Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease

Abstract

Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (−α3.7 deletion) and β-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the −α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the −α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the −α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the −α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and β-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.

HbS/β+ thalassemia: Really a mild disease? A National survey from the AIEOP Sickle Cell Disease Study Group with genotype‐phenotype correlation

“…Since the description of a cohort of HbS/β+ patients in Southern Italy, the frequency of SCD patients has grown in the entire country with important changes in the genotypes . The clinical presentation of affected patients depends mainly on the quantitative β mutation, although other genetic modifiers, such as high levels of HbF or deletion of the alpha thalassemia gene may influence the clinical course . Mutations of the HBB gene interfering with the transcription, RNA cleavage, or mRNA splicing are associated with a β+ phenotype.…”

Haemolysis in sickle cell anaemia: effects of polymorphisms in α‐globin gene regulatory elements

“…The effects of α‐thalassaemia on the haematology and clinical features of sickle cell anaemia and HbAS were recently confirmed in an analysis of whole genome sequences in individuals with HbAS and from genome‐wide SNP analysis in patients with sickle cell anaemia (Raffield et al , ). rs11865131 and rs11248850 ( r 2 = 0·999) in NPRL3 altered both haematological and clinical phenotypes by modifying the expression of the α‐globin genes ( HBA1 / HBA2 ).…”

“…When α‐thalassaemia accompanies HbAS, HbS levels are reduced to 30–35%. These haematological changes are accompanied by a reduced prevalence of hyposthenuria and improved renal function (Gupta et al , ; Raffield et al , ).…”

“…rs11865131 and rs11248850 ( r 2 = 0·999) in NPRL3 altered both haematological and clinical phenotypes by modifying the expression of the α‐globin genes ( HBA1 / HBA2 ). These variants were associated with normalized erythrocyte indices in carriers of the common −3·7 kb gene deletion α‐thalassaemia and reversal of the protective effect of α‐thalassaemia on stroke in sickle cell anaemia, suggesting that HBA1/2 expression was upregulated (Raffield et al , ). Linkage disequilibrium or LD (a measure of the association between two loci) between rs7203560 and rs11865131 and rs11248850 was suggested by a D’ (a measure of the coinheritance of these SNPs) of 0·937 for both SNPs.…”

“…The low MAF of rs7203560 made it difficult to detect any interaction with rs11865131 and rs11248850. In individuals with HbAS without α‐thalassaemia, the MAF of rs11248850 was 0·27; in HbAS‐α‐thalassaemia the MAF was 0·14 (Raffield et al , ); the MAF was 0·2318 in patients of the Cooperative Study of Sickle Cell Disease (CSSCD) (Milton et al , ).…”