A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

Abstractβ-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.

[1]  F. Grosveld,et al.  Deletion of a region that is a candidate for the difference between the deletion forms of hereditary persistence of fetal hemoglobin and δβ‐thalassemia affects β‐ but not γ‐globin gene expression , 1999, The EMBO journal.

[2]  T. Spector,et al.  The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. , 2007, Blood.

[3]  K. Abel,et al.  β‐Globin gene cluster polymorphisms are strongly associated with severity of HbE/β0‐thalassemia , 2007 .

[4]  K. Abel,et al.  b-Globin gene cluster polymorphisms are strongly associated with severity , 2007 .

[5]  J. Hirschhorn,et al.  Supporting Online Material Materials and Methods Figs. S1 to S10 Tables S1 to S7 References Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-specific Repressor Bcl11a , 2022 .

[6]  A. Michelson.  From Genetic Association to Genetic Switch , 2008, Science.

[7]  Cameron S. Osborne,et al.  Intergenic Transcription, Cell-Cycle and the Developmentally Regulated Epigenetic Profile of the Human Beta-Globin Locus , 2007, PloS one.

[8]  J. Flint,et al.  The population genetics of the haemoglobinopathies. , 1993, Bailliere's clinical haematology.

[9]  S. Fucharoen,et al.  Coinheritance of the different copy numbers of alpha-globin gene modifies severity of beta-thalassemia/Hb E disease. , 2008, Annals of hematology.

[10]  Cameron S. Osborne,et al.  Heterogeneity of the ɛγδβ‐thalassaemias: characterization of three novel English deletions , 2005, British journal of haematology.

[11]  J. Hirschhorn,et al.  DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease , 2008, Proceedings of the National Academy of Sciences.

[12]  M. Lathrop,et al.  The HBS1L-MYB intergenic interval associated with elevated HbF levels shows characteristics of a distal regulatory region in erythroid cells. , 2009, Blood.

[13]  S. Fucharoen,et al.  Prenatal diagnosis of β‐thalassaemia by reverse dot‐blot hybridization , 1999 .

[14]  TEA Peto,et al.  Haemoglobin E β thalassaemia in Sri Lanka , 2005, The Lancet.

[15]  D. Higgs,et al.  Simplified multiplex-PCR diagnosis of common southeast asian deletional determinants of alpha-thalassemia. , 2000, Clinical chemistry.

[16]  Swee Lay Thein,et al.  Molecular therapies in β‐thalassaemia , 2007, British journal of haematology.

[17]  P. Sebastiani,et al.  BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. , 2008, Blood cells, molecules & diseases.

[18]  S. Thein.  Genetic modifiers of beta-thalassemia. , 2005, Haematologica.

[19]  T. Spector,et al.  Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults , 2007, Proceedings of the National Academy of Sciences.

[20]  S. Fucharoen,et al.  Genetic Factors Affecting Clinical Severity in &bgr;-Thalassemia Syndromes , 2000, Journal of pediatric hematology/oncology.

[21]  Simon Heath,et al.  A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15 , 2007, Nature Genetics.

[22]  T. Spector,et al.  Ethnic differences in F cell levels in Jamaica: a potential tool for identifying new genetic loci controlling fetal haemoglobin , 2009, British journal of haematology.

[23]  S. Phadke,et al.  Phenotype score to grade the severity of thalassemia intermedia , 2003, Indian journal of pediatrics.

[24]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[25]  P. Wilairat,et al.  Severity differences in β‐thalassaemia/haemoglobin E syndromes: implication of genetic factors , 1993 .

[26]  S. Fucharoen,et al.  Coinheritance of the different copy numbers of α-globin gene modifies severity of β-thalassemia/Hb E disease , 2008, Annals of Hematology.

[27]  Yusuke Nakamura,et al.  A high-throughput SNP typing system for genome-wide association studies , 2001, Journal of Human Genetics.

[28]  C. Nusbaum,et al.  Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. , 2006, Genome research.

[29]  A. Chuansumrit,et al.  A scoring system for the classification of β‐thalassemia/Hb E disease severity , 2008, American journal of hematology.

[30]  S. Fucharoen,et al.  Prenatal diagnosis of β‐thalassaemia by reverse dot‐blot hybridization , 1999 .

[31]  P. Fraser,et al.  Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta-globin locus. , 2000, Molecular cell.

[32]  R. Nagel,et al.  Polymerase chain reaction amplification applied to the determination of β‐like globin gene cluster haplotypes , 1989, American journal of hematology.