A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E
β-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 β0-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 β-globin gene cluster (chr.11p15), and rs2071348 of the HBBP1 gene revealed the most significant association [P = 2.96 × 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 × 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 × 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 β0-thalassemia/HbE patients. This study revealed that all the three reported loci and the α-globin gene locus are the best and common predictors of the disease severity in β-thalassemia.
KeywordsThalassemia Linkage Disequilibrium Block Locus Control Region Indonesian Population Fetal Hemoglobin Level
We thank all of the patients who participated in this study, and we thank Dr. Sumonmaln Klamchuen, Nakorn Pathom Hospital; Dr. Su-on Chainunsamit, Khon Kaen Hospital; Dr. Issarang Nuchprayoon, Chulalongkorn Hospital, Dr. Leelawan Wiboonmongkol, Rachaburi Hospital; Dr. Ampaiwan Chuansumrit, Ramathibodi Hospital, Thailand for their kind support in contacting subjects. We thank Siti Ayu Putriasih from Department of Child Health Medical Faculty, University of Indonesia, Cipto Mangunkusumo National Hospital. We thank Budi Amarta Putra, Dessy Handayani, Felix Liaw from Medical Faculty University of Indonesia. We thank Ita Margaretha Nainggolan, Mewahyu Dewi, and Arleen Nugraha Suryatenggara from Eijkman Institute for Molecular Biology, Indonesia for their kind support in contacting subjects for replication study in the Indonesian population. We acknowledge the Thailand Research Fund for encouraging the study. This work was mainly supported by the DMSc-RIKEN collaboration and the National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand. Additional support was provided by the Higher Education Commission, the Siriraj Graduate Thesis Scholarship and the Medical Scholar Program, Mahidol University, Thailand.
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