Fetal hemoglobin modulates neurocognitive performance in sickle cell anemia✰,✰✰ - 07/05/22
, Jennifer Longoria a, Evadnie Rampersaud b, Sara R. Rashkin b, c, Jeremie H. Estepp c, Victoria I. Okhomina d, Winfred C. Wang c, Darcy Raches a, Brian Potter a, Martin H. Steinberg e, Allison A. King f, Guolian Kang d, a, 1, Jane S. Hankins c, 1Summary |
Purpose of the study |
Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA.
Patients and methods |
The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR).
Results |
HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05.
Conclusion |
As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention.
Il testo completo di questo articolo è disponibile in PDF.Keywords : Sickle cell, Anemia, Fetal hemoglobin, Hematology, Genetic, Neurocognitive, Intelligence, Neuropsychology
Mappa
| ✰Contributions: A.M.H, G.K., and J.S.H designed the research; A.M.H, J.S.H., J.L., E.R., S.R., J.E., W.C.W., D.R., B.P., M.H.S., and A.A.K performed research and collected data; A.M.H, V.I.O., and J.S.H., analyzed and interpreted the data; G.K. and V.I.O verified the underlying data; all authors wrote the manuscript and provided final approval of the manuscript. |
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| ✰✰Acknowledgements: The authors would like to thank Michael R. DeBaun, MD, for his critical review and suggestions to improve the manuscript. The authors would like to thank Jason Hodges, PhD, Pei-Lin Chen, MPH, Courtney Mays, Katie Stokes, Erin MacArthur, MS, Madelene Wilson, Tiana Thomas, Ruth Johnson, and Michelle Brignac, for support with data collection and regulatory matters. |
Vol 70 - N° 3
Articolo 103335- luglio 2022 Ritorno al numero
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