Genetic modifiers of Hb E/beta0 thalassemia identified by a two-stage genome-wide association study.

Abstract

BACKGROUND:

Patients with Hb E/beta0 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/beta0 thalassemia and normal alpha-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 beta-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 x 10(-13)). Seven SNPs in two distinct LD blocks within a region centromeric to the beta-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 x 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 beta-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.

• 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
• Journal: BMC medical genetics (BMC Med Genet) Vol. 11 Pg. 51 (Mar 30 2010) ISSN: 1471-2350 [Electronic] England
• PMID: 20353593 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• beta-Globins
• Hemoglobin E

Topics

• Female
• Gene Frequency
• Genome-Wide Association Study
• Genotype
• Hemoglobin E (genetics)
• Humans
• Male
• Polymorphism, Single Nucleotide
• Severity of Illness Index
• beta-Globins (genetics)
• beta-Thalassemia (genetics)