A molecular study on the role of alpha-hemoglobin-stabilizing protein in hemoglobin H disease.
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.
Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.
Pacharapan
P
Surapolchai
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Ampaiwan
A
Chuansumrit
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Nongnuch
N
Sirachainan
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Praguywan
P
Kadegasem
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Ka-Chun
KC
Leung
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. scc@pathology.hku.hk.
Chi-Chiu
CC
So
D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics*; D002681:China; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013785:Thailand; D055815:Young Adult; D017085:alpha-Thalassemia / Q000208:ethnology / Q000235:genetics* / Q000473:pathology
C468768:AHSP protein, human; D001798:Blood Proteins; D018832:Molecular Chaperones
AHSP; Alpha-thalassemia; Biomarker; Disease severity; HbH disease