Genetic modifiers of Hb E/β⁰thalassemia identified by a two-stage genome-wide association study

• Main Authors: Winichagoon Pranee (Author), Makarasara Wattanan (Author), Angkachatchai Vach (Author), Whitacre Johanna (Author), Ma Qianli (Author), Abel Kenneth (Author), Sripichai Orapan (Author), Sherva Richard (Author), Svasti Saovaros (Author), Fucharoen Suthat (Author), Braun Andreas (Author), Farrer Lindsay A (Author)
• Format: Book
• Published: BMC, 2010-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<p>Abstract</p> <p>Background</p> <p>Patients with Hb E/β⁰thalassemia 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/β⁰thalassemia and normal α-globin genes.</p> <p>Methods</p> <p>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 <it>P </it>< 0.02 by pooling were selected for individual genotyping.</p> <p>Results</p> <p>After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (<it>P </it>< 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, <it>P </it>= 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, <it>P </it>= 3.7 × 10^-11). Several previously unreported SNPs were also significantly associated with disease severity.</p> <p>Conclusions</p> <p>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.</p>

Item Description

10.1186/1471-2350-11-51
1471-2350