Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy

Xuan Wang; Molei Liu; Isabelle-Emmanuella Nogues; Tony Chen; Xin Xiong; Clara-Lea Bonzel; Harrison Zhang; Chuan Hong; Yin Xia; Kumar Dahal; Lauren Costa; Jing Cui; J. Michael Gaziano; Seoyoung C. Kim; Yuk-Lam Ho; Kelly Cho; Tianxi Cai; Katherine P. Liao; Sumitra Muralidhar; Jennifer Moser; Jennifer E. Deen; Philip S. Tsao; Elizabeth Hauser; Amy Kilbourne; Shiuh-Wen Luoh; Michael Matheny; Dave Oslin; Lori Churby; Stacey B. Whitbourne; Jessica V. Brewer; Shahpoor Shayan; Luis E. Selva; Saiju Pyarajan; Scott L. DuVall; Mary T. Brophy; Brady Stephens; Todd Connor; Themistocles L. Assimes; Adriana Hung; Henry Kranzler; Samuel Aguayo; Sunil Ahuja; Kathrina Alexander; Xiao M. Androulakis; Prakash Balasubramanian; Zuhair Ballas; Jean Beckham; Sujata Bhushan; Edward Boyko; David Cohen; Louis Dellitalia; L. Christine Faulk; Joseph Fayad; Daryl Fujii; Saib Gappy; Frank Gesek; Jennifer Greco; Michael Godschalk; Todd W. Gress; Samir Gupta; Salvador Gutierrez; John Harley; Kimberly Hammer; Mark Hamner; Robin Hurley; Pran Iruvanti; Frank Jacono; Darshana Jhala; Scott Kinlay; Jon Klein; Michael Landry; Peter Liang; Suthat Liangpunsakul; Jack Lichy; C. Scott Mahan; Ronnie Marrache; Stephen Mastorides; Elisabeth Mates; Kristin Mattocks; Paul Meyer; Jonathan Moorman; Timothy Morgan; Maureen Murdoch; James Norton; Olaoluwa Okusaga; Kris Ann Oursler; Ana Palacio; Samuel Poon; Emily Potter; Michael Rauchman; Richard Servatius; Satish Sharma; River Smith; Peruvemba Sriram; Patrick Strollo; VA Million Vet Program

doi:10.1038/s41598-024-54063-3

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Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy

Journal article

Peer reviewed

Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy

Xuan Wang, Molei Liu, Isabelle-Emmanuella Nogues, Tony Chen, Xin Xiong, Clara-Lea Bonzel, Harrison Zhang, Chuan Hong, Yin Xia, Kumar Dahal, …

Scientific reports, Vol.14(1), pp.8021-12

2024-04-05

DOI: https://doi.org/10.1038/s41598-024-54063-3

PMID: 38580710

Appears in Miller School of Medicine - Latest Publications

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 x 10-3), and higher white blood cell count (p-value for heterogeneity = 8.5 x 10-131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype-phenotype screens in diverse populations.

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Title: Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy
Creators: Xuan Wang - University of Utah
Molei Liu - Columbia University
Isabelle-Emmanuella Nogues - Harvard University
Tony Chen - Supreme Council Of Health
Xin Xiong - Harvard University
Clara-Lea Bonzel - Harvard University
Harrison Zhang - Harvard University
Chuan Hong - Duke University
Yin Xia - Fudan University
Kumar Dahal - Duke University
Lauren Costa - VA Boston Healthcare System
Jing Cui - Duke University
J. Michael Gaziano - Brigham and Women's Hospital
Seoyoung C. Kim - Brigham and Women's Hospital
Yuk-Lam Ho - VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA 02130 USA
Kelly Cho - Brigham and Women's Hospital
Tianxi Cai - Harvard University
Katherine P. Liao - VA Boston Healthcare System
Sumitra Muralidhar - United States Department of Veterans Affairs
Jennifer Moser - Sioux Falls VA Health Care System
Jennifer E. Deen - VA Salt Lake City Healthcare System
Philip S. Tsao - VA Palo Alto Health Care System
J. Michael Gaziano - Brigham and Women's Hospital
Elizabeth Hauser - Durham VA Medical Center
Amy Kilbourne - Health Services Research & Development
Shiuh-Wen Luoh - VA Portland Hlth Care Syst, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA
Michael Matheny - VA Tennessee Valley Healthcare System
Dave Oslin - Philadelphia VA Medical Center
Lori Churby - The Coordinating Center
Stacey B. Whitbourne - VA Salt Lake City Healthcare System
Jessica V. Brewer - VA Salt Lake City Healthcare System
Shahpoor Shayan - VA Boston Healthcare System
Luis E. Selva - VA Boston Healthcare System
Saiju Pyarajan - VA Palo Alto Health Care System
Kelly Cho - Brigham and Women's Hospital
Scott L. DuVall - VA Salt Lake City Healthcare System
Mary T. Brophy - The Huntington Library, Art Museum, and Botanical Gardens
J. Michael Gaziano - Brigham and Women's Hospital
Philip S. Tsao - VA Palo Alto Health Care System
Brady Stephens - Canandaigua VA Medical Center
Todd Connor - Clin Res Pharm Coordinating Ctr, Cooperat Studies Program, Albuquerque, NM USA
Themistocles L. Assimes - VA Salt Lake City Healthcare System
Adriana Hung - VA Tennessee Valley Healthcare System
Henry Kranzler - Philadelphia VA Medical Center
Samuel Aguayo - Phoenix VA Health Care System
Sunil Ahuja - South Texas Veterans Health Care System
Kathrina Alexander - Veterans Health Care System of the Ozarks
Xiao M. Androulakis - Columbia VA Health Care System
Prakash Balasubramanian - William S. Middleton Memorial Veterans Hospital
Zuhair Ballas - Iowa City VA Health Care System
Jean Beckham - Durham VA Medical Center
Sujata Bhushan - VA North Texas Health Care System
Edward Boyko - VA Puget Sound Health Care System
David Cohen - Portland VA Medical Center
Louis Dellitalia - College Station Medical Center
L. Christine Faulk - Robert J. Dole VA Medical Center
Joseph Fayad - VA Southern Nevada Healthcare System
Daryl Fujii - VA Pacific Islands Health Care System
Saib Gappy - John D. Dingell VA Medical Center
Frank Gesek - White River Junction VA Medical Center
Jennifer Greco - Sioux Falls VA Health Care System
Michael Godschalk - Hunter Holmes McGuire VA Medical Center
Todd W. Gress - Hershel Woody Williams VA Medical Center
Samir Gupta - VA San Diego Healthcare System
Salvador Gutierrez - Edward Hines, Jr. VA Hospital
John Harley - Cincinnati VA Medical Center
Kimberly Hammer - Fargo VA Health Care System
Mark Hamner - Ralph H. Johnson VA Medical Center
Adriana Hung - VA Tennessee Valley Healthcare System
Robin Hurley - W. G. (Bill) Hefner VA Medical Center
Pran Iruvanti - Hampton VA Medical Center
Frank Jacono - VA Northeast Ohio Healthcare System
Darshana Jhala - Philadelphia VA Medical Center
Scott Kinlay - VA Boston Healthcare System
Jon Klein - Louisville VA Medical Center
Michael Landry - Southeast Louisiana Veterans Health Care System
Peter Liang - VA NY Harbor Healthcare System
Suthat Liangpunsakul - Indiana University – Purdue University Indianapolis
Jack Lichy - Washington DC VA Medical Center
C. Scott Mahan - Charles George VA Medical Center
Ronnie Marrache - MaineHealth
Stephen Mastorides - James A. Haley Veterans' Hospital
Elisabeth Mates - VA Sierra Nevada Health Care System
Kristin Mattocks - VA Central Western Massachusetts Healthcare System
Paul Meyer - Southern Arizona VA Health Care System
Jonathan Moorman - James H. Quillen VA Medical Center
Timothy Morgan - VA Long Beach Healthcare System
Maureen Murdoch - Minneapolis VA Health Care System
James Norton - New York/New Jersey VA Health Care Network
Olaoluwa Okusaga - Michael E. DeBakey VA Medical Center
Kris Ann Oursler - Salem VA Medical Center
Ana Palacio - Miami VA Healthcare System
Samuel Poon - Manchester VA Medical Center
Emily Potter - VA Eastern Kansas Health Care System
Michael Rauchman - VA St. Louis Health Care System
Richard Servatius - Syracuse VA Medical Center
Satish Sharma - Providence VA Medical Center
River Smith - Eastern Oklahoma VA Health Care System
Peruvemba Sriram - North Florida/South Georgia Veterans Health System
Patrick Strollo - VA Pittsburgh Healthcare System
VA Million Vet Program
Publication Details: Scientific reports, Vol.14(1), pp.8021-12
Publisher: NATURE PORTFOLIO
Number of pages: 12
Grant note: P30 AR072577 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA US Veterans' Health Administration Million Veterans Program
Academic Unit: Miller School of Medicine; UMMG Department of Medicine; UMMG Department of Public Health Sciences Research
Language: English
Resource Type: Journal article
PMID: 38580710
Record Identifier: 991032796207302976