According to research published in Blood Advances, non-coding genetic variants of the pyruvate kinase gene (PKLR) are associated with annualized hospitalization rates for acute pain in sickle cell disease (SCD).

To evaluate the role of PKLR variants in acute pain episodes in SCD, researchers performed a candidate gene association study and conducted allele-specific expression analyses of PKLR.

For the association study, the researchers used DNA samples from 2 cohorts: 242 adult patients with SCD-HbSS, with 10-year hospitalization records, and 977 pediatric patients with SCD-HbSS or SCD-HbSβ0 thalassemia, with 3-year hospitalization records.

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Among patients of the adult cohort, the researchers identified 47 variants within the PKLR gene region. Of those, 7 variants were associated with the annualized hospitalization rate. All were non-coding variants located within introns of PKLR (intron 4: rs2071053; intron 2: rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964). The team found that all 7 variants had consistent effect directions in both cohorts, but the associations of the variants with annualized hospitalization rates did not reach statistical significance in the pediatric cohort.

In a weighted Fisher’s meta-analyses combining the adult and pediatric cohorts, all 7 variants were significantly associated with annualized hospitalization rate after correcting for multiple testing.

Because the minor alleles of the variants within intron 2 are strongly associated with each other (in linkage disequilibrium), the researchers termed this group of variants the “PKLR intron 2 ‘risk’ haplotype.” They then used an independent cohort of 52 adult patients with SCD to evaluate PKLR allele-specific expression levels in patients with (heterozygous; n=29) or without (n=23) the PKLR intron 2 “risk” haplotype. This analysis demonstrated a significant deviation from the expected expression ratio in patients heterozygous for the intron 2 “risk” haplotype (mean, 0.2073±0.0135) compared with to those without the “risk” haplotype (mean, 0.1239±0.0682); P =.0297).

“This preliminary study highlights that a group of PKLR intron 2 variants in linkage

disequilibrium affects gene expression, but it is not clear from this study if presence of the intron 2 ‘risk’ haplotype increases or decreases PKLR expression, and it is also not clear which of the six intron 2 variants is causative,” the researchers concluded in their report. “Nonetheless, our results support PKLR as a genetic modifier of acute pain in SCD and activating [pyruvate kinase] as an anti-sickling strategy.”

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Wang X, Gardner K, Tegegn MB, 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