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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 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC10997791 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Wang Xuan X Liu Molei M Nogues Isabelle-Emmanuella IE Chen Tony T Xiong Xin X Bonzel Clara-Lea CL Zhang Harrison H Hong Chuan C Xia Yin Y Dahal Kumar K Costa Lauren L Cui Jing J Gaziano J Michael JM Kim Seoyoung C SC Ho Yuk-Lam YL Cho Kelly K Cai Tianxi T Liao Katherine P KP

Scientific reports 20240405 1

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 develope ...[more]

PMID: 38580710

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Project description:BackgroundEvidence suggests a complex interplay between infections and allergic diseases.ObjectiveTo explore the association of 14 common viruses with eczema, asthma, and rhinoconjunctivitis in childhood.MethodsWe used cross-sectional (n = 686) and prospective (n = 440) data from children participating in the Rhea birth cohort. Immunoglobulin G to polyomaviruses (BK polyomavirus, JC polyomavirus, KI polyomavirus [KIPyV], WU polyomavirus [WUPyV], human polyomavirus 6, human polyomavirus 7, Trichodysplasia spinulosa polyomavirus, Merkel cell polyomavirus, human polyomavirus 9, and human polyomavirus 10) and herpesviruses (Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus-1, Herpes simplex virus-2) were measured at age 4 years by fluorescent bead-based multiplex serology. Definitions of eczema, asthma, and rhinoconjunctivitis at ages 4 and 6 years were based on questionnaires. Mediation of the associations by immune biomarkers was tested.ResultsLess likely to have eczema at age 4 years were KIPyV-seropositive (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.27-0.82) and human polyomavirus 6 (OR, 0.44; 95% CI, 0.26-0.73) compared with their seronegative counterparts. Seropositivity to Epstein-Barr virus was negatively associated with eczema at age 4 years (OR, 0.39; 95% CI, 0.22-0.67) and 6 years (OR, 0.50; 95% CI, 0.25-0.99). Children with a higher burden of herpesviruses or of skin polyomaviruses had the lowest odds of eczema at age 4 years. Higher odds for asthma at age 4 years were found for WUPyV-seropositive children (OR, 3.98; 95% CI, 1.38-11.51), and for children seropositive to both respiratory polyomaviruses (KIPyV and WUPyV) (OR, 7.35; 95% CI, 1.66-32.59) compared with children seronegative to both. No associations were observed for rhinoconjunctivitis. There was no evidence of mediation by immune biomarkers.ConclusionA heterogeneous pattern of infections and allergic diseases was observed with common infections associated with a decreased eczema risk and an increased asthma risk in children.

Dataset Information

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

Publications

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

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