Abstract
Fetal hemoglobin (HbF) is a recognized modulator of sickle cell disease (SCD) severity. HbF levels are strongly influenced by genetic variants at three major genetic loci, Xmn1‐HBG2, HMIP‐2, and BCL11A, but the effect of these loci on the hematological phenotype in SCD, has so far not been investigated. In a cohort of individuals with SCD in Tanzania (HbSS and HbS/β° thalassemia, n = 726, aged 5 or older), HbF levels were positively correlated with hemoglobin, red blood cell (RBC) indices, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), and negatively with white blood cell (WBC) and platelet counts (all P < 0.0001). We subsequently assessed the contribution of the three HbF modifier loci and detected diverse effects, including a reduction in anemia, leukocytosis, and thrombocytosis associated with certain HbF‐promoting alleles. The presence of the ‘T’ allele at Xmn1‐HBG2 led to a significant increase in hemoglobin (P = 9.8 × 10−3) but no changes in cellular hemoglobin content. Xmn1‐HBG2 ‘T’ also has a weak effect decreasing WBC (P = 0.06) and platelet (P = 0.06) counts. The BCL11A variant (rs11886868‐‘C’) increases hemoglobin (P = 2 × 10−3) and one of the HBS1L‐MYB variants decreases WBC values selectively (P = 2.3 × 10−4). The distinct pattern of effects of each variant suggests that both, disease alleviation through increased HbF production, and ‘pleiotropic’ effects on blood cells, are involved, affecting a variety of pathways. Am. J. Hematol. 90:E1–E4, 2015. © 2014 Wiley Periodicals, Inc.
Highlights
Sickle cell disease (SCD) is an inherited hemoglobin disorder caused by the Glu6Val mutation in the b globin chain
We detected a significant influence of HbF levels and of variants at three major HbF modifier loci, BCL11A, HMIP, and Xmn1-HBG2, on the hematological phenotype of Tanzanian SCD patients
Hb gains with higher HbF were accompanied by increases in mean corpuscular volume (MCV) (Beta 5 0.43, P 5 9.9 3 1029) and mean corpuscular hemoglobin (MCH) (Beta 5 0.16, P 5 2.95 3 1029), while red blood cell (RBC) was unchanged (P 5 0.97)
Summary
Sickle cell disease (SCD) is an inherited hemoglobin disorder caused by the Glu6Val mutation in the b globin chain. It has a devastating impact in Sub-Saharan Africa, where it is highly prevalent and a significant cause of childhood mortality [1]. BCL11A variants have generally weaker pleiotropic effects, on RBC, MCV, and MCH [5,8] Subtle effects such as these might be hard to discern in SCD, where blood parameters are expected to primarily reflect diseaserelated processes, such as variable degrees of anemia, leukocytosis, and thrombocytosis [11,12,13,14]. A wide variation of HbF levels has been observed in patients with HbSS, which is mainly ascribed to the underlying genetic background of other coinherited factors
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