HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Ann K. Daly; Peter T. Donaldson; Pallav Bhatnagar; Yufeng Shen; Itsik Pe'er; Aris Floratos; Mark J. Daly; David B. Goldstein; Sally John; Matthew R. Nelson; Julia Graham; B. Kevin Park; John F. Dillon; William Bernal; Heather J. Cordell; Munir Pirmohamed; Guruprasad P. Aithal; Christopher P. Day

doi:10.1038/ng.379

HLA-B^∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Ann K. Daly, Peter T. Donaldson, Pallav Bhatnagar, Yufeng Shen, Itsik Pe'er, Aris Floratos, Mark J. Daly, David B. Goldstein, Sally John, Matthew R. Nelson, Julia Graham, B. Kevin Park, John F. Dillon, William Bernal, Heather J. Cordell, Munir Pirmohamed, Guruprasad P. Aithal, Christopher P. Day

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948 Citations (Scopus)

Abstract

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 ^-33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B^*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 ^-19). The association was replicated in a second cohort of 23 cases. In HLA-B^*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 ^-8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

Original language	English
Pages (from-to)	816-819
Number of pages	4
Journal	Nature Genetics
Volume	41
Issue number	7
DOIs	https://doi.org/10.1038/ng.379
Publication status	Published - 1 Jul 2009

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Daly, A. K., Donaldson, P. T., Bhatnagar, P., Shen, Y., Pe'er, I., Floratos, A., Daly, M. J., Goldstein, D. B., John, S., Nelson, M. R., Graham, J., Park, B. K., Dillon, J. F., Bernal, W., Cordell, H. J., Pirmohamed, M., Aithal, G. P., & Day, C. P. (2009). HLA-B^∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics, 41(7), 816-819. https://doi.org/10.1038/ng.379

@article{f2cb7485beac4690bedc634376cc9a30,

title = "HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin",

abstract = "Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.",

author = "Daly, {Ann K.} and Donaldson, {Peter T.} and Pallav Bhatnagar and Yufeng Shen and Itsik Pe'er and Aris Floratos and Daly, {Mark J.} and Goldstein, {David B.} and Sally John and Nelson, {Matthew R.} and Julia Graham and Park, {B. Kevin} and Dillon, {John F.} and William Bernal and Cordell, {Heather J.} and Munir Pirmohamed and Aithal, {Guruprasad P.} and Day, {Christopher P.}",

year = "2009",

month = jul,

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doi = "10.1038/ng.379",

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journal = "Nature Genetics",

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Daly, AK, Donaldson, PT, Bhatnagar, P, Shen, Y, Pe'er, I, Floratos, A, Daly, MJ, Goldstein, DB, John, S, Nelson, MR, Graham, J, Park, BK, Dillon, JF, Bernal, W, Cordell, HJ, Pirmohamed, M, Aithal, GP & Day, CP 2009, 'HLA-B^∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin', Nature Genetics, vol. 41, no. 7, pp. 816-819. https://doi.org/10.1038/ng.379

TY - JOUR

T1 - HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

AU - Daly, Ann K.

AU - Donaldson, Peter T.

AU - Bhatnagar, Pallav

AU - Shen, Yufeng

AU - Pe'er, Itsik

AU - Floratos, Aris

AU - Daly, Mark J.

AU - Goldstein, David B.

AU - John, Sally

AU - Nelson, Matthew R.

AU - Graham, Julia

AU - Park, B. Kevin

AU - Dillon, John F.

AU - Bernal, William

AU - Cordell, Heather J.

AU - Pirmohamed, Munir

AU - Aithal, Guruprasad P.

AU - Day, Christopher P.

PY - 2009/7/1

Y1 - 2009/7/1

N2 - Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

AB - Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

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U2 - 10.1038/ng.379

DO - 10.1038/ng.379

M3 - Letter

C2 - 19483685

AN - SCOPUS:67649859295

SN - 1061-4036

VL - 41

SP - 816

EP - 819

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

HLA-B^∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

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