A polygenic score for acute vaso-occlusive pain in pediatric sickle cell disease

<p><a href="https://viz.stjude.cloud/communityData/PGS_snpLists.xlsx">Polygenic Risk Scores</a>&nbsp;is from the Pain study described below:</p> <p>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&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/1710777/">PMID: 1710777</a>. While the genetics of VOP in sickle cell patients has been studied (PMID:&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/29205277/">29205277</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/27883292/">27883292</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/25102390/">25102390</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/30079801/">30079801</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/22925497/">22925497</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/29531649/">29531649</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/29620434/">29620434</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/19468207/">19468207</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/20172753/">20172753</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/22576309/">22576309</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/30031848/">30031848</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/24136375/">24136375</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/27603703/">27603703</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/29559808/">29559808</a>), it is not fully understood.</p> <p>Using WGS, we interrogated the&nbsp;<em>a</em>-thalassemia deletion -<em>a</em>3.7 and 133 candidate risk single nucleotide polymorphisms (SNPs) across an additional 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:&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/29559808/">29559808</a>,&nbsp;<a href="https://pubmed.ncbi.nlm.nih.gov/215537663/">15537663</a>). We also defined a final PGS comprised of these 16 SNPs plus another 5 internally-validated candidate SNPs (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.</p>