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Genetic variants as...
Genetic variants associated with antithyroid drug-induced agranulocytosis : a genome-wide association study in a European population
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- Hallberg, Pär (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos,Science for Life Laboratory, SciLifeLab
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- Eriksson, Niclas (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos,Science for Life Laboratory, SciLifeLab,Uppsala kliniska forskningscentrum (UCR)
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- Ibanez, Luisa (author)
- Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Fundacio Inst Catala Farmacol, E-08193 Barcelona, Spain.
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- Bondon-Guitton, Emmanuelle (author)
- Univ Toulouse, Serv Pharmacol Med & Clin, Ctr Hosp Univ, Fac Med, Toulouse, France.
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- Kreutz, Reinhold (author)
- Charite, Inst Klin Pharmakol & Toxikol, D-13353 Berlin, Germany.
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- Carvajal, Alfonso (author)
- Univ Valladolid, Ctr Estudios Seguridad Medicamentos, Valladolid, Spain.
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- Isabel Lucena, M. (author)
- Univ Malaga, Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga, Farmacol Clin S, E-29071 Malaga, Spain.;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain.
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- Sancho Ponce, Esther (author)
- Hosp Gen Cataluna, Serv Hematol & Banc Sang, Sant Cugat Del Valles, Spain.
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- Molokhia, Mariam (author)
- Guys & St Thomas NHS Fdn Trust, Res Biomed Res Ctr, Natl Inst Hlth, Dept Primary Care & Publ Hlth Sci, London, England.;Kings Coll London, London WC2R 2LS, England.
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- Martin, Javier (author)
- CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain.
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- Axelsson, Tomas (author)
- Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab
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- Yue, Qun-Ying (author)
- Med Prod Agcy, Uppsala, Sweden.
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- Magnusson, Patrik K. E. (author)
- Karolinska Institutet
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- Wadelius, Mia (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2016
- 2016
- English.
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In: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 4:6, s. 507-516
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population.Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count <= 0.5 x 10(9)/L [<= 500/mu L]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 x 10(-8).Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3.24 (95% CI 2.31-4.55, p = 1.20 x 10(-11)) for HLA-B*27:05 and 3.57 (2.61-4.90, p = 2.32 x 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27: 05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27: 05 was 7.30 (3.81-13.96) when antithyroid drug-induced agranulocytosis was compared with population controls (p= 1.91 x 10(-9)) and 16.91 (3.44-83.17) when compared with a small group of hyperthyroid controls (p = 5.04 x 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4.73, 95% CI 3.00-7.44, p= 1.92 x 10(-11)) and rs199564443 (17.42, 7.38-41.12, p = 7.04 x 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5.27, 3.06-9.10, p = 2.35 x 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped.Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B* 27: 05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism.
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- By the author/editor
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Hallberg, Pär
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Eriksson, Niclas
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Ibanez, Luisa
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Bondon-Guitton, ...
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Kreutz, Reinhold
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Carvajal, Alfons ...
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Isabel Lucena, M ...
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Sancho Ponce, Es ...
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Molokhia, Mariam
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Martin, Javier
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Axelsson, Tomas
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Yue, Qun-Ying
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Magnusson, Patri ...
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Wadelius, Mia
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The Lancet Diabe ...
- By the university
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Uppsala University
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Karolinska Institutet