR29","first-page":"179","volume":"1816","author":"M Christmann","year":"2011","unstructured":"Christmann M, Verbeek B, Roos WP, Kaina B. O (6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry. Biochim Biophys Acta. 2011;1816:179\u201390.","journal-title":"Biochim Biophys Acta"},{"key":"251_CR30","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.1002\/ijc.25229","volume":"127","author":"M Christmann","year":"2010","unstructured":"Christmann M, Nagel G, Horn S, Krahn U, Wiewrodt D, Sommer C, et al. MGMT activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and glioblastoma. Int J Cancer. 2010;127:2106\u201318.","journal-title":"Int J Cancer"},{"key":"251_CR31","first-page":"825","volume":"15","author":"D Przepiorka","year":"1995","unstructured":"Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825\u20138.","journal-title":"Bone Marrow Transplant"},{"key":"251_CR32","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1182\/blood-2015-09-669846","volume":"128","author":"SG Holtan","year":"2016","unstructured":"Holtan SG, Khera N, Levine JE, Chai X, Storer B, Liu HD, et al. Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors. Blood. 2016;128:2350\u20138.","journal-title":"Blood"},{"key":"251_CR33","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1214\/aos\/1176350951","volume":"16","author":"RJ Gray","year":"1988","unstructured":"Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141\u201354.","journal-title":"Ann Stat"}],"container-title":["The Pharmacogenomics Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41397-021-00251-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41397-021-00251-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41397-021-00251-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T08:06:39Z","timestamp":1643270799000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41397-021-00251-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,28]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["251"],"URL":"https:\/\/doi.org\/10.1038\/s41397-021-00251-7","relation":{},"ISSN":["1470-269X","1473-1150"],"issn-type":[{"value":"1470-269X","type":"print"},{"value":"1473-1150","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,28]]},"assertion":[{"value":"11 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"None to declare related to the submitted work. Outside the submitted work, BH has received honoraria from Jazz Pharmacueticals and Novartis. JJB has received honoraria from Avrobio, Advanced Clinical, BlueRock, Omeros, Race oncology, and Takeda Pharmaceuticals. CY has received honoraria from INCYTE, ABBVIE, GILEAD, ROCHE, Astra-Zeneca, Jazz Pharmaceuticals, and MSD.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}