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Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy: A Phenome-Wide Association Study
Journal article   Open access   Peer reviewed

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

Tianxi Cai, Yichi Zhang, Yuk-Lam Ho, Nicholas Link, Jiehuan Sun, Jie Huang, Tianrun A. Cai, Scott Damrauer, Yuri Ahuja, Jacqueline Honerlaw, …
JAMA cardiology, Vol.3(9), pp.849-857
08/08/2018
DOI: 10.1001/jamacardio.2018.2287
PMCID: PMC6233652
PMID: 30090940
url
https://doi.org/10.1001/jamacardio.2018.2287View
Published (Version of record) Open Access

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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