A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease.

Authors

Li Liu, University of Texas at Dallas
Alexander Pertsemlidis, University of Texas Health Science Center at San Antonio
Liang-Hao Ding, University of Texas Southwestern Medical Center
Michael D Story, University of Texas Southwestern Medical Center
Martin H Steinberg, Boston UniversityFollow
Paola Sebastiani, Boston University School of Public Health
Carolyn Hoppe, UCSF Benioff Children’s HospitalFollow
Samir K. Ballas, Thomas Jefferson UniversityFollow
Betty S Pace, Augusta University

Document Type

Article

Publication Date

3-27-2016

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Experimental Biology and Medicine, Volume 241, Issue 7, March 2016, Pages 706-718.

The published version is available at DOI: 10.1177/1535370216642047. Copyright © Sage

Abstract

Sickle cell disease (SCD) is a group of inherited blood disorders that have in common a mutation in the sixth codon of the β-globin (HBB) gene on chromosome 11. However, people with the same genetic mutation display a wide range of clinical phenotypes. Fetal hemoglobin (HbF) expression is an important genetic modifier of SCD complications leading to milder symptoms and improved long-term survival. Therefore, we performed a genome-wide association study (GWAS) using a case-control experimental design in 244 African Americans with SCD to discover genetic factors associated with HbF expression. The case group consisted of subjects with HbF≥8.6% (133 samples) and control group subjects with HbF≤£3.1% (111 samples). Our GWAS results replicated SNPs previously identified in an erythroid-specific enhancer region located in the second intron of theBCL11Agene associated with HbF expression. In addition, we identified SNPs in theSPARC,GJC1,EFTUD2andJAZF1genes as novel candidates associated with HbF levels. To gain insights into mechanisms of globin gene regulation in theHBBlocus, linkage disequilibrium (LD) and haplotype analyses were conducted. We observed strong LD in the low HbF group in contrast to a loss of LD and greater number of haplotypes in the high HbF group. A search of knownHBBlocus regulatory elements identified SNPs 5' of δ-globin located in an HbF silencing region. In particular, SNP rs4910736 created a binding site for a known transcription repressor GFi1 which is a candidate protein for further investigation. Another HbF-associated SNP, rs2855122 in the cAMP response element upstream of Gγ-globin, was analyzed for functional relevance. Studies performed with siRNA-mediated CREB binding protein (CBP) knockdown in primary erythroid cells demonstrated γ-globin activation and HbF induction, supporting a repressor role for CBP. This study identifies possible molecular determinants of HbF production.

Recommended Citation

Liu, Li; Pertsemlidis, Alexander; Ding, Liang-Hao; Story, Michael D; Steinberg, Martin H; Sebastiani, Paola; Hoppe, Carolyn; Ballas, Samir K.; and Pace, Betty S, "A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease." (2016). Cardeza Foundation for Hematologic Research. Paper 33.
https://jdc.jefferson.edu/cardeza_foundation/33