Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults

Abstract

Individual variation in fetal hemoglobin (HbF, ␣2␥2) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and ␤ thalassemia. HbF levels and HbF-associated quantitative traits (e.g., F cell levels) are highly heritable. We have previously mapped a major quantitative trait locus (QTL) controlling F cell levels in an extended Asian-Indian kindred with ␤ thalassemia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBS1L, a member of the GTP-binding protein family that is expressed in erythroid progenitor cells. In this high-resolution association study, we have identified multiple genetic variants within and 5 to HBS1L at 6q23 that are strongly associated with F cell levels in families of Northern European ancestry (P ‫؍‬ 10 ؊75 ). The region accounts for 17.6% of the F cell variance in northern Europeans. Although mRNA levels of HBS1L and MYB in erythroid precursors grown in vitro are positively correlated, only HBS1L expression correlates with high F cell alleles. The results support a key role for the HBS1L-related genetic variants in HbF control and illustrate the biological complexity of the mechanism of 6q QTL as a modifier of fetal hemoglobin levels in the ␤ hemoglobinopathies.

pHCR: a Parallel Haplotype Configuration Reduction algorithm for haplotype interaction analysis

“…However, DEPDC2 and HBS1L, located on chromosome 8 and chromosome 6, respectively, are in the proximity of the previously reported QTL region that associates with the fetal hemoglobin level. [32][33][34] Thus, the results produced from pHCR analysis are consistent with the known biological factors for this disease, reaffirming the interplay of these two regions.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…In a subsequent high-resolution association study, the same authors identified multiple genetic variants within and 5′ to HBS1L at 6q23 that are strongly associated with F-cell levels in families of Northern European ancestry [35]. Studies on erythroid progenitors in vitro have clearly shown that only HBS1L expression correlates with high F-cell alleles [36]. It is of interest to note that the HBS1L-MYB intergenic region on chromosome 6q23.3 influences not only F-cell frequency but also a series of hematological parameters, including erythrocyte, platelet, and monocyte counts in humans [37].…”

BCL11Acontrôle l’expression de l’hémoglobine fœtale

“…Thein (King's College, Londres, Royaume-Uni). Sa mise en évidence remonte à 2007 ; les auteurs avaient alors défini plusieurs segments dans cet intervalle, la liaison la plus forte étant localisée dans une séquence de 24 kb, située à peu près à égale distance de l'un et l'autre des deux gènes [6]. Ces gènes sont tous deux exprimés dans les précurseurs érythroïde.…”