{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T09:27:01Z","timestamp":1781342821136,"version":"3.54.1"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T00:00:00Z","timestamp":1743811200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K23HL157554"],"award-info":[{"award-number":["K23HL157554"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL\u2010153161"],"award-info":[{"award-number":["R01 HL\u2010153161"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Albuminuria is associated with high\u2010risk apolipoprotein\u2010L1 variants (<jats:italic>APOL1<\/jats:italic> G1\/G2) in patients with sickle cell anemia (SCA). However, this gene variant does not account for all chronic kidney disease (CKD) risk. We hypothesized that we could develop a polygenic risk score (PRS) for CKD in SCA, combining <jats:italic>APOL1 G1\/G2<\/jats:italic> with other candidate genes that modify SCA severity and further stratify patients into risk categories based on this risk score. Variants in <jats:italic>APOL1<\/jats:italic>, <jats:italic>HMOX1<\/jats:italic> (rs743811), <jats:italic>BCL11A<\/jats:italic> (rs1424407), and \u03b1\u2010thalassemia (<jats:italic>\u03b1<\/jats:italic>\n<jats:sup>\u22123.7<\/jats:sup>) were identified in children with SCA enrolled in the Sickle Cell Clinical Research and Intervention Program longitudinal cohort (SCCRIP). We individually tested the association of these variants with persistent albuminuria, tested a three\u2010variant PRS (PRS\u20103) (<jats:italic>APOL1<\/jats:italic>, <jats:italic>BCL11A<\/jats:italic> (rs1424407), and \u03b1<jats:sup>\u22123.7<\/jats:sup>), and developed a four\u2010variant PRS (PRS\u20104) after adding <jats:italic>HMOX1<\/jats:italic> (rs743811) to PRS\u20103 using the summation of high\u2010risk alleles. An adult SCA cohort from the University of Illinois, Chicago (UIC), was used for validation. Persistent albuminuria was defined as having a urine albumin\u2010to\u2010creatinine ratio (UACR) \u2265\u200930\u2009mg\/g on at least 2 of 3 consecutive measurements. In both cohorts, <jats:italic>APOL1<\/jats:italic> risk variants increased the risk while \u03b1\u2010thalassemia protected against persistent albuminuria. PRS\u20104 was significantly associated with persistent albuminuria (SCCRIP: <jats:italic>p<\/jats:italic>\u2009=\u20090.004; UIC: <jats:italic>p<\/jats:italic>\u2009=\u20090.00016). When stratifying patients into three and four risk categories based on the PRS, 58% and 86% of the high\u2010risk (PRS\u20103) and 54% and 89% of very high\u2010risk (PRS\u20104) categories developed persistent albuminuria cases in the SCCRIP and UIC cohorts, respectively. A PRS may identify high\u2010risk SCA patients for albuminuria. Applying this PRS to guide the early implementation of disease modifiers and renoprotective therapies may help reduce the burden of SCA\u2010related CKD.<\/jats:p><jats:p>\n<jats:bold>Trial Registration:<\/jats:bold> NCT02098863<\/jats:p>","DOI":"10.1002\/ajh.27678","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T19:58:22Z","timestamp":1743883102000},"page":"1019-1028","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development of Polygenic Risk Score for Persistent Albuminuria in Children and Adults With Sickle Cell Anemia"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-7195","authenticated-orcid":false,"given":"Rima S.","family":"Zahr","sequence":"first","affiliation":[{"name":"Department of Paediatric Nephrology and Hypertension UTHSC  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guolian","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7732-1385","authenticated-orcid":false,"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Haematology and Oncology, Sickle Cell Center, UIC  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-6891","authenticated-orcid":false,"given":"Sara R.","family":"Rashkin","sequence":"additional","affiliation":[{"name":"Department of Hematology, St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8204-911X","authenticated-orcid":false,"given":"Csaba P.","family":"Kovesdy","sequence":"additional","affiliation":[{"name":"Department of Nephrology UTHSC  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford","family":"Takemoto","sequence":"additional","affiliation":[{"name":"Department of Hematology, St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2460-3036","authenticated-orcid":false,"given":"Mitch","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Hematology, St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Lebensburger","sequence":"additional","affiliation":[{"name":"Department of Hematology, UAB  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4501-9982","authenticated-orcid":false,"given":"Kenneth I.","family":"Ataga","sequence":"additional","affiliation":[{"name":"UTHSC, Sickle Cell Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8584-4194","authenticated-orcid":false,"given":"Santosh L.","family":"Saraf","sequence":"additional","affiliation":[{"name":"Department of Haematology and Oncology, Sickle Cell Center, UIC  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.18494"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12024"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-023-06136-0"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.267419"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-853929"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.02720320"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003\u20104819\u2010158\u201011\u2010201306040\u201000007"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001378"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19636"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023011765"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023010101"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011040388"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ackd.2014.06.005"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2018.06.020"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2011.08832.x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1193032"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015101152"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015020124"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1310345"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1522913113"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.15161219"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.154153"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.212779"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1242088"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14842"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.124875"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V1051014"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14724"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27228"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004634"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17647"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25329"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014111126"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(98)00056-4"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.20296"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24810"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2017.09.006"},{"issue":"1","key":"e_1_2_9_39_1","first-page":"64","article-title":"Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, Following Single\u2010 and Multiple\u2010Ascending Doses in Healthy Adults","volume":"4","author":"Egbuna O.","year":"2024","journal-title":"Glomerular Diseases"},{"issue":"26","key":"e_1_2_9_40_1","first-page":"2491","article-title":"Inaxaplin for Proteinuric Kidney Disease in Persons With Two APOL1 Variants. Reply","volume":"388","author":"Egbuna O.","year":"2023","journal-title":"New England Journal of Medicine"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.27678","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T09:49:07Z","timestamp":1754905747000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.27678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,5]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/ajh.27678"],"URL":"https:\/\/doi.org\/10.1002\/ajh.27678","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"value":"0361-8609","type":"print"},{"value":"1096-8652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,5]]},"assertion":[{"value":"2024-11-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}