ArticleBlood advances2022
Genetic variants of PKLR are associated with acute pain in sickle cell disease.
Article in Blood advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 12 citations in OpenAlex.
- Genetic Variation and Sickle Cell Disease Severity: A Systematic Review and Meta-Analysis.JAMA network open · 2023Pooled it
- Pyruvate kinase deficiency modifies sickle hemoglobin carrier and sickle cell disease phenotypes in mice.JCI insight · 2026Article
- Genetic Modifiers Associated with Vaso-Occlusive Crises and Acute Pain Phenomena in Sickle Cell Disease: A Scoping Review.International journal of molecular sciences · 2025Article
- Gene-environmental influence of space and microgravity on red blood cells with sickle cell disease.NPJ genomic medicine · 2024Review
- Can we use biomarkers to identify those at risk of acute pain from sickle cell disease?Expert review of hematology · 2024Review
- Article
- Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport.Frontiers in physiology · 2024Review
- Pyruvate kinase activators: targeting red cell metabolism in sickle cell disease.Hematology. American Society of Hematology. Education Program · 2023Article
- Single nucleotide polymorphisms and sickle cell disease-related pain: a systematic review.Frontiers in pain research (Lausanne, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
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-HbSβ0 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.
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