Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

Pei Lung Chen; Shyang Rong Shih; Pei Wen Wang; Ying Chao Lin; Chen Chung Chu; Jung Hsin Lin; Szu Chi Chen; Ching Chung Chang; Tien Shang Huang; Keh Sung Tsai; Fen Yu Tseng; Chih Yuan Wang; Jin Ying Lu; Wei Yih Chiu; Chien Ching Chang; Yu Hsuan Chen; Yuan Tsong Chen; Cathy Shen Jang Fann; Wei Shiung Yang; Tien Chun Chang

doi:10.1038/ncomms8633

Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

Pei Lung Chen, Shyang Rong Shih, Pei Wen Wang, Ying Chao Lin, Chen Chung Chu, Jung Hsin Lin, Szu Chi Chen, Ching Chung Chang, Tien Shang Huang, Keh Sung Tsai, Fen Yu Tseng, Chih Yuan Wang, Jin Ying Lu, Wei Yih Chiu, Chien Ching Chang, Yu Hsuan Chen, Yuan Tsong Chen, Cathy Shen Jang Fann^*, Wei Shiung Yang, Tien Chun Chang

^*Corresponding author for this work

School of Traditional Chinese Medicine

Research output: Contribution to journal › Journal Article › peer-review

81 Scopus citations

Abstract

Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B∗38:02 (Armitage trend P_combined =6.75 × 10 ^-32) and HLA-DRB1∗08:03 (P _combined =1.83 × 10 ^-9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B∗38:02 and HLA-DRB1∗08:03 increases odds ratio to 48.41 (P _combined =3.32 × 10 ^-21, 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

Original language	English
Article number	7633
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8633
State	Published - 07 07 2015

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Chen, P. L., Shih, S. R., Wang, P. W., Lin, Y. C., Chu, C. C., Lin, J. H., Chen, S. C., Chang, C. C., Huang, T. S., Tsai, K. S., Tseng, F. Y., Wang, C. Y., Lu, J. Y., Chiu, W. Y., Chang, C. C., Chen, Y. H., Chen, Y. T., Fann, C. S. J., Yang, W. S., & Chang, T. C. (2015). Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study. Nature Communications, 6, Article 7633. https://doi.org/10.1038/ncomms8633

@article{a5b2933326bc488782c5ec6005871f31,

title = "Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study",

abstract = "Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B∗38:02 (Armitage trend Pcombined =6.75 × 10 -32) and HLA-DRB1∗08:03 (P combined =1.83 × 10 -9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B∗38:02 and HLA-DRB1∗08:03 increases odds ratio to 48.41 (P combined =3.32 × 10 -21, 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.",

author = "Chen, {Pei Lung} and Shih, {Shyang Rong} and Wang, {Pei Wen} and Lin, {Ying Chao} and Chu, {Chen Chung} and Lin, {Jung Hsin} and Chen, {Szu Chi} and Chang, {Ching Chung} and Huang, {Tien Shang} and Tsai, {Keh Sung} and Tseng, {Fen Yu} and Wang, {Chih Yuan} and Lu, {Jin Ying} and Chiu, {Wei Yih} and Chang, {Chien Ching} and Chen, {Yu Hsuan} and Chen, {Yuan Tsong} and Fann, {Cathy Shen Jang} and Yang, {Wei Shiung} and Chang, {Tien Chun}",

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Chen, PL, Shih, SR, Wang, PW, Lin, YC, Chu, CC, Lin, JH, Chen, SC, Chang, CC, Huang, TS, Tsai, KS, Tseng, FY, Wang, CY, Lu, JY, Chiu, WY, Chang, CC, Chen, YH, Chen, YT, Fann, CSJ, Yang, WS & Chang, TC 2015, 'Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study', Nature Communications, vol. 6, 7633. https://doi.org/10.1038/ncomms8633

TY - JOUR

T1 - Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

AU - Chen, Pei Lung

AU - Shih, Shyang Rong

AU - Wang, Pei Wen

AU - Lin, Ying Chao

AU - Chu, Chen Chung

AU - Lin, Jung Hsin

AU - Chen, Szu Chi

AU - Chang, Ching Chung

AU - Huang, Tien Shang

AU - Tsai, Keh Sung

AU - Tseng, Fen Yu

AU - Wang, Chih Yuan

AU - Lu, Jin Ying

AU - Chiu, Wei Yih

AU - Chang, Chien Ching

AU - Chen, Yu Hsuan

AU - Chen, Yuan Tsong

AU - Fann, Cathy Shen Jang

AU - Yang, Wei Shiung

AU - Chang, Tien Chun

PY - 2015/7/7

Y1 - 2015/7/7

N2 - Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B∗38:02 (Armitage trend Pcombined =6.75 × 10 -32) and HLA-DRB1∗08:03 (P combined =1.83 × 10 -9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B∗38:02 and HLA-DRB1∗08:03 increases odds ratio to 48.41 (P combined =3.32 × 10 -21, 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

AB - Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B∗38:02 (Armitage trend Pcombined =6.75 × 10 -32) and HLA-DRB1∗08:03 (P combined =1.83 × 10 -9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B∗38:02 and HLA-DRB1∗08:03 increases odds ratio to 48.41 (P combined =3.32 × 10 -21, 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

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U2 - 10.1038/ncomms8633

DO - 10.1038/ncomms8633

M3 - 文章

C2 - 26151496

AN - SCOPUS:84936760867

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7633

ER -

Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

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