Sherva, RichardSripichai, OrapanAbel, KennethMa, QianliWhitacre, JohannaAngkachatchai, VachMakarasara, WattananWinichagoon, PraneeSvasti, SaovarosFucharoen, SuthatBraun, AndreasFarrer, Lindsay A.2011-12-292011-12-2920102010-3-30Sherva, Richard, Orapan Sripichai, Kenneth Abel, Qianli Ma, Johanna Whitacre, Vach Angkachatchai, Wattanan Makarasara, Pranee Winichagoon, Saovaros Svasti, Suthat Fucharoen, Andreas Braun, Lindsay A Farrer. "Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study" BMC Medical Genetics 11:51. (2010)1471-2350https://hdl.handle.net/2144/2497BACKGROUND: 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.enCopyright 2010 Sherva et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/2.0Article10.1186/1471-2350-11-51203535932853425