HbA₂ levels in normal adults are influenced by two distinct genetic mechanisms

Abstract

SummaryUsing a genome-wide association study, we found that common inter-individual differences in haemoglobin A 2 (HbA 2 , a 2 d 2 ) levels are largely governed by genetic factors (42% of variability). The influence of age (1%) and sex (4%) was small. HbA 2 levels were influenced by two loci: the HBS1L-MYB locus on chromosome 6q, which has been shown to have pleiotropic effects on other haematological traits; and a second locus surrounding HBB, the gene encoding b-globin. Our results suggest that HbA 2 levels in adults are influenced by two different biological processes: one via kinetics of erythropoiesis, and the other, via competition between HBB and HBD activity.

Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants

“…Previous reports have provided evidence for association of several variants with haematological and related traits at the 11p15.4 locus23242526272829303132333435. The association of rs12274659 and rs11035019 with MCV after conditioning on the published variants remains genome-wide significant ( P <4.4 × 10 −18 ).…”

“…Rs7116019 is located at the 3′ end of the TRIM68 gene that functions as an ubiquitin E3 ligase and can act as a coactivator of androgen receptor depending on its ubiquitin ligase activity51. Previous reports have highlighted several independent variants at the chr11p15.4 locus to be associated with anaemias, traits underlying haemoglobin composition, red blood cell indices and the clinical manifestation of thalassemias2425272930313233. Previously a mutation in the HBB (haemoglobin, beta) gene, HbO-Arab (E122K), has been reported to have drifted up in frequency in the Pomak population and appears to have originated on a local haplotype about 2,000 years ago52.…”

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

“…The δ-globin gene does not have KLF1 binding sites. Hence, mutations of KLF1, which may also result in increased HbA2 levels, probably act indirectly, impairing the looping of LCR with the β-globin gene in favor of the competing δ-globin gene [5,6]. Expression studies have demonstrated that the mild increase in HbA2 in KLF1 mutation carriers is associated with an increased δ/δ+β ratio, most likely due to decreased β-globin gene expression as opposed to increased δ-globin gene expression [7,35].…”

“…First, HbA2 increases because of a post-transcriptional mechanism resulting from the β-globin deficit and the increased availability of α-globin chains [4]. Additionally, given that transcription factors of the globin genes are present in rate-limiting quantities, if there is inefficient binding to the altered or deleted β-promoters, more factors would be free to trigger the δ-promoter on the cis-locus by the locus control region (LCR) loop and on the trans-locus, and consequently increase the output of both δ-globin genes [1,5,6]. …”

HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

“…General diagnostic erythroid parameters such as RBC, MCV, MCH, and others (5,7,8,10,13) have also been found to be highly associated with the presence of the 6q23 variants. Traits with weaker, but significant association are packed blood cell volume (PCV, also referred to as hematocrit) (7,10,13), total Hb (13), HbA 2 (12), and even nonerythroid traits (i.e., monocyte and platelet counts) (5,10). The genetic regulation of HbF levels is of particular therapeutic interest, as increased HbF levels significantly ameliorate disease severity of the 2 main β-hemoglobinopathies -β-thalassemias and sickle cell disease (16,17) -which represent some of the most common human genetic disorders (18).…”