Abstract
The clinical course of hemoglobin H (HbH) disease is remarkably variable. It is not completely clear how genetic and environmental factors interplay to modify clinical severity in affected individuals. Previous studies suggested that altered structure or function of alpha-hemoglobin-stabilizing protein (AHSP) could modify the clinical phenotypes of thalassemias. The present study attempted to explore the potential role of AHSP in the pathophysiology of HbH disease in 95 Chinese and Thai/Sino-Thai patients with deletional and non-deletional form of this disease. We identified six polymorphic sites in AHSP which were subgrouped into major haplotype clades. No association between AHSP genotypes or haplotypes and clinical phenotypes was observed. Instead, multiple linear regression analysis indicated that expression of AHSP correlated negatively with age (P < 0.001) and hemoglobin (P = 0.007), but positively with reticulocyte count (P = 0.003) and severity score (P = 0.003). Subgroup analysis showed that AHSP expression was higher in the non-deletional form than in the deletional form (P < 0.001). Moreover, specific types of non-deletional HbH disease with production of mutant alpha-globin chains that do not bind to AHSP (Hb Constant Spring and Hb Pakse) showed the highest AHSP expression. The present findings demonstrate that AHSP expression is a biomarker of HbH disease severity and infer an important role of AHSP in modulating the pathophysiology of this disease. Pharmacological or genetic means to alter AHSP expression may be a novel approach for amelioration of disease severity in HbH disease.
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Acknowledgements
This study is supported by the Children’s Thalassaemia Foundation of Hong Kong. The authors thank all patients and their guardians for their cooperation and Paskorn Sritipsukho and Umaporn Udomsubpayakul for their contribution to the statistical analysis.
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Written informed consent for enrollment in the study was obtained from individuals or guardians. The study protocol was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster and the Ethics Committee of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
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Surapolchai, P., Chuansumrit, A., Sirachainan, N. et al. A molecular study on the role of alpha-hemoglobin-stabilizing protein in hemoglobin H disease. Ann Hematol 96, 1005–1014 (2017). https://doi.org/10.1007/s00277-017-2978-x
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DOI: https://doi.org/10.1007/s00277-017-2978-x