Multiple-ancestry genome-wide association study identifies 27 loci associated with measures of hemolysis following blood storage
Grier P. Page, … , Mark T. Gladwin, the National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology Donor Evaluation Study–III (REDS-III) program
Grier P. Page, … , Mark T. Gladwin, the National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology Donor Evaluation Study–III (REDS-III) program
Published May 20, 2021
Citation Information: J Clin Invest. 2021;131(13):e146077. https://doi.org/10.1172/JCI146077.
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Clinical Medicine Genetics

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

Abstract

Background The 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.Methods We 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.Results GWAS 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.Conclusions Many 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.

Authors

Grier P. Page, Tamir Kanias, Yuelong J. Guo, Marion C. Lanteri, Xu Zhang, Alan E. Mast, Ritchard G. Cable, Bryan R. Spencer, Joseph E. Kiss, Fang Fang, Stacy M. Endres-Dighe, Donald Brambilla, Mehdi Nouraie, Victor R. Gordeuk, Steve Kleinman, Michael P. Busch, Mark T. Gladwin, the National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology Donor Evaluation Study–III (REDS-III) program

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Figure 3

LocusZoom and box-and-whisker plots for 2 nonoverlapping genome-wide significant loci in ANK1.

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LocusZoom and box-and-whisker plots for 2 nonoverlapping genome-wide sig...
(A) LocusZoom plot centered on rs4737010 in ANK1. (B) LocusZoom plot of rs34664882 in ANK1. In these plots, each data point represents an SNP passing quality control in the linear regression analysis of imputed dosage plotted with its P value as a function of genomic position (GRCh38 Assembly). The lead SNP is represented by the purple symbol. The color coding of all other SNPs indicates LD with the lead SNP (estimated by Phase II HapMap CEU r2 values): red, r2 ≥ 0.8; gold, 0.6 ≤ r2 < 0.8; green, 0.4 ≤ r2 < 0.6; cyan, 0.2 ≤ r2 < 0.4; blue, r2 < 0.2; gray, r2 unknown. Recombination rates are estimated from 1000 Genomes phase 3 data. (C) Box-and-whisker plot of osmotic hemolysis measure by genotype and genetic ancestry group for rs4737010. (D) Box-and-whisker plot of osmotic hemolysis measure by genotype and genetic ancestry group for rs34664882. These figures illustrate 2 nonoverlapping genome-wide significant loci with the ANK1 gene. For the box-and-whisker plots, the bounds of the box are the 25th and 75th percentiles, the line in the box is the 50th percentile/median. The whiskers are 1.5 times the interquartile range (25%–75%), and black dots are values outside the whiskers. Ancestry groups: AFR, African Americans; EUR, non-Hispanic Whites; EAS, East Asians; SAS, South Asians; CIH, Caribbean Island Hispanics; MCAH, Mexican/Central American Hispanics; OTH, other.