A genome-wide association identified the common genetic variants  influence disease severity in beta0-thalassemia/hemoglobin E.
b-Thalassemia/HbE disease is clinically variable. In searching for genetic factors modifying the disease severity, patients were selected based on their disease severities, and a genome-wide association study (GWAS) was performed. Genotyping was conducted with the Illumina Human 610-Quad BeadChips array using DNAs from 618 Thai b0-thalassemia/HbE patients who were classified as 383 severe and 235 mild phenotypes by a validated scoring system. Twenty-three SNPs in three independent genes/regions were identified as being significantly associated with the disease severity. The highest association was observed with SNPs in the b-globin gene cluster (chr.11p15), and rs2071348 of the HBBP1 gene revealed the most significant association [P = 2.96 9 10(-13), odds ratio (OR) = 4.33 (95% confidence interval (CI), 2.74-6.84)]. The second was identified in the intergenic region between the HBS1L and MYB genes (chr.6q23), among which rs9376092 was the most significant [P = 2.36 9 10(-10), OR = 3.07 (95% CI, 2.16-4.38)]. The third region was located in the BCL11A gene (chr.2p16.1), and rs766432 showed the most significant association [P = 5.87 9 10-10, OR = 3.06 (95% CI, 2.15-4.37)]. All three loci were replicated in an independent cohort of 174 Indonesian patients. The associations to fetal hemoglobin levels were also observed with SNPs on these three regions. Our data indicate that several genetic loci act in concert to influence HbF levels of beta(0)-thalassemia/HbE patients. This study revealed that all the three reported loci and the alpha-globin gene locus are the best and common predictors of the disease severity in beta-thalassemia.
Nuinoon
Manit
M
Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Phutthamonthon, Nakhonpathom 73170, Thailand.
Makarasara
Wattanan
W
Mushiroda
Taisei
T
Setianingsih
Iswari
I
Wahidiyat
Pustika Amalia
PA
Sripichai
Orapan
O
Kumasaka
Natsuhiko
N
Takahashi
Atsushi
A
Svasti
Saovaros
S
Munkongdee
Thongperm
T
Mahasirimongkol
Surakameth
S
Peerapittayamongkol
Chayanon
C
Viprakasit
Vip
V
Kamatani
Naoyuki
N
Winichagoon
Pranee
P
Kubo
Michiaki
M
Nakamura
Yusuke
Y
Fucharoen
Suthat
S
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006446:Hemoglobin E / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055815:Young Adult; D055542:alpha-Globins / Q000235:genetics; D055544:beta-Globins / Q000235:genetics; D017086:beta-Thalassemia / Q000150:complications / Q000235:genetics* / Q000473:pathology
D055542:alpha-Globins; D055544:beta-Globins; D006446:Hemoglobin E