Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy
Authors: Wang Xuan , Liu Molei , Nogues Isabelle-Emmanuella , Chen Tony , Xiong Xin , Bonzel Clara-Lea , Zhang Harrison , Hong Chuan , Xia Yin , Dahal Kumar , Costa Lauren , Cui Jing ,   VA Million Veteran Program,   MVP Program Office, Muralidhar Sumitra , Moser Jennifer , Deen Jennifer E. ,   MVP Executive Committee, Tsao Philip S. , Muralidhar Sumitra , Gaziano J. Michael , Hauser Elizabeth , Kilbourne Amy , Luoh Shiuh-Wen , Matheny Michael , Oslin Dave ,   MVP Co-Principal Investigators, Gaziano J. Michael , Tsao Philip S. ,   MVP Core Operations, Churby Lori , Whitbourne Stacey B. , Brewer Jessica V. , Shayan Shahpoor , Selva Luis E. , Pyarajan Saiju , Cho Kelly , DuVall Scott L. , Brophy Mary T. ,   MVP Coordinating Centers, Gaziano J. Michael , Tsao Philip S. , Stephens Brady , Connor Todd ,   MVP Publications and Presentations Committee, Assimes Themistocles L. , Hung Adriana , Kranzler Henry ,   MVP Local Site Investigators, Aguayo Samuel , Ahuja Sunil , Alexander Kathrina , Androulakis Xiao M. , Balasubramanian Prakash , Ballas Zuhair , Beckham Jean , Bhushan Sujata , Boyko Edward , Cohen David , Dellitalia Louis , Faulk L. Christine , Fayad Joseph , Fujii Daryl , Gappy Saib , Gesek Frank , Greco Jennifer , Godschalk Michael , Gress Todd W. , Gupta Samir , Gutierrez Salvador , Harley John , Hammer Kimberly , Hamner Mark , Hung Adriana , Hurley Robin , Iruvanti Pran , Jacono Frank , Jhala Darshana , Kinlay Scott , Klein Jon , Landry Michael , Liang Peter , Liangpunsakul Suthat , Lichy Jack , Mahan C. Scott , Marrache Ronnie , Mastorides Stephen , Mates Elisabeth , Mattocks Kristin , Meyer Paul , Moorman Jonathan , Morgan Timothy , Murdoch Maureen , Norton James , Okusaga Olaoluwa , Oursler Kris Ann , Palacio Ana , Poon Samuel , Potter Emily , Rauchman Michael , Servatius Richard , Sharma Satish , Smith River , Sriram Peruvemba , Strollo Patrick , Tandon Neeraj , Tsao Philip , Villareal Gerardo , Wallbom Agnes , Walsh Jessica , Wells John , Whittle Jeffrey , Whooley Mary , Williams Allison E. , Wilson Peter , Xu Junzhe , Yeh Shing Shing , Gaziano J. Michael , Kim Seoyoung C. , Ho Yuk-Lam , Cho Kelly , Cai Tianxi , Liao Katherine P. 
Published: April 2024

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g.,IL6Rvariant 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 anIL6RPheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences inIL6Rvariant-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 × 10–3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 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.