Thyreostatika u. Agranulozytose

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Thyreostatika u. Agranulozytose

Postby Werner » Tue 9. Aug 2016, 18:16

Genetic variants associated with antithyroid drug-induced
agranulocytosis: a genome-wide association study in a
European population
Pär Hallberg, Niclas Eriksson, Luisa Ibañez, Emmanuelle Bondon-Guitton, Reinhold Kreutz, Alfonso Carvajal, M Isabel Lucena, Esther Sancho Ponce,
Mariam Molokhia, Javier Martin, Tomas Axelsson, Qun-Ying Yue, Patrik K E Magnusson, Mia Wadelius, for the EuDAC collaborators*
Summary
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 × 10⁹/L [≤500/μL]) 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 signifi cance threshold was p<5 × 10–⁸.
Findings Agranulocytosis induced by non-chemotherapy drugs in general was signifi cantly associated with the HLA
region on chromosome 6, with odds ratios (ORs) of 3·24 (95% CI 2·31–4·55, p=1·20 × 10–¹¹) for HLA-B*27:05 and
3·57 (2·61–4·90, p=2·32 × 10–¹⁵) for the top SNP (rs114291795). Drug-specifi c 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 × 10–⁹) and 16·91 (3·44–83·17) when compared with a small group of hyperthyroid
controls (p=5·04 × 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 × 10–¹¹) and rs199564443 (17·42, 7·38–41·12, p=7·04 × 10–¹¹), which
were independent of HLA-B*27:05, and rs1071816 (5·27, 3·06–9·10, p=2·35 × 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 diff erently 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 intensifi ed
monitoring or off ered alternative treatment for hyperthyroidism.
Funding Swedish Research Council, Swedish Heart and Lung Foundation, Clinical Research Support at Uppsala
University, German Federal Institute for Drugs and Medical Devices, Carlos III Spanish Health Institute, European
Regional Development Fund, UK National Institute for Health Research, The Selander’s Foundation, Thuréus
Foundation, European Commission, and Science for Life Laboratory.

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