Dataset Information

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 (Pcombined=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 (Pcombined=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.

SUBMITTER: Chen PL

PROVIDER: S-EPMC4506516 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Chen Pei-Lung PL Shih Shyang-Rong SR Wang Pei-Wen PW Lin Ying-Chao YC Chu Chen-Chung CC Lin Jung-Hsin JH Chen Szu-Chi SC Chang Ching-Chung CC Huang Tien-Shang TS Tsai Keh Sung KS Tseng Fen-Yu FY Wang Chih-Yuan CY Lu Jin-Ying JY Chiu Wei-Yih WY Chang Chien-Ching CC Chen Yu-Hsuan YH Chen Yuan-Tsong YT Fann Cathy Shen-Jang CS Yang Wei-Shiung WS Chang Tien-Chun TC

Nature communications 20150707

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)) ...[more]

PMID: 26151496

Similar Datasets

Project description:BackgroundDrug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Levamisole is an antihelminthic and immunomodulator withdrawn from North American markets in 2005 after reports of agranulocytosis. Previous studies of levamisole, suggest that the human leukocyte antigen (HLA)-B27 confers a genetic predisposition to this adverse drug event. Since 2009, emergency room visits due to agranulocytosis in individuals consuming levamisole-adulterated crack-cocaine have increased.MethodsWe performed a case-control study using a genotyping assay and novel gene chip to test the association between cocaine-associated agranulocytosis (CAA) and HLA-B27 and to identify pharmacokinetic and pharmacodynamic gene variants associated with the phenotype.ResultsFifty-one CAA cases were identified through a provincial physician reporting system between 2008 and 2011. We examined eight of these cases and 26 matched controls. Genotyping revealed a significant association between HLA-B27 and CAA (odds ratio [OR] 9.2, 95% confidence interval [CI], 1.54-54.6). We also observed a similar association with the HLA-B27 tag single nucleotide polymorphism rs4349859 (OR 9.2, 95% CI 1.5-54.6) and rs13202464 (OR 6.7, 95% CI 1.1-41). Further associations were identified with variants in the ARBCC12 (OR 10.0, 95% CI 2.7-36.8) and CYP11A1 (OR 7.4, 95% CI 2.1-26.6) genes, while a novel protective association was observed with variants in the ARDB1 gene (OR 0.06, 95% CI 0.007-0.46).ConclusionsWe confirmed the association of HLA-B27 with CAA and identified additional susceptibility variants. Health care providers should inform people who are identified as having CAA that it is genetically determined and can recur with continued cocaine use. The severity of infections and subsequent hospitalization, and the risk of recurrence may prompt health-promoting behaviour changes of the affected individuals. These genetic associations warrant the attention of public health and knowledge translation efforts to highlight the implications for susceptibility to this severe adverse drug event.

Project description:AimsAntithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD-induced agranulocytosis. To examine the associations between HLA genotypes and ATD-induced agranulocytosis, we conducted a systematic review and meta-analysis of pharmacogenomics studies.MethodsWe searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case-control studies on the associations between HLA genotypes with ATD-induced agranulocytosis. The Newcastle-Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random-effects model meta-analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD-induced agranulocytosis.ResultsWe included 5 studies with 142 ATD-induced agranulocytosis cases, 1529 matched ATD-tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD-induced agranulocytosis was associated with HLA-B*27:05 (OR 10.97; 95% CI 0.75-159.99), HLA-B*38:02 (OR 19.85; 95% CI 7.94-49.57) and HLA-DRB1*08:03 (OR 5.29; 95% CI 3.44-8.14). After excluding propylthiouracil, the associations of ATD-induced agranulocytosis with HLA-B*27:05 and HLA-B*38:02 were strengthened (OR being 20.61 (95% CI 5.21-81.58) and 40.59 (95% CI 13.24-124.47), respectively). The associations of ATD-induced agranulocytosis with HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86-14.07), 36.43 (95% CI 12.80-103.70) and 5.42 (95% CI 2.36-12.47), respectively). HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.ConclusionsHLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets