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Title: Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study
Authors: Richard Sherva
Orapan Sripichai
Kenneth Abel
Qianli Ma
Johanna Whitacre
Vach Angkachatchai
Wattanan Makarasara
Pranee Winichagoon
Saovaros Svasti
Suthat Fucharoen
Andreas Braun
Lindsay A Farrer
Mahidol University. Institute of Molecular Biosciences. Thalassemi a Research Center
Mahidol University. Faculty of Science. Department of Biochemistry
Keywords: Genetic modifiers;Hb E/β0;thalassemia identified;a two-stage;genome-wide;association;Open Access article
Issue Date: 2010
Citation: BMC Medical Genetics. Vol.11, No.1 (2010), 1-9
Abstract: Background Patients with Hb E/β0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/β0 thalassemia and normal α-globin genes. Methods First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs) in pooled DNAs from different severity groups. The 756 SNPs that showed reproducible allelic differences at P < 0.02 by pooling were selected for individual genotyping. Results After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (P < 0.05) after Bonferroni adjustment for multiple testing. Forty-one SNPs in a large LD block within the β-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 × 10-13). Seven SNPs in two distinct LD blocks within a region centromeric to the β-globin gene cluster that contains many olfactory receptor genes were also associated with disease severity; rs3886223 had the strongest association (OR = 3.03, P = 3.7 × 10-11). Several previously unreported SNPs were also significantly associated with disease severity. Conclusions These results suggest that there may be an additional regulatory region centromeric to the β-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.
ISSN: 1471-2350 (Online)
Appears in Collections:MB-Article

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