Abstractβ-Thalassemia/HbE disease has a wide spectrum of clinical phenotypes ranging from asymptomatic to dependent on regular blood transfusions. Ability to predict disease severity is helpful for clinical management and treatment decision making. A thalassemia severity score has been developed from Mediterranean β-thalassemia patients. However, different ethnic groups may have different allele frequency and linkage disequilibrium structures. Here, Thai β0-thalassemia/HbE disease genome-wild association studies (GWAS) data of 487 patients were analyzed by SNP interaction prioritization algorithm, interacting Loci (iLoci), to find predictive SNPs for disease severity. Three SNPs from two SNP interaction pairs associated with disease severity were identifies. The three-SNP disease severity risk score composed of rs766432 in BCL11A, rs9399137 in HBS1L-MYB and rs72872548 in HBE1 showed more than 85% specificity and 75% accuracy. The three-SNP predictive score was then validated in two independent cohorts of Thai and Malaysian β0-thalassemia/HbE patients with comparable specificity and accuracy. The SNP risk score could be used for prediction of clinical severity for Southeast Asia β0-thalassemia/HbE population.

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Hemoglobin (Hb) disorder is a significant health problem in Southeast Asia, where HbE (β E ; codon 26 [GAG>AAG; human betaglobin gene, HBB:c.79G>A]) is a common hemoglobin variant in this region. 1,2 The interaction of HbE and other globin gene mutations can cause a nontransfusion and transfusion-dependent thalassemia syndrome. [2][3][4] By contrast, Hb Nottingham (β Nottingham ) is a rare unstable hemoglobin caused by a missense mutation at codon 98 (GTG>GGG; HBB:c.296T>G). 5 This variant was first described in 1973, 6 and only six reports have been published on Hb Nottingham worldwide. [6][7][8][9][10][11] This current report describes two Malay monozygotic twins with a rare interaction of HbE and Hb Nottingham (β E /β Nottingham ) that gave a clinical picture similar to that of transfusion-dependent HbE/beta-thalassemia. The literature reporting Hb Nottingham since 1973 was also reviewed.