Causal association between genetically predicted circulating immune cell counts and frailty: a two-sample Mendelian randomization study

Xiao-Guang Guo; Ya-Juan Zhang; Ya-Xin Lu; Jia-Mei Lu; Jie Zhang; Hui-Xin Li; Chao-Jin Chen; Jian-Jun Yang

doi:10.3389/fimmu.2024.1336498

Causal association between genetically predicted circulating immune cell counts and frailty: a two-sample Mendelian randomization study

Front Immunol. 2024 Jan 23:15:1336498. doi: 10.3389/fimmu.2024.1336498. eCollection 2024.

Authors

Xiao-Guang Guo¹, Ya-Juan Zhang², Ya-Xin Lu³, Jia-Mei Lu⁴, Jie Zhang¹, Hui-Xin Li¹, Chao-Jin Chen^{3

4}, Jian-Jun Yang¹

Affiliations

¹ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Big Data and Artificial Intelligence Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
⁴ Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Abstract

Background: Despite the recognized link between immune responses and frailty, the association between immune cell counts and frailty based on previous observational studies remains disputed, with uncertain causal nexus. This study aimed to elucidate causal association between genetically predicted circulating immune cell counts and frailty.

Methods: We conducted the two-sample Mendelian randomization (MR) study with independent genetic variants associated with six immune cell subtype counts from genome-wide association studies in 563,946 European individuals. Frailty summary data, assessed via frailty index (FI), was obtained from study comprising 175,226 subjects. Univariate MR, reverse MR and multivariate MR were conducted to comprehensive investigate the association between immune cell counts and FI, with two-step MR analysis for mediation analysis.

Results: Univariate MR evidence indicated that among six leukocyte subtype counts, only elevated eosinophil count was significantly correlated with higher FI (β = 0.059, 95% confidence interval [CI], 0.042-0.078, P=5.63E-11), with no reverse causal relationship identified in reverse MR. In multivariate MR, the causal effect of eosinophil count retained statistical significance (β = 0.063, 95% CI, 0.021-0.104, P = 0.003). Ultimately, the two-step MR analysis demonstrated two mediators in this causal pathway: asthma (β= 0.019, 95% CI, 0.013-0.025, P = 35.84E-10, mediated proportion, 31.732%) and rheumatoid arthritis (β= 0.004, 95% CI, 0.001-0.006, P=1.75E-03, mediated proportion, 6.411%).

Conclusions: Within immune cell subtypes, MR evidence indicated only genetically predicted circulating eosinophil count had irreversible and independent causal effect on frailty, with asthma and rheumatoid arthritis possibly serving as partial mediators. The finding stressed the need for further exploring physiological functions of eosinophils in order to develop effective strategies against frailty.

Keywords: Mendelian randomization; eosinophil count; frailty index; immune cell; inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid*
Asthma*
Frailty*
Genome-Wide Association Study
Humans
Leukocyte Count
Mendelian Randomization Analysis

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. CC received grants from the Natural Science Foundation of Guangdong Province (No. 2022A1515012603), National Natural Science Foundation of China (No.82102297), and the Medjaden Academy & Research Foundation for Young Scientists (No.MJA202306062). JY received grants from the Central Plains Science and Technology Innovation Leading Talent Funding Project (No.2060299).