Differential Associations of Interleukin 6 Receptor Variant Across Genetic Ancestries and Implications for Targeted Therapies

Abstract

Genomic data are increasingly incorporated into high-throughput approaches such as the Phenome-Wide Association Study (PheWAS) to query potential effects of targeted therapies. Genetic variants, such as the interleukin-6 receptor (IL6R) genetic variant rs2228145 (Asp358Ala), have been identified with a downstream effect similar to the drug, e.g., tocilizumab which targets IL6R, and can be used to screen for potential protective or harmful signal across a broad range of traits in large biobanks with linked genomic and clinical data. To date, there are limited approaches to determine whether these effects may differ across diverse populations to inform potential differential drug effects especially in populations under-represented in clinical trials. In this study, we developed and applied an approach to detect heterogeneous associations, using the IL6R variant as an example, in African vs European ancestry. We identified a total of 29 traits with a differential association between the IL6R variant, with notable differences including a lower risk of type 2 diabetes in AFR vs EUR, and a higher white blood cell count. With the increasing use of targeted blockade of the IL6 pathway in conditions ranging from rheumatologic to cardiovascular conditions, the findings from this study can inform ongoing studies targeting IL6; general approach to test for heterogeneity of associations can be applied broadly to any PheWAS.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

NIH P30 AR072577

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB of VA Boston healthcare center gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors

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