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BMC Med Genet. 2010 Mar 30;11:51. doi: 10.1186/1471-2350-11-51.

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

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  • 1Department of Medicine, Genetics Program, Boston University School of Medicine, Boston 02118, USA.

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.

PMID:
20353593
[PubMed - indexed for MEDLINE]
PMCID:
PMC2853425
Free PMC Article
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