Sickle Cell Disease Pain Study

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: 2955980815537663). 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.

Association studies of polygenic scores with acute VOP event rate in the SCCRIP cohort
Association studies of polygenic scores with acute VOP event rate in the SCCRIP cohort

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 +   +
rs6738440 BCL11A +   +
rs1427407 BCL11A +   +
rs7606173 BCL11A +   +
rs66650371 HBS1L–MYB +   +
rs6028892 HBS1L–MYB +   +
rs9389268 HBS1L–MYB +   +
rs9494142 HBS1L–MYB +   +
rs6269 IL1A   + +
rs4633 IL1A   + +
rs4818 IL1A   + +
rs4680 IL1A   + +
rs165599 IL1A   + +
rs6858735 TBC1D1     +
rs2835914 KCNJ6     +
rs2295632 FAAH     +
rs2963155 NR3C1     +
rs1800587 IL1A     +