Multiple-ancestry genome-wide association study identifies 27 loci associated with measures of hemolysis following blood storage

J Clin Invest. 2021 Jul 1;131(13):e146077. doi: 10.1172/JCI146077.

Abstract

BackgroundThe evolutionary pressure of endemic malaria and other erythrocytic pathogens has shaped variation in genes encoding erythrocyte structural and functional proteins, influencing responses to hemolytic stress during transfusion and disease.MethodsWe sought to identify such genetic variants in blood donors by conducting a genome-wide association study (GWAS) of 12,353 volunteer donors, including 1,406 African Americans, 1,306 Asians, and 945 Hispanics, whose stored erythrocytes were characterized by quantitative assays of in vitro osmotic, oxidative, and cold-storage hemolysis.ResultsGWAS revealed 27 significant loci (P < 5 × 10-8), many in candidate genes known to modulate erythrocyte structure, metabolism, and ion channels, including SPTA1, ALDH2, ANK1, HK1, MAPKAPK5, AQP1, PIEZO1, and SLC4A1/band 3. GWAS of oxidative hemolysis identified variants in genes encoding antioxidant enzymes, including GLRX, GPX4, G6PD, and SEC14L4 (Golgi-transport protein). Genome-wide significant loci were also tested for association with the severity of steady-state (baseline) in vivo hemolytic anemia in patients with sickle cell disease, with confirmation of identified SNPs in HBA2, G6PD, PIEZO1, AQP1, and SEC14L4.ConclusionsMany of the identified variants, such as those in G6PD, have previously been shown to impair erythrocyte recovery after transfusion, associate with anemia, or cause rare Mendelian human hemolytic diseases. Candidate SNPs in these genes, especially in polygenic combinations, may affect RBC recovery after transfusion and modulate disease severity in hemolytic diseases, such as sickle cell disease and malaria.

Trial registration: ClinicalTrials.gov NCT00492531.

Keywords: Genetic variation; Genetics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • African Americans / genetics
  • Asian Americans / genetics
  • Blood Donors
  • Blood Preservation / adverse effects*
  • Blood Preservation / methods*
  • Cohort Studies
  • Cold Temperature
  • Erythrocyte Transfusion / adverse effects
  • Erythrocytes / metabolism*
  • Evolution, Molecular
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hemolysis / genetics*
  • Hispanic or Latino / genetics
  • Humans
  • In Vitro Techniques
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Osmotic Pressure
  • Oxidative Stress
  • Polymorphism, Single Nucleotide*
  • Young Adult

Associated data

  • ClinicalTrials.gov/NCT00492531