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Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.

Publication ,  Journal Article
Nicoletti, P; Aithal, GP; Bjornsson, ES; Andrade, RJ; Sawle, A; Arrese, M; Barnhart, HX; Bondon-Guitton, E; Hayashi, PH; Bessone, F; Daly, MJ ...
Published in: Gastroenterology
April 2017

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.

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

April 2017

Volume

152

Issue

5

Start / End Page

1078 / 1089

Location

United States

Related Subject Headings

  • White People
  • Ticlopidine
  • Terbinafine
  • Sertraline
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Phenotype
  • Odds Ratio
  • Naphthalenes
  • Middle Aged
 

Citation

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Nicoletti, P., Aithal, G. P., Bjornsson, E. S., Andrade, R. J., Sawle, A., Arrese, M., … International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium, . (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. https://doi.org/10.1053/j.gastro.2016.12.016
Nicoletti, Paola, Guruprasad P. Aithal, Einar S. Bjornsson, Raul J. Andrade, Ashley Sawle, Marco Arrese, Huiman X. Barnhart, et al. “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, no. 5 (April 2017): 1078–89. https://doi.org/10.1053/j.gastro.2016.12.016.
Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. 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. 2017 Apr;152(5):1078–89.
Nicoletti, Paola, et al. “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, vol. 152, no. 5, Apr. 2017, pp. 1078–89. Pubmed, doi:10.1053/j.gastro.2016.12.016.
Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernández N, Ibáñez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK, International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. 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. 2017 Apr;152(5):1078–1089.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

April 2017

Volume

152

Issue

5

Start / End Page

1078 / 1089

Location

United States

Related Subject Headings

  • White People
  • Ticlopidine
  • Terbinafine
  • Sertraline
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Phenotype
  • Odds Ratio
  • Naphthalenes
  • Middle Aged