Recurrent acute pain, or vaso-occlusive pain crisis (VOP), is the most common complication of sickle cell disease and correlates strongly with increased hospital visits and early mortality (PMID: 1710777). While the genetics of VOP in sickle cell patients has been studied (PMID: 29205277, 27883292, 25102390, 30079801, 22925497, 29531649, 29620434, 19468207, 20172753, 22576309, 30031848, 24136375, 27603703, 29559808), it is not fully understood.
Using whole genome sequencing, we interrogated 133 candidate risk single nucleotide polymorphisms (SNPs) across 65 genes for association with VOP: 11 SNPs in 3 gene regions associated with fetal hemoglobin (HbF) and 122 additional SNPs in 62 genes previously reported to be associated with pain due to SCD and/or other etiologies. We then constructed unweighted polygenic risk scores (PGSs) by counting the total number of risk alleles per individual across the 11 HbF SNPs (PGSHbF) and the 5 SNPs in COMT (PGSCOMT), where COMT is the gene previously associated with SCD pain (PMID: 29559808, 15537663). We also defined a final PGS comprised of these 16 SNPs plus another 5 of the candidate SNPs that were internally validated (PGSHbF+COMT+5snps), which was more strongly associated with acute VOP than any individual variant. Additionally, patients with the highest 5% of scores had 3-fold more pain events than the bottom 5% but were 5 times more likely to be on hydroxyurea, indicating that patients with high scores might benefit from a second drug.
Estimated VOP event rate (y-axis) according to each PGS model. Each symbol represents an estimated value of the VOP event rate, with the fitted linear regression line being shown for each PGS. P values were calculated based on a generalized linear mixed model (GLMM) to test for associations between VOP event rate and the indicated PGS, adjusted for sex, hydroxyurea therapy, 5 PCs, −α3.7, and PGS-age interaction.
Click variant to see NLM NIH dbSNP data.
|rs3834466||β-globin gene cluster||+||+|
|rs28440105||β-globin gene cluster||+||+|
|rs10128556||β-globin gene cluster||+||+|
|rs968857||β-globin gene cluster||+||+|