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Both conditions are associated with oxidative stress, hemolysis and anemia. The <jats:italic>CYB5R3<\/jats:italic> gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. <jats:italic>CYB5R3<\/jats:italic><jats:sup>c.350C\u2009&gt;\u2009G<\/jats:sup> encoding CYB5R3<jats:sup>T117S<\/jats:sup>, the most frequent recognized African\u2010specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose\u20106\u2010phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African\u2010polymorphic X\u2010linked A+ and A\u2010 alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of <jats:italic>CYB5R3<\/jats:italic><jats:sup>c.350C\u2009&gt;\u2009G<\/jats:sup> with severe anemia (hemoglobin &lt;5\u2009g\/dL) in the context of <jats:italic>G6PD<\/jats:italic> A+ and A\u2010 status among 165 Zambian children with malaria. <jats:italic>CYB5R3<\/jats:italic><jats:sup>c.350C\u2009&gt;\u2009G<\/jats:sup> offered protection against severe malarial anemia in children without G6PD deficiency (<jats:italic>G6PD<\/jats:italic> wild type or A+\/A\u2010 heterozygotes) (odds ratio 0.29, <jats:italic>P<\/jats:italic> =\u2009.022) but not in <jats:italic>G6PD<\/jats:italic> A+ or A\u2010 hemizygotes\/homozygotes. We also examined the relationship of <jats:italic>CYB5R3<\/jats:italic><jats:sup>c.350C\u2009&gt;\u2009G<\/jats:sup> with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (\u03b2 = 0.29, <jats:italic>P<\/jats:italic> =\u2009.022 children; \u03b2 = 0.33, <jats:italic>P<\/jats:italic> =\u2009.004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3<jats:sup>T117S<\/jats:sup> compared to wildtype CYB5R3 and higher NADH\/NAD+ ratios. In conclusion, <jats:italic>CYB5R3<\/jats:italic><jats:sup>c.350C\u2009&gt;\u2009G<\/jats:sup> appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for <jats:italic>CYB5R3<\/jats:italic><jats:sup>c.350C\u2009&gt;\u2009G<\/jats:sup> selection and its high prevalence.<\/jats:p>","DOI":"10.1002\/ajh.25941","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T15:49:50Z","timestamp":1595432990000},"page":"1269-1279","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The <scp><i>CYB5R3<\/i><sup>c<\/sup><\/scp><sup>.<scp>350C<\/scp>&gt;G<\/sup> and <scp><i>G6PD<\/i><\/scp> A alleles modify severity of anemia in malaria and sickle cell disease"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4725-7295","authenticated-orcid":false,"given":"Victor R.","family":"Gordeuk","sequence":"first","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binal N.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7732-1385","authenticated-orcid":false,"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip E.","family":"Thuma","sequence":"additional","affiliation":[{"name":"Macha Research Trust  Choma Zambia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stenford","family":"Zulu","sequence":"additional","affiliation":[{"name":"Macha Research Trust  Choma Zambia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodgers","family":"Moono","sequence":"additional","affiliation":[{"name":"Macha Research Trust  Choma Zambia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0806-5661","authenticated-orcid":false,"given":"N. Scott","family":"Reading","sequence":"additional","affiliation":[{"name":"University of Utah and ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihyun","family":"Song","sequence":"additional","affiliation":[{"name":"University of Utah and ARUP Laboratories  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingze","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7465-0581","authenticated-orcid":false,"given":"Mehdi","family":"Nouraie","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8829-0043","authenticated-orcid":false,"given":"Andrew","family":"Campbell","sequence":"additional","affiliation":[{"name":"Children's National Medical Center  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina P.","family":"Minniti","sequence":"additional","affiliation":[{"name":"Center for Sickle Cell Disease Montefiore Medical Center  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohail R.","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child Health Howard University Hospital  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepika S.","family":"Darbari","sequence":"additional","affiliation":[{"name":"Children's National Medical Center  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-3217","authenticated-orcid":false,"given":"Gregory J.","family":"Kato","sequence":"additional","affiliation":[{"name":"CSL Behring King of Prussia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Niu","sequence":"additional","affiliation":[{"name":"Center for Sickle Cell Disease Howard University  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oswaldo L.","family":"Castro","sequence":"additional","affiliation":[{"name":"Center for Sickle Cell Disease Howard University  Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Machado","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine Indianapolis, IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark T.","family":"Gladwin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh Medical Center  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef T.","family":"Prchal","sequence":"additional","affiliation":[{"name":"University of Utah Salt Lake City, Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,9,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2003.09.011"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0035-9203(99)90180-3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-08-2437"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110724"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05834.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/376246a0"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3107"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.84.3.500"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-04-084921"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-01-0313"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198202043060504"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)97086-9"},{"key":"e_1_2_7_14_1","first-page":"789","volume-title":"Methemoglobinemia and Other Causes of Cyanosis. 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