Clin Genet 2007: 72: 497–505 Printed in Singapore. All rights reserved # 2007 The Authors Journal compilation # 2007 Blackwell Munksgaard CLINICAL GENETICS doi: 10.1111/j.1399-0004.2007.00897.x Original Article b-Globin gene cluster polymorphisms are strongly associated with severity of HbE/b 0 -thalassemia Ma Q, Abel K, Sripichai O, Whitacre J, Angkachatchai V, Makarasara W, Winichagoon P, Fucharoen S, Braun A, Farrer LA. b-Globin gene cluster polymorphisms are strongly associated with severity of HbE/b 0 - thalassemia. Clin Genet 2007: 72: 497–505. # Blackwell Munksgaard, 2007 We evaluated the contribution of 67 single nucleotide polymorphisms (SNPs) within the b-globin gene cluster to disease severity in groups of 207 mild- and 305 severe unrelated patients from Thailand with Hemoglobin E (HbE)/b 0 -thalassemia and normal a-globin genes. Our analysis showed that these SNPs comprise two distinct linkage disequilibrium blocks, one containing the b-globin gene and the other extending from the locus control region (LCR) to the d gene, which are separated by a recombination hotspot in the narrow region of the b- globin gene promoter. Forty-five SNPs within the interval including the LCR region and the d gene showed strong association with disease severity. The strongest association was observed with the XmnI polymorphism located 158-bp upstream to the Gg gene (p ¼ 4.6E212). Carriers of the T allele of XmnI were more likely to have a milder disease course and higher level of fetal hemoglobin (HbF) in both the mild (p ¼ 0.005) and severe (p ¼ 8.7E206) patient groups. Haplotype analysis revealed that the T allele of XmnI was nearly always in cis with the HbE allele. The high frequency of this haplotype may be favored by positive selection against malarial infection. Further studies are needed to validate this hypothesis and determine whether XmnI or another closely linked variant modulates severity and HbF levels in patients with b 0 - thalassemia/HbE disease. Q Ma a , K Abel b , O Sripichai c,d , J Whitacre b , V Angkachatchai b , W Makarasara c , P Winichagoon c , S Fucharoen c , A Braun b, * and LA Farrer a,e a Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA, b Sequenom, Inc., San Diego, CA, USA, c Thalassemia Research Center, Institute of Science and Technology for Research and Development, d Department of Biochemistry, Faculty of Science, Mahidol University, Salaya, Phuttamonthon, Nakornpathom, Thailand, and e Departments of Neurology, Genetics and Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA *Current address: Dx Innovations, Inc., 3935 Lago di Grata Circle, San Diego, CA 92130, USA Key words: association – b-globin gene cluster – HbE/b 0 -thalassemia – SNP Corresponding author: Dr Lindsay A. Farrer, Department of Medicine (Genetics Program L-320), Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. Tel.: 11 617 6385393; fax: 11 617 6384275; e-mail: farrer@bu.edu Received 30 May 2007, revised and accepted for publication 1 August 2007 Thalassemia arises from a genetically determined defect in hemoglobin synthesis. b-thalassemia, which is caused by the decreased production of normal b-globin chains, is extremely common in South-East Asia (1). More than 200 point mutations and rare deletions in the b-globin gene accounting for these b-chain deficiencies have been characterized, and result in reduced levels (b 1 -thalassemia) or complete lack (b 0 -thalassemia) of the encoded b-chains (2). Hemoglobin E (HbE), associated with a G/A substitution in codon 26 (Glu/Lys) of the b-globin gene, is prevalent in South-East Asian populations (3). This mutation results in b 1 - thalassemia, because the formation of functional HbE-mRNA is decreased because of abnormal 497