The CYB5R3 c .350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease

• Published in: American journal of hematology 2020-11, Vol.95 (11), p.1269-1279
• Main Authors: Gordeuk, Victor R, Shah, Binal N, Zhang, Xu, Thuma, Philip E, Zulu, Stenford, Moono, Rodgers, Reading, N Scott, Song, Jihyun, Zhang, Yingze, Nouraie, Mehdi, Campbell, Andrew, Minniti, Caterina P, Rana, Sohail R, Darbari, Deepika S, Kato, Gregory J, Niu, Mei, Castro, Oswaldo L, Machado, Roberto, Gladwin, Mark T, Prchal, Josef T
• Format: Article
• Language: English
• Subjects: Alleles; Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - metabolism; Anemia, Sickle Cell - parasitology; Child, Preschool; Cytochrome-B Reductase - genetics; Cytochrome-B Reductase - metabolism; Female; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase - metabolism; Humans; Infant; Malaria, Falciparum - genetics; Malaria, Falciparum - metabolism; Male; Plasmodium falciparum - metabolism; Point Mutation; Severity of Illness Index; Zambia
• ISSN: 0361-8609; 1096-8652
• DOI: 10.1002/ajh.25941

Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3 encoding CYB5R3 , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3 with severe anemia (hemoglobin