Researchers revealed an association between some genetic variations of the PKLR gene with acute pain episodes in patients with sickle cell disease (SCD) and published their results in Blood Advances.

This retrospective study conducted by Wang and colleagues included a total of 1219 patients previously diagnosed with SCD, divided into 2 separate cohorts—242 adults with homozygous SCD and 977 children with either homozygous SCD or sickle-beta thalassemia. Among the 47 studied variants of PKLR, 7 coincided with increased hospitalizations, including 1 in intron 4, and 6 in intron 2.

Studies show that acute pain episodes are the leading motive for hospitalization in patients with SCD, therefore, the authors extrapolated to assume the same variants could be linked to acute pain episodes. Although these results remain significant, they did not replicate in the pediatric cohort, possibly due to the age difference and definition of acute pain episode since the 2 cohorts corresponded to different healthcare centers.

Moreover, after analyzing an independent cohort of 52 adults with SCD, intronic variants related to acute pain episodes possibly affect the expression of PKLR, therefore reducing the activity of the pyruvate kinase (PKR) enzyme.

“PKR levels are a spectrum, and could represent a quantitative trait which modifies the risk of sickling and frequency of [acute pain episodes],” the authors wrote.

Read more about SCD comorbidities

Acute pain episodes are the most common complication in patients with this disease, and their frequency is often used as a marker of severity and predictor of early mortality. Although the characteristics of acute pain episodes could vary within a genotypic group and multiple variants have previously been studied for their capacity to modulate pain, no specific mutations have been identified as risk factors for acute pain episodes in SCD.

Previous findings allowed scientists to explore PKR as a therapeutic target. To this date, 2 PKR activators (mitapivat and FT2101) are undergoing clinical analysis. However, the authors pointed out that “the intron 2 PKLR variants are frequent and may underlie variation in response to the PKR activators, although the influence may be subtle given the myriad of factors that could influence sickling,” as a possible limitation obtained in the study.


Wang X, Gardner K, Tegegn M, et al. Genetic variants of PKLR are associated with acute pain in sickle cell disease. Blood Adv. Published online March 10, 2022. doi:10.1182/bloodadvances.2021006668