TY - JOUR
T1 - Genetic variants of PKLR are associated with acute pain in sickle cell disease
AU - Wang, Xunde
AU - Gardner, Kate
AU - Tegegn, Mickias B.
AU - Dalgard, Clifton L.
AU - Alba, Camille
AU - Menzel, Stephan
AU - Patel, Hamel
AU - Pirooznia, Mehdi
AU - Fu, Yi Ping
AU - Seifuddin, Fayaz T.
AU - Thein, Swee Lay
N1 - Funding Information:
This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health.
Publisher Copyright:
© 2022 American Society of Hematology. All rights reserved.
PY - 2022/6/14
Y1 - 2022/6/14
N2 - Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSb0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P, .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.
AB - Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSb0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P, .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.
UR - http://www.scopus.com/inward/record.url?scp=85132717885&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2021006668
DO - 10.1182/bloodadvances.2021006668
M3 - Article
C2 - 35271708
AN - SCOPUS:85132717885
SN - 2473-9529
VL - 6
SP - 3535
EP - 3540
JO - Blood Advances
JF - Blood Advances
IS - 11
ER -