Contributions
Abstract: P1589
Type: LB Poster
Abstract Category: Late Breaking News
Background and Aim: One in 50 adults with MS exposed to an interferon-beta (IFN-β) experience drug-induced liver injury (DILI). There are few strategies to prevent serious adverse drug reactions (ADRs) to the MS biological agents. We report the results of a genome-wide association study aiming to identify pharmacogenomic biomarkers of IFN-β associated liver injury to broaden the understanding of liver injury due to these biologic agents.
Methods: 204 MS patients (63 cases, 141 controls) exposed to IFN-β were recruited through Canada- and USA-based MS clinics and two ADR surveillance networks (Sweden and USA). DILI cases were defined as temporally associated rises in serum alanine aminotransferase ≥ 5x the upper limit of normal occurring during IFN-β exposure. Standardized ADR causality assessments were applied to assist with excluding competing etiologies. Controls had ≥ 2 years exposure to IFN-β and no biochemical evidence of liver injury. Genome-wide association analyses were performed to discover relevant biomarkers followed by replication. Fine mapping was used to identify putative causal variants.
Results: A genome-wide discovery scan was performed using 151 IFN-β exposed patients (38 cases, 113 controls). A chromosome 1 variant (allele frequency: 0.24 cases, 0.04 controls) was significantly associated with IFN-β induced liver injury (adjusted odds ratio (OR) 11.1; 95%CI: 4.2-29.4). In the replication stage, the genomic variant remained significantly associated with liver injury and was detected only in cases (p=0.02). Over the combined analyses, the genomic variant reached genome-wide significance (p=9.4x10-9, OR = 9.8; 95%CI: 4.0-24.1). The genomic variant is highly specific (93.7%; 95%CI: 87.9-97.2%) and has a sensitivity of 41.1% (95%CI: 28.1-55.0) for DILI. Variant annotation revealed that the marker is associated with increased hepatic expression of interferon regulatory factor 6 (IRF6).
Conclusions: In this first genome-wide association study of an ADR from an MS drug, we found carriers of an IRF variant had a ten-fold increased risk of experiencing IFN-β induced liver injury. The association of increased hepatic expression of an IFN-β transcription factor-related variant with liver injury due to IFN-β reveals a potential mechanistic understanding of this ADR. This highly significant and specific finding is relevant in predicting IFN-β associated liver injury and offers insight into the safer use of this biological therapy.
Disclosure: KK receives funding from the Canadian Institutes of Health Research (Banting and Best Canada Graduate Scholarship and the Drug Safety and Effectiveness Network), the Multiple Sclerosis Society of Canada and the University of British Columbia.
GEBW received funding the Canadian Institutes of Health Research (Postdoctoral Fellowship).
BID receives funding from the BC Children"s Hospital Foundation (Child and Family Research Institute Bertram Hoffmeister Postdoctoral Fellowship).
FA receives funding from Child & Family Research Institute (Bertram Hoffmeister Postdoctoral Fellowship), Michael Smith Foundation for Health Research (Postdoctoral Fellowship), CIHR Drug Safety and Effectiveness Cross-Disciplinary Training Program (Postdoctoral Fellowship).
APB has no disclosures.
EK has no disclosures.
AT has received grant support from Hoffman la Roche and Sanofi Genzyme; steering committee membership for Hoffman la Roche; consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Sanofi Genzyme, Teva Neuroscience.
EY is an investigator of clinical trials sponsored by Gilead Inc, Merck Inc, Vertex Inc, Hoffman LaRoche Inc, Abbvie Inc, Janssen Inc, Boeringher Ingelheim Inc. He has received honoraria for CME lectures from Merck Canada, Gilead Canada. He has been a speaker at Advisory Board Meetings of Boeringher Ingelheim Canada, Hoffman LaRoche Canada, Abbvie Canada for which he received an honorarium. He is a member of the Gilead Canada compassionate release program adjudication committee for which he has received an honorarium.
RAM has conducted clinical trials for Sanofi-Aventis. She receives research funding from CIHR, the MS Society of Canada, the NMSS, Rx&D Health Research Foundation and Research Manitoba.
MK: No actual or potential conflict of interest in relation to this work, however, in the last two years MK or MK"s institution has received consulting fees, research support or grants from CIHR, MS Society of Canada, Bayer, Biogen, Genzyme, Novartis, Sanofi-Aventis, Serono, and Teva.
TC was a principle investigator for a research study for Biogen Idec Canada; has received honoraria for lectures from EMD Merck Serono Canada, Biogen Idec Canada, Teva Canada Innovation, and Genzyme; has participated/spoken at Advisory Board Meetings of EMD Merck Serono, Teva Canada Innovation, Biogen Idec Canada, Genzyme, and Novartis for which an honorarium and travel support was received to attend the meeting.
PD has received support as a consultant, membership on advisory councils, and grants from the pharmaceutical industry. He is funded by the MS Society of Canada, and by the CIHR.
NC has consulting agreements with Abbvie, Lilly, DS Biopharma, Tobira, NuSirt, Celgene and Allergan and research grants from Gilead, Galectin and Intercept. But none represent a potential conflict for this abstract.
MW and PH have no conflict of interest. They receive funding from the Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), the Clinical Research Support (ALF) at Uppsala University, and MW also has grants from the Swedish Heart and Lung Foundation (20120557 and 20140291).
ZX was a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology and is supported by NIH K08-NS079493.
PDJ has research funding from Sanofi/Genzyme and Biogen and has consulted for TEVA and Sanofi/Genzyme.
CR receives funding support from the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Canadian Hearing Foundation, BC Children´s Hospital Foundation, Child & Family Research Institute, Canadian Gene Cure Foundation, Teva Pharmaceutical Industries Inc., Genome BC, and the CIHR Drug Safety & Effectiveness Network.
HT is funded as a Canada Research Chair and has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust and travel expenses to attend meetings or conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015).
BC has received financial support for his pharmacogenomics research from various provincial and federal granting programs, including: Canada Foundation for Innovation, Canadian Institutes of Health Research, Genome Canada, Genome British Columbia and the Provincial Health Services Authority, the University of British Columbia and the Child & Family Research Institute, Vancouver, Canada. He has also received required matching funds support for Genome Canada funding from Pfizer Canada (unrestricted).
Abstract: P1589
Type: LB Poster
Abstract Category: Late Breaking News
Background and Aim: One in 50 adults with MS exposed to an interferon-beta (IFN-β) experience drug-induced liver injury (DILI). There are few strategies to prevent serious adverse drug reactions (ADRs) to the MS biological agents. We report the results of a genome-wide association study aiming to identify pharmacogenomic biomarkers of IFN-β associated liver injury to broaden the understanding of liver injury due to these biologic agents.
Methods: 204 MS patients (63 cases, 141 controls) exposed to IFN-β were recruited through Canada- and USA-based MS clinics and two ADR surveillance networks (Sweden and USA). DILI cases were defined as temporally associated rises in serum alanine aminotransferase ≥ 5x the upper limit of normal occurring during IFN-β exposure. Standardized ADR causality assessments were applied to assist with excluding competing etiologies. Controls had ≥ 2 years exposure to IFN-β and no biochemical evidence of liver injury. Genome-wide association analyses were performed to discover relevant biomarkers followed by replication. Fine mapping was used to identify putative causal variants.
Results: A genome-wide discovery scan was performed using 151 IFN-β exposed patients (38 cases, 113 controls). A chromosome 1 variant (allele frequency: 0.24 cases, 0.04 controls) was significantly associated with IFN-β induced liver injury (adjusted odds ratio (OR) 11.1; 95%CI: 4.2-29.4). In the replication stage, the genomic variant remained significantly associated with liver injury and was detected only in cases (p=0.02). Over the combined analyses, the genomic variant reached genome-wide significance (p=9.4x10-9, OR = 9.8; 95%CI: 4.0-24.1). The genomic variant is highly specific (93.7%; 95%CI: 87.9-97.2%) and has a sensitivity of 41.1% (95%CI: 28.1-55.0) for DILI. Variant annotation revealed that the marker is associated with increased hepatic expression of interferon regulatory factor 6 (IRF6).
Conclusions: In this first genome-wide association study of an ADR from an MS drug, we found carriers of an IRF variant had a ten-fold increased risk of experiencing IFN-β induced liver injury. The association of increased hepatic expression of an IFN-β transcription factor-related variant with liver injury due to IFN-β reveals a potential mechanistic understanding of this ADR. This highly significant and specific finding is relevant in predicting IFN-β associated liver injury and offers insight into the safer use of this biological therapy.
Disclosure: KK receives funding from the Canadian Institutes of Health Research (Banting and Best Canada Graduate Scholarship and the Drug Safety and Effectiveness Network), the Multiple Sclerosis Society of Canada and the University of British Columbia.
GEBW received funding the Canadian Institutes of Health Research (Postdoctoral Fellowship).
BID receives funding from the BC Children"s Hospital Foundation (Child and Family Research Institute Bertram Hoffmeister Postdoctoral Fellowship).
FA receives funding from Child & Family Research Institute (Bertram Hoffmeister Postdoctoral Fellowship), Michael Smith Foundation for Health Research (Postdoctoral Fellowship), CIHR Drug Safety and Effectiveness Cross-Disciplinary Training Program (Postdoctoral Fellowship).
APB has no disclosures.
EK has no disclosures.
AT has received grant support from Hoffman la Roche and Sanofi Genzyme; steering committee membership for Hoffman la Roche; consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Sanofi Genzyme, Teva Neuroscience.
EY is an investigator of clinical trials sponsored by Gilead Inc, Merck Inc, Vertex Inc, Hoffman LaRoche Inc, Abbvie Inc, Janssen Inc, Boeringher Ingelheim Inc. He has received honoraria for CME lectures from Merck Canada, Gilead Canada. He has been a speaker at Advisory Board Meetings of Boeringher Ingelheim Canada, Hoffman LaRoche Canada, Abbvie Canada for which he received an honorarium. He is a member of the Gilead Canada compassionate release program adjudication committee for which he has received an honorarium.
RAM has conducted clinical trials for Sanofi-Aventis. She receives research funding from CIHR, the MS Society of Canada, the NMSS, Rx&D Health Research Foundation and Research Manitoba.
MK: No actual or potential conflict of interest in relation to this work, however, in the last two years MK or MK"s institution has received consulting fees, research support or grants from CIHR, MS Society of Canada, Bayer, Biogen, Genzyme, Novartis, Sanofi-Aventis, Serono, and Teva.
TC was a principle investigator for a research study for Biogen Idec Canada; has received honoraria for lectures from EMD Merck Serono Canada, Biogen Idec Canada, Teva Canada Innovation, and Genzyme; has participated/spoken at Advisory Board Meetings of EMD Merck Serono, Teva Canada Innovation, Biogen Idec Canada, Genzyme, and Novartis for which an honorarium and travel support was received to attend the meeting.
PD has received support as a consultant, membership on advisory councils, and grants from the pharmaceutical industry. He is funded by the MS Society of Canada, and by the CIHR.
NC has consulting agreements with Abbvie, Lilly, DS Biopharma, Tobira, NuSirt, Celgene and Allergan and research grants from Gilead, Galectin and Intercept. But none represent a potential conflict for this abstract.
MW and PH have no conflict of interest. They receive funding from the Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), the Clinical Research Support (ALF) at Uppsala University, and MW also has grants from the Swedish Heart and Lung Foundation (20120557 and 20140291).
ZX was a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology and is supported by NIH K08-NS079493.
PDJ has research funding from Sanofi/Genzyme and Biogen and has consulted for TEVA and Sanofi/Genzyme.
CR receives funding support from the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Canadian Hearing Foundation, BC Children´s Hospital Foundation, Child & Family Research Institute, Canadian Gene Cure Foundation, Teva Pharmaceutical Industries Inc., Genome BC, and the CIHR Drug Safety & Effectiveness Network.
HT is funded as a Canada Research Chair and has received research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, and the UK MS Trust and travel expenses to attend meetings or conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014), American Academy of Neurology (2013, 2014, 2015).
BC has received financial support for his pharmacogenomics research from various provincial and federal granting programs, including: Canada Foundation for Innovation, Canadian Institutes of Health Research, Genome Canada, Genome British Columbia and the Provincial Health Services Authority, the University of British Columbia and the Child & Family Research Institute, Vancouver, Canada. He has also received required matching funds support for Genome Canada funding from Pfizer Canada (unrestricted).