Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-04-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-54063-3 |
| _version_ | 1797219778631303168 |
|---|---|
| author | 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 VA Million Veteran Program J. Michael Gaziano Seoyoung C. Kim Yuk-Lam Ho Kelly Cho Tianxi Cai Katherine P. Liao |
| author_facet | 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 VA Million Veteran Program J. Michael Gaziano Seoyoung C. Kim Yuk-Lam Ho Kelly Cho Tianxi Cai Katherine P. Liao |
| author_sort | Xuan Wang |
| collection | DOAJ |
| description | Abstract 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 × 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. |
| first_indexed | 2024-04-24T12:39:03Z |
| format | Article |
| id | doaj.art-1870bafdb1b84d8393259bd11cb9e9bb |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T12:39:03Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1870bafdb1b84d8393259bd11cb9e9bb2024-04-07T11:17:53ZengNature PortfolioScientific Reports2045-23222024-04-0114111210.1038/s41598-024-54063-3Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapyXuan Wang0Molei Liu1Isabelle-Emmanuella Nogues2Tony Chen3Xin Xiong4Clara-Lea Bonzel5Harrison Zhang6Chuan Hong7Yin Xia8Kumar Dahal9Lauren Costa10Jing Cui11VA Million Veteran ProgramJ. Michael Gaziano12Seoyoung C. Kim13Yuk-Lam Ho14Kelly Cho15Tianxi Cai16Katherine P. Liao17Department of Population Health Sciences, University of UtahDepartment of Biostatistics, Mailman School of Public Health, Columbia UniversityDepartment of Biostatistics, Harvard T.H. Chan School of Public HealthDepartment of Biostatistics, Harvard T.H. Chan School of Public HealthDepartment of Biostatistics, Harvard T.H. Chan School of Public HealthDepartment of Biostatistics, Harvard T.H. Chan School of Public HealthDepartment of Biomedical Informatics, Harvard Medical SchoolDepartment of Biostatistics, Duke UniversityDepartment of Statistics and Data Science, Fudan UniversityDepartment of Biostatistics, Duke UniversityMassachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare SystemDepartment of Biostatistics, Duke UniversityMassachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare SystemDivision of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s HospitalMassachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare SystemMassachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare SystemDepartment of Biostatistics, Harvard T.H. Chan School of Public HealthDepartment of Biomedical Informatics, Harvard Medical SchoolAbstract 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 × 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.https://doi.org/10.1038/s41598-024-54063-3 |
| spellingShingle | 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 VA Million Veteran Program J. Michael Gaziano Seoyoung C. Kim Yuk-Lam Ho Kelly Cho Tianxi Cai Katherine P. Liao Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy Scientific Reports |
| title | Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy |
| title_full | Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy |
| title_fullStr | Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy |
| title_full_unstemmed | Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy |
| title_short | Heterogeneous associations between interleukin-6 receptor variants and phenotypes across ancestries and implications for therapy |
| title_sort | heterogeneous associations between interleukin 6 receptor variants and phenotypes across ancestries and implications for therapy |
| url | https://doi.org/10.1038/s41598-024-54063-3 |
| work_keys_str_mv | AT xuanwang heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT moleiliu heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT isabelleemmanuellanogues heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT tonychen heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT xinxiong heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT claraleabonzel heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT harrisonzhang heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT chuanhong heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT yinxia heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT kumardahal heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT laurencosta heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT jingcui heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT vamillionveteranprogram heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT jmichaelgaziano heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT seoyoungckim heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT yuklamho heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT kellycho heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT tianxicai heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy AT katherinepliao heterogeneousassociationsbetweeninterleukin6receptorvariantsandphenotypesacrossancestriesandimplicationsfortherapy |