期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 109, 期 4, 页码 1125-1135出版社
WILEY
DOI: 10.1002/cpt.2100
关键词
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资金
- International Serious Adverse Events Consortium
- Abbott
- Amgen
- Daiichi-Sankyo
- GlaxoSmithKline
- Merck
- Novartis
- Pfizer
- Roche
- Sanofi-Aventis
- Takeda
- Wellcome Trust
- National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit
- NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust [BRC-1215-20003]
- University of Nottingham
- Spanish Medicine Agency
- Fondo Europeo de Desarrollo Regional -FEDER [P10-CTS-6470, FIS PI12/00378, PI16/01748]
- Instituto de Salud Carlos III
- Swedish Medical Products Agency
- Swedish Society of Medicine [2008-21619]
- Swedish Research Council [521-2011-2440, 521-2014-3370, 201700641]
- Swedish Heart and Lung Foundation [20120557]
- IMI2 TransBioLine Project
- MRC [MR/L006758/1] Funding Source: UKRI
HLA genotype has a small impact on TB drug-related DILI while the role of NAT2 gene is complex. NAT2*5 frequency is lower, and NAT2*6 and NAT2*7 are more common in cases, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases.
Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 x 10(-5)). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.
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