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Original Investigation
September 2018

Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy: A Phenome-Wide Association Study

Author Affiliations
  • 1Veterans Affairs Boston Healthcare System, Boston, Massachusetts
  • 2Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 3Harvard Medical School, Boston, Massachusetts
  • 4Brigham and Women’s Hospital, Boston, Massachusetts
  • 5Corporal Michael Crescenz Veterans Affairs Medical Center, Perlman School of Medicine, University of Pennsylvania, Philadelphia
  • 6Boston University School of Public Health, Boston, Massachusetts
  • 7Emory University Schools of Medicine and Public Health, Atlanta, Georgia
  • 8Atlanta Veterans Affairs Medical Center, Atlanta, Georgia
  • 9Veterans Affairs Palo Alto Health Care System, Palo Alto, California
  • 10Department of Medicine, Stanford University of Medicine, Stanford, California
  • 11Associate Editor, JAMA Cardiology
JAMA Cardiol. 2018;3(9):849-857. doi:10.1001/jamacardio.2018.2287
Key Points

Question  Can a phenome-wide association study enable the use of genetics to inform drug development?

Findings  In this phenome-wide association study using electronic health record and genetic data from 332 799 US veterans, the association between a genetic variant of interleukin 6 receptor (IL6R) with potential effects of IL6R blocker therapy was assessed. The study identified a recently approved indication for IL6R blocker therapy associated with aortic aneurysm and identified off-target effects observed from clinical trials.

Meaning  The phenome-wide association study approach using large biobanks and genetics is a promising tool to assess potential beneficial and adverse effects of therapeutic agents with known pathways and related genes.

Abstract

Importance  Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene–drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade.

Objective  To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials.

Design, Setting, and Participants  Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center.

Exposures  IL6R SNPs (rs2228145; rs4129267).

Main Outcomes and Measures  Phenotypes defined by International Classification of Diseases, Ninth Revision codes.

Results  Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank.

Conclusions and Relevance  In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

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