Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study

Nicoletti, Paola, Aithal, Guruprasad P., Bjornsson, Einar S., Andrade, Raul J. A, Sawle, Ashley, Arrese, Marco, Barnhart, Huiman X., Bondon-Guitton, Emmanuelle, Hayashi, Paul H., Bessone, Fernando, Carvajal, Alfonso, Cascorbi, Ingolf, Cirulli, Elizabeth T., Chalasani, Naga, Conforti, Anita, Coulthard, Sally A., Daly, Mark J., Day, Christopher P., Dillon, John F., Fontana, Robert J., Grove, Jane I., Hallberg, Pär, Hernandez, Nelia, Ibanez, Luisa, Kullak-Ublick, Gerd A. , Laitinen, Tarja, Larrey, Dominique, Lucena, M. Isabel, Maitland-van der Zee, Anke H., Martin, Jennifer H., Molokhia, Mariam, Pirmohamed, Munir, Powell, Elizabeth E., Qin, Shengying, Serrano, Jose, Stephens, Camilla, Stolz, Andrew, Wadelius, Mia, Watkins, Paul B., Floratos, Aris, Shen, Yufeng, Nelson, Matthew R., Urban, Thomas J. and Daly, Ann K. (2017) Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology, 152 5: 1078-1089. doi:10.1053/j.gastro.2016.12.016

Author Nicoletti, Paola
Aithal, Guruprasad P.
Bjornsson, Einar S.
Andrade, Raul J. A
Sawle, Ashley
Arrese, Marco
Barnhart, Huiman X.
Bondon-Guitton, Emmanuelle
Hayashi, Paul H.
Bessone, Fernando
Carvajal, Alfonso
Cascorbi, Ingolf
Cirulli, Elizabeth T.
Chalasani, Naga
Conforti, Anita
Coulthard, Sally A.
Daly, Mark J.
Day, Christopher P.
Dillon, John F.
Fontana, Robert J.
Grove, Jane I.
Hallberg, Pär
Hernandez, Nelia
Ibanez, Luisa
Kullak-Ublick, Gerd A.
Laitinen, Tarja
Larrey, Dominique
Lucena, M. Isabel
Maitland-van der Zee, Anke H.
Martin, Jennifer H.
Molokhia, Mariam
Pirmohamed, Munir
Powell, Elizabeth E.
Qin, Shengying
Serrano, Jose
Stephens, Camilla
Stolz, Andrew
Wadelius, Mia
Watkins, Paul B.
Floratos, Aris
Shen, Yufeng
Nelson, Matthew R.
Urban, Thomas J.
Daly, Ann K.
Title Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study
Journal name Gastroenterology   Check publisher's open access policy
ISSN 1528-0012
Publication date 2017-04-01
Year available 2016
Sub-type Article (original research)
DOI 10.1053/j.gastro.2016.12.016
Open Access Status Not yet assessed
Volume 152
Issue 5
Start page 1078
End page 1089
Total pages 12
Place of publication Maryland Heights, MO, United States
Publisher W.B. Saunders
Collection year 2018
Language eng
Formatted abstract
Background & Aims: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.

Methods: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs.

Results: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9−3.8; P = 2.4 × 10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6−2.5; P = 9.7 × 10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6−2.7; P = 4.8 × 10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0−9.5; P = 7.1 × 10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224.

Conclusions: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non−drug-specific risk factors.
Keyword Anti-fungal agent
Liver damage
Side effect
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Medicine Publications
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