TY - JOUR
T1 - Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
AU - the International Drug-Induced Liver Injury Consortium (iDILIC)
AU - Nicoletti, Paola
AU - Aithal, Guruprasad P.
AU - Chamberlain, Thomas C.
AU - Coulthard, Sally
AU - Alshabeeb, Mohammad
AU - Grove, Jane I.
AU - Andrade, Raul J.
AU - Bjornsson, Einar
AU - Dillon, John F.
AU - Hallberg, Par
AU - Lucena, M. Isabel
AU - Maitland-van der Zee, Anke H.
AU - Martin, Jennifer H.
AU - Molokhia, Mariam
AU - Pirmohamed, Munir
AU - Wadelius, Mia
AU - Shen, Yufeng
AU - Nelson, Matthew R.
AU - Daly, Ann K.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Some patients prescribed flucloxacillin (~ 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10 −97 ). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10 −6 ). Within the HLA-B protein sequence, imputation showed valine 97 , common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10 −97 ). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.
AB - Some patients prescribed flucloxacillin (~ 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10 −97 ). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10 −6 ). Within the HLA-B protein sequence, imputation showed valine 97 , common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10 −97 ). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.
UR - http://www.scopus.com/inward/record.url?scp=85063089249&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/cpt.1375
DO - https://doi.org/10.1002/cpt.1375
M3 - Article
C2 - 30661239
SN - 0009-9236
VL - 106
SP - 245
EP - 253
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 1
ER -