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, Lauren Costa, Petra Schubert, Chuan Hong, David Gagnon, Yan Sun, Yan V. Sun, J. Michael Gaziano, Peter Wilson, Kelly Cho, Philip Tsao & 82 others Christopher J. O'Donnell, Katherine P. Liao, Michael J. Gaziano, Rachel Ramoni, Jim Breeling, Kyong Mi Chang, Grant Huang, Sumitra Muralidhar, Philip S. Tsao, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan Mai T. Nguyen, Saiju Pyarajan, Elizabeth Hauser, Hongyu Zhao, Rachel McArdle, Louis Dellitalia, John Harley, Jeffrey Whittle, Jean Beckham, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Scott Kinlay, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)849-857
Number of pages9
JournalJAMA Cardiology
Volume3
Issue number9
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

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Interleukin-6 Receptors
Cardiovascular Diseases
Single Nucleotide Polymorphism
Veterans
Aortic Aneurysm
Therapeutics
Electronic Health Records
Phenotype
Linear Models
Logistic Models
Clinical Trials
Pharmaceutical Preparations
Giant Cell Arteritis
International Classification of Diseases
Drug Discovery

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy : A phenome - Wide association study. / Cai, Tianxi; Zhang, Yichi; Ho, Yuk Lam; Link, Nicholas; Sun, Jiehuan; Huang, Jie; Cai, Tianrun A.; Damrauer, Scott; Ahuja, Yuri; Honerlaw, Jacqueline; Costa, Lauren; Schubert, Petra; Hong, Chuan; Gagnon, David; Sun, Yan; Sun, Yan V.; Gaziano, J. Michael; Wilson, Peter; Cho, Kelly; Tsao, Philip; O'Donnell, Christopher J.; Liao, Katherine P.; Gaziano, Michael J.; Ramoni, Rachel; Breeling, Jim; Chang, Kyong Mi; Huang, Grant; Muralidhar, Sumitra; Tsao, Philip S.; Moser, Jennifer; Whitbourne, Stacey B.; Brewer, Jessica V.; Concato, John; Warren, Stuart; Argyres, Dean P.; Stephens, Brady; Brophy, Mary T.; Humphries, Donald E.; Do, Nhan; Shayan, Shahpoor; Nguyen, Xuan Mai T.; Pyarajan, Saiju; Hauser, Elizabeth; Zhao, Hongyu; McArdle, Rachel; Dellitalia, Louis; Harley, John; Whittle, Jeffrey; Beckham, Jean; Wells, John; Gutierrez, Salvador; Gibson, Gretchen; Kaminsky, Laurence; Villareal, Gerardo; Xu, Junzhe; Hamner, Mark; Haddock, Kathlyn Sue; Bhushan, Sujata; Iruvanti, Pran; Godschalk, Michael; Ballas, Zuhair; Buford, Malcolm; Mastorides, Stephen; Klein, Jon; Ratcliffe, Nora; Florez, Hermes; Swann, Alan; Murdoch, Maureen; Sriram, Peruvemba; Kinlay, Scott; Yeh, Shing Shing; Washburn, Ronald; Jhala, Darshana; Aguayo, Samuel; Cohen, David; Sharma, Satish; Callaghan, John; Oursler, Kris Ann; Whooley, Mary; Ahuja, Sunil; Gutierrez, Amparo; Schifman, Ronald; Greco, Jennifer; Rauchman, Michael; Servatius, Richard; Oehlert, Mary; Wallbom, Agnes; Fernando, Ronald; Morgan, Timothy; Stapley, Todd; Sherman, Scott; Anderson, Gwenevere; Sonel, Elif; Boyko, Edward; Meyer, Laurence; Gupta, Samir; Fayad, Joseph; Hung, Adriana; Lichy, Jack; Hurley, Robin; Robey, Brooks; Striker, Robert.

In: JAMA Cardiology, Vol. 3, No. 9, 01.09.2018, p. 849-857.

Research output: Contribution to journalArticle

Cai, T, Zhang, Y, Ho, YL, Link, N, Sun, J, Huang, J, Cai, TA, Damrauer, S, Ahuja, Y, Honerlaw, J, Costa, L, Schubert, P, Hong, C, Gagnon, D, Sun, Y, Sun, YV, Gaziano, JM, Wilson, P, Cho, K, Tsao, P, O'Donnell, CJ, Liao, KP, Gaziano, MJ, Ramoni, R, Breeling, J, Chang, KM, Huang, G, Muralidhar, S, Tsao, PS, Moser, J, Whitbourne, SB, Brewer, JV, Concato, J, Warren, S, Argyres, DP, Stephens, B, Brophy, MT, Humphries, DE, Do, N, Shayan, S, Nguyen, XMT, Pyarajan, S, Hauser, E, Zhao, H, McArdle, R, Dellitalia, L, Harley, J, Whittle, J, Beckham, J, Wells, J, Gutierrez, S, Gibson, G, Kaminsky, L, Villareal, G, Xu, J, Hamner, M, Haddock, KS, Bhushan, S, Iruvanti, P, Godschalk, M, Ballas, Z, Buford, M, Mastorides, S, Klein, J, Ratcliffe, N, Florez, H, Swann, A, Murdoch, M, Sriram, P, Kinlay, S, Yeh, SS, Washburn, R, Jhala, D, Aguayo, S, Cohen, D, Sharma, S, Callaghan, J, Oursler, KA, Whooley, M, Ahuja, S, Gutierrez, A, Schifman, R, Greco, J, Rauchman, M, Servatius, R, Oehlert, M, Wallbom, A, Fernando, R, Morgan, T, Stapley, T, Sherman, S, Anderson, G, Sonel, E, Boyko, E, Meyer, L, Gupta, S, Fayad, J, Hung, A, Lichy, J, Hurley, R, Robey, B & Striker, R 2018, 'Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy: A phenome - Wide association study', JAMA Cardiology, vol. 3, no. 9, pp. 849-857. https://doi.org/10.1001/jamacardio.2018.2287
Cai, Tianxi ; Zhang, Yichi ; Ho, Yuk Lam ; Link, Nicholas ; Sun, Jiehuan ; Huang, Jie ; Cai, Tianrun A. ; Damrauer, Scott ; Ahuja, Yuri ; Honerlaw, Jacqueline ; Costa, Lauren ; Schubert, Petra ; Hong, Chuan ; Gagnon, David ; Sun, Yan ; Sun, Yan V. ; Gaziano, J. Michael ; Wilson, Peter ; Cho, Kelly ; Tsao, Philip ; O'Donnell, Christopher J. ; Liao, Katherine P. ; Gaziano, Michael J. ; Ramoni, Rachel ; Breeling, Jim ; Chang, Kyong Mi ; Huang, Grant ; Muralidhar, Sumitra ; Tsao, Philip S. ; Moser, Jennifer ; Whitbourne, Stacey B. ; Brewer, Jessica V. ; Concato, John ; Warren, Stuart ; Argyres, Dean P. ; Stephens, Brady ; Brophy, Mary T. ; Humphries, Donald E. ; Do, Nhan ; Shayan, Shahpoor ; Nguyen, Xuan Mai T. ; Pyarajan, Saiju ; Hauser, Elizabeth ; Zhao, Hongyu ; McArdle, Rachel ; Dellitalia, Louis ; Harley, John ; Whittle, Jeffrey ; Beckham, Jean ; Wells, John ; Gutierrez, Salvador ; Gibson, Gretchen ; Kaminsky, Laurence ; Villareal, Gerardo ; Xu, Junzhe ; Hamner, Mark ; Haddock, Kathlyn Sue ; Bhushan, Sujata ; Iruvanti, Pran ; Godschalk, Michael ; Ballas, Zuhair ; Buford, Malcolm ; Mastorides, Stephen ; Klein, Jon ; Ratcliffe, Nora ; Florez, Hermes ; Swann, Alan ; Murdoch, Maureen ; Sriram, Peruvemba ; Kinlay, Scott ; Yeh, Shing Shing ; Washburn, Ronald ; Jhala, Darshana ; Aguayo, Samuel ; Cohen, David ; Sharma, Satish ; Callaghan, John ; Oursler, Kris Ann ; Whooley, Mary ; Ahuja, Sunil ; Gutierrez, Amparo ; Schifman, Ronald ; Greco, Jennifer ; Rauchman, Michael ; Servatius, Richard ; Oehlert, Mary ; Wallbom, Agnes ; Fernando, Ronald ; Morgan, Timothy ; Stapley, Todd ; Sherman, Scott ; Anderson, Gwenevere ; Sonel, Elif ; Boyko, Edward ; Meyer, Laurence ; Gupta, Samir ; Fayad, Joseph ; Hung, Adriana ; Lichy, Jack ; Hurley, Robin ; Robey, Brooks ; Striker, Robert. / Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy : A phenome - Wide association study. In: JAMA Cardiology. 2018 ; Vol. 3, No. 9. pp. 849-857.
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title = "Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy: A phenome - Wide association study",
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.",
author = "Tianxi Cai and Yichi Zhang and Ho, {Yuk Lam} and Nicholas Link and Jiehuan Sun and Jie Huang and Cai, {Tianrun A.} and Scott Damrauer and Yuri Ahuja and Jacqueline Honerlaw and Lauren Costa and Petra Schubert and Chuan Hong and David Gagnon and Yan Sun and Sun, {Yan V.} and Gaziano, {J. Michael} and Peter Wilson and Kelly Cho and Philip Tsao and O'Donnell, {Christopher J.} and Liao, {Katherine P.} and Gaziano, {Michael J.} and Rachel Ramoni and Jim Breeling and Chang, {Kyong Mi} and Grant Huang and Sumitra Muralidhar and Tsao, {Philip S.} and Jennifer Moser and Whitbourne, {Stacey B.} and Brewer, {Jessica V.} and John Concato and Stuart Warren and Argyres, {Dean P.} and Brady Stephens and Brophy, {Mary T.} and Humphries, {Donald E.} and Nhan Do and Shahpoor Shayan and Nguyen, {Xuan Mai T.} and Saiju Pyarajan and Elizabeth Hauser and Hongyu Zhao and Rachel McArdle and Louis Dellitalia and John Harley and Jeffrey Whittle and Jean Beckham and John Wells and Salvador Gutierrez and Gretchen Gibson and Laurence Kaminsky and Gerardo Villareal and Junzhe Xu and Mark Hamner and Haddock, {Kathlyn Sue} and Sujata Bhushan and Pran Iruvanti and Michael Godschalk and Zuhair Ballas and Malcolm Buford and Stephen Mastorides and Jon Klein and Nora Ratcliffe and Hermes Florez and Alan Swann and Maureen Murdoch and Peruvemba Sriram and Scott Kinlay and Yeh, {Shing Shing} and Ronald Washburn and Darshana Jhala and Samuel Aguayo and David Cohen and Satish Sharma and John Callaghan and Oursler, {Kris Ann} and Mary Whooley and Sunil Ahuja and Amparo Gutierrez and Ronald Schifman and Jennifer Greco and Michael Rauchman and Richard Servatius and Mary Oehlert and Agnes Wallbom and Ronald Fernando and Timothy Morgan and Todd Stapley and Scott Sherman and Gwenevere Anderson and Elif Sonel and Edward Boyko and Laurence Meyer and Samir Gupta and Joseph Fayad and Adriana Hung and Jack Lichy and Robin Hurley and Brooks Robey and Robert Striker",
year = "2018",
month = "9",
day = "1",
doi = "10.1001/jamacardio.2018.2287",
language = "English (US)",
volume = "3",
pages = "849--857",
journal = "JAMA Cardiology",
issn = "2380-6583",
publisher = "American Medical Association",
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TY - JOUR

T1 - Association of interleukin 6 receptor variant with cardiovascular disease effects of interleukin 6 receptor blocking therapy

T2 - A phenome - Wide association study

AU - Cai, Tianxi

AU - Zhang, Yichi

AU - Ho, Yuk Lam

AU - Link, Nicholas

AU - Sun, Jiehuan

AU - Huang, Jie

AU - Cai, Tianrun A.

AU - Damrauer, Scott

AU - Ahuja, Yuri

AU - Honerlaw, Jacqueline

AU - Costa, Lauren

AU - Schubert, Petra

AU - Hong, Chuan

AU - Gagnon, David

AU - Sun, Yan

AU - Sun, Yan V.

AU - Gaziano, J. Michael

AU - Wilson, Peter

AU - Cho, Kelly

AU - Tsao, Philip

AU - O'Donnell, Christopher J.

AU - Liao, Katherine P.

AU - Gaziano, Michael J.

AU - Ramoni, Rachel

AU - Breeling, Jim

AU - Chang, Kyong Mi

AU - Huang, Grant

AU - Muralidhar, Sumitra

AU - Tsao, Philip S.

AU - Moser, Jennifer

AU - Whitbourne, Stacey B.

AU - Brewer, Jessica V.

AU - Concato, John

AU - Warren, Stuart

AU - Argyres, Dean P.

AU - Stephens, Brady

AU - Brophy, Mary T.

AU - Humphries, Donald E.

AU - Do, Nhan

AU - Shayan, Shahpoor

AU - Nguyen, Xuan Mai T.

AU - Pyarajan, Saiju

AU - Hauser, Elizabeth

AU - Zhao, Hongyu

AU - McArdle, Rachel

AU - Dellitalia, Louis

AU - Harley, John

AU - Whittle, Jeffrey

AU - Beckham, Jean

AU - Wells, John

AU - Gutierrez, Salvador

AU - Gibson, Gretchen

AU - Kaminsky, Laurence

AU - Villareal, Gerardo

AU - Xu, Junzhe

AU - Hamner, Mark

AU - Haddock, Kathlyn Sue

AU - Bhushan, Sujata

AU - Iruvanti, Pran

AU - Godschalk, Michael

AU - Ballas, Zuhair

AU - Buford, Malcolm

AU - Mastorides, Stephen

AU - Klein, Jon

AU - Ratcliffe, Nora

AU - Florez, Hermes

AU - Swann, Alan

AU - Murdoch, Maureen

AU - Sriram, Peruvemba

AU - Kinlay, Scott

AU - Yeh, Shing Shing

AU - Washburn, Ronald

AU - Jhala, Darshana

AU - Aguayo, Samuel

AU - Cohen, David

AU - Sharma, Satish

AU - Callaghan, John

AU - Oursler, Kris Ann

AU - Whooley, Mary

AU - Ahuja, Sunil

AU - Gutierrez, Amparo

AU - Schifman, Ronald

AU - Greco, Jennifer

AU - Rauchman, Michael

AU - Servatius, Richard

AU - Oehlert, Mary

AU - Wallbom, Agnes

AU - Fernando, Ronald

AU - Morgan, Timothy

AU - Stapley, Todd

AU - Sherman, Scott

AU - Anderson, Gwenevere

AU - Sonel, Elif

AU - Boyko, Edward

AU - Meyer, Laurence

AU - Gupta, Samir

AU - Fayad, Joseph

AU - Hung, Adriana

AU - Lichy, Jack

AU - Hurley, Robin

AU - Robey, Brooks

AU - Striker, Robert

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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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JO - JAMA Cardiology

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