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

• Authors: Tianxi Cai, Veterans Affairs Boston Healthcare System; Yichi Zhang, Veterans Affairs Boston Healthcare System; Yuk-Lam Ho, Veterans Affairs Boston Healthcare System; Nicholas Link, Veterans Affairs Boston Healthcare System; Jiehuan Sun, Veterans Affairs Boston Healthcare System; Jie Huang, Veterans Affairs Boston Healthcare System; Tianrun A. Cai, Veterans Affairs Boston Healthcare System; Scott Damrauer, University of Pennsylvania; Yuri Ahuja, Harvard University; Jacqueline Honerlaw, Veterans Affairs Boston Healthcare System; Jie Huang, Veterans Affairs Boston Healthcare System; Lauren Costa, Veterans Affairs Boston Healthcare System; Petra Schubert, Veterans Affairs Boston Healthcare System; Chuan Hong, Harvard University; David Gagnon, Veterans Affairs Boston Healthcare System; Yan Sun, Emory University; J. Michael Gaziano, Veterans Affairs Boston Healthcare System; Peter Wilson, Emory University; Kelly Cho, Veterans Affairs Boston Healthcare System; Phillip Tsao, Veterans Affairs Palo Alto Health Care System; Christopher J. O'Donnell, Veterans Affairs Boston Healthcare System; Katherine P. Liao, Veterans Affairs Boston Healthcare System
• Journal Title: JAMA Cardiology
• Volume: Volume 3, Number 9
• Publisher: American Medical Association (AMA) | 2018-09-01, Pages 849-857
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1001/jamacardio.2018.2287
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Cardiovascular System & Cardiology; CORONARY-HEART-DISEASE; GIANT-CELL ARTERITIS; ACTIVE RHEUMATOID-ARTHRITIS; ABDOMINAL AORTIC-ANEURYSM; PLACEBO-CONTROLLED TRIAL; FALSE DISCOVERY RATE; DOUBLE-BLIND; TOCILIZUMAB MONOTHERAPY; INADEQUATE RESPONSE; MONOCLONAL-ANTIBODY

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.