Genetic modifiers of Hb E/beta0 thalassemia identified by a two-stage genome-wide association study.
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.
Sherva
Richard
R
Department of Medicine, Genetics Program, Boston University School of Medicine, Boston 02118, USA.
Sripichai
Orapan
O
Abel
Kenneth
K
Ma
Qianli
Q
Whitacre
Johanna
J
Angkachatchai
Vach
V
Makarasara
Wattanan
W
Winichagoon
Pranee
P
Svasti
Saovaros
S
Fucharoen
Suthat
S
Braun
Andreas
A
Farrer
Lindsay A
LA
D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006446:Hemoglobin E / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
D055544:beta-Globins; D006446:Hemoglobin E