A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e

Manit Nuinoon, Wattanan Makarasara, Taisei Mushiroda, Iswari Setianingsih, Pustika Amalia Wahidiyat, Orapan Sripichai, Natsuhiko Kumasaka, Atsushi Takahashi, Saovaros Svasti, Thongperm Munkongdee, Surakameth Mahasirimongkol, Chayanon Peerapittayamongkol, Vip Viprakasit, Naoyuki Kamatani, Pranee Winichagoon, Michiaki Kubo, Yusuke Nakamura, Suthat Fucharoen

Research output: Contribution to journal › Article

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Abstract

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 β 0 -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 β 0 -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.

Original languageEnglish
Pages (from-to)303-314
Number of pages12
JournalHuman Genetics
Volume127
Issue number3
DOIs
Publication statusPublished - 01-01-2010

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Thalassemia
Hemoglobins
Genome
Single Nucleotide Polymorphism
Globins
Genes
Odds Ratio
Confidence Intervals
Fetal Hemoglobin
Intergenic DNA
Genetic Loci
Genome-Wide Association Study
Multigene Family
Oligonucleotide Array Sequence Analysis
Phenotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Nuinoon, M., Makarasara, W., Mushiroda, T., Setianingsih, I., Wahidiyat, P. A., Sripichai, O., ... Fucharoen, S. (2010). A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e Human Genetics, 127(3), 303-314. https://doi.org/10.1007/s00439-009-0770-2
Nuinoon, Manit ; Makarasara, Wattanan ; Mushiroda, Taisei ; Setianingsih, Iswari ; Wahidiyat, Pustika Amalia ; Sripichai, Orapan ; Kumasaka, Natsuhiko ; Takahashi, Atsushi ; Svasti, Saovaros ; Munkongdee, Thongperm ; Mahasirimongkol, Surakameth ; Peerapittayamongkol, Chayanon ; Viprakasit, Vip ; Kamatani, Naoyuki ; Winichagoon, Pranee ; Kubo, Michiaki ; Nakamura, Yusuke ; Fucharoen, Suthat. / A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e In: Human Genetics. 2010 ; Vol. 127, No. 3. pp. 303-314.
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abstract = "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 β 0 -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 β 0 -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.",
author = "Manit Nuinoon and Wattanan Makarasara and Taisei Mushiroda and Iswari Setianingsih and Wahidiyat, {Pustika Amalia} and Orapan Sripichai and Natsuhiko Kumasaka and Atsushi Takahashi and Saovaros Svasti and Thongperm Munkongdee and Surakameth Mahasirimongkol and Chayanon Peerapittayamongkol and Vip Viprakasit and Naoyuki Kamatani and Pranee Winichagoon and Michiaki Kubo and Yusuke Nakamura and Suthat Fucharoen",
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Nuinoon, M, Makarasara, W, Mushiroda, T, Setianingsih, I, Wahidiyat, PA, Sripichai, O, Kumasaka, N, Takahashi, A, Svasti, S, Munkongdee, T, Mahasirimongkol, S, Peerapittayamongkol, C, Viprakasit, V, Kamatani, N, Winichagoon, P, Kubo, M, Nakamura, Y & Fucharoen, S 2010, ' A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e ', Human Genetics, vol. 127, no. 3, pp. 303-314. https://doi.org/10.1007/s00439-009-0770-2

A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e . / Nuinoon, Manit; Makarasara, Wattanan; Mushiroda, Taisei; Setianingsih, Iswari; Wahidiyat, Pustika Amalia; Sripichai, Orapan; Kumasaka, Natsuhiko; Takahashi, Atsushi; Svasti, Saovaros; Munkongdee, Thongperm; Mahasirimongkol, Surakameth; Peerapittayamongkol, Chayanon; Viprakasit, Vip; Kamatani, Naoyuki; Winichagoon, Pranee; Kubo, Michiaki; Nakamura, Yusuke; Fucharoen, Suthat.

In: Human Genetics, Vol. 127, No. 3, 01.01.2010, p. 303-314.

Research output: Contribution to journal › Article

TY - JOUR

T1 - A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e

AU - Nuinoon, Manit

AU - Makarasara, Wattanan

AU - Mushiroda, Taisei

AU - Setianingsih, Iswari

AU - Wahidiyat, Pustika Amalia

AU - Sripichai, Orapan

AU - Kumasaka, Natsuhiko

AU - Takahashi, Atsushi

AU - Svasti, Saovaros

AU - Munkongdee, Thongperm

AU - Mahasirimongkol, Surakameth

AU - Peerapittayamongkol, Chayanon

AU - Viprakasit, Vip

AU - Kamatani, Naoyuki

AU - Winichagoon, Pranee

AU - Kubo, Michiaki

AU - Nakamura, Yusuke

AU - Fucharoen, Suthat

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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 β 0 -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 β 0 -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.

AB - 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 β 0 -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 β 0 -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.

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Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O et al. A genome-wide association identified the common genetic variants influence disease severity in β 0 -thalassemia/hemoglobin e Human Genetics. 2010 Jan 1;127(3):303-314. https://doi.org/10.1007/s00439-009-0770-2

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