Publication: Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study
Issued Date
2010
Resource Type
Language
eng
ISSN
1471-2350 (Online)
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Mahidol University
Bibliographic Citation
BMC Medical Genetics. Vol.11, No.1 (2010), 1-9
Suggested Citation
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 Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study. BMC Medical Genetics. Vol.11, No.1 (2010), 1-9. doi:10.1186/1471-2350-11-51 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/1836
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Title
Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study
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.