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The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9\u201311 SNPs as well as peri-transplant CXCL9\u201311 serum levels were analyzed in 688 patients without (training cohort;<jats:italic>n<\/jats:italic>\u2009=\u2009287) or with statin-based endothelial protection cohort (<jats:italic>n<\/jats:italic>\u2009=\u2009401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort (<jats:italic>n<\/jats:italic>\u2009=\u2009202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33\u20134.64,<jats:italic>P<\/jats:italic>\u2009=\u20090.004) and validation cohort (HR 2.95, 95% CI 1.56\u20135.58,<jats:italic>P<\/jats:italic>\u2009=\u20090.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and rs884004 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10\u20131.73,<jats:italic>P<\/jats:italic>\u2009=\u20090.006). This study identifies patients with high genetic risk to develop severe cGVHD.<\/jats:p>","DOI":"10.1038\/s41408-021-00434-2","type":"journal-article","created":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T19:11:18Z","timestamp":1614453078000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD"],"prefix":"10.1038","volume":"11","author":[{"given":"Hao","family":"Dai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivaramakrishna P.","family":"Rachakonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Penack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor W.","family":"Blau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Blau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Radujkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"M\u00fcller-Tidow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7429-8570","authenticated-orcid":false,"given":"Peter","family":"Dreger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0387-1640","authenticated-orcid":false,"given":"Thomas","family":"Luft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,27]]},"reference":[{"key":"434_CR1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1056\/NEJM199907013410103","volume":"341","author":"G Socie","year":"1999","unstructured":"Socie, G. et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N. Engl. J. Med. 341, 14\u201321 (1999).","journal-title":"N. Engl. J. Med."},{"key":"434_CR2","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1200\/JCO.2010.33.7212","volume":"29","author":"JR Wingard","year":"2011","unstructured":"Wingard, J. R. et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J. Clin. Oncol. 29, 2230\u20132239 (2011).","journal-title":"J. Clin. Oncol."},{"key":"434_CR3","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.bbmt.2014.10.021","volume":"21","author":"S Arai","year":"2015","unstructured":"Arai, S. et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol. 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