The bidirectional genetic causality between immunocyte phenotypes and dilated cardiomyopathy: A bidirectional Mendelian randomization study

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Dilated cardiomyopathy (n=359138). Intervention: Immunocyte phenotypes (CD28 on secreting regulatory T cells) vs. Genetic predisposition to lower levels. Primary outcome: Risk of dilated cardiomyopathy (OR 0.928, 95% CI 0.872-0.988, p=<.05).

Q: What does this research mean for the field?

Specific immunocyte phenotypes exhibit a bidirectional causal relationship with dilated cardiomyopathy, with genetically predicted levels of 14 phenotypes increasing risk and 15 conferring protection. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Wenshuai Feng; Xindi Chang; Qiaozhi Li; Zhengwei Dong; Ge Jin; Jinyu Huang; Genhao Fan; 邢作英; Yongxia Wang

doi:10.1097/md.0000000000049691

July 17, 2026MedicineOpen Access

The bidirectional genetic causality between immunocyte phenotypes and dilated cardiomyopathy: A bidirectional Mendelian randomization study

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Key result

Genetically predicted higher levels of CD28 on secreting regulatory T cells were associated with a reduced risk of dilated cardiomyopathy (OR 0.928), with a reciprocal effect observed.

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Why the study?

Although the link between immunocyte phenotypes and DCM has been explored, the exact pathogenesis of the relationship remains unclear.

Do genetically predicted immunocyte phenotypes causally affect the risk of dilated cardiomyopathy, and vice versa?

Key Points

To validate and clarify the bidirectional causal relationship between 731 immunocyte phenotypes and dilated cardiomyopathy (DCM) using genetic instrumental variables.
Conducted a bidirectional two-sample Mendelian randomization study using genome-wide association study summary statistics from European individuals, including 1444 DCM cases, 353,937 controls, and 3757 adults assessed for 731 immunocyte phenotypes.
Evaluated causal estimates using inverse variance weighted (IVW), MR-Egger regression, weighted median estimator, weighted mode, and simple mode, alongside Cochran Q, MR-Egger intercept, MR-PRESSO, and leave-one-out sensitivity analyses.
Forward IVW analysis identified 14 immunocyte phenotypes that increased DCM risk (P < .05, OR > 1; e.g., IgD− CD38dim AC: OR = 1.156, 95% CI = 1.034–1.294) and 15 phenotypes conferring protection against DCM (P < .05, OR < 1; e.g., naive DN AC: OR = 0.861, 95% CI = 0.767–0.966).
Reverse IVW analysis demonstrated that DCM development causally increased levels of 17 immunocyte phenotypes (P < .05, OR > 1; e.g., CD11b on basophils: OR = 1.157, 95% CI = 1.031–1.297) and decreased levels of 9 phenotypes (P < .05, OR < 1; e.g., CD28 on secreting Treg: OR = 0.881, 95% CI = 0.810–0.958).
CD28 on secreting regulatory T cells exhibited a reciprocal protective relationship, mitigating DCM risk (OR = 0.928, 95% CI = 0.872–0.988), while DCM progression conversely reduced CD28 expression on secreting Tregs (OR = 0.881, 95% CI = 0.810–0.958).

Study Design

Type

Observational (n=359,138)

Structured PICO

Do genetically predicted immunocyte phenotypes causally affect the risk of dilated cardiomyopathy, and vice versa?

P

Population

A Mendelian randomization study utilizing GWAS summary statistics from over 350,000 individuals to assess the bidirectional causal relationship between 731 immunocyte phenotypes and dilated cardiomyopathy.

E

Exposure

Genetically predicted levels of 731 immunocyte phenotypes (forward Mendelian randomization) and genetically predicted dilated cardiomyopathy (reverse Mendelian randomization)

O

Outcome

Risk of dilated cardiomyopathy (forward MR) and levels of immunocyte phenotypes (reverse MR)

Main Result

Odds Ratio: 0.928 (95% CI 0.872–0.988)

p-value: p=<.05

Limitations

Multiple statistical tests with reliance on nominal significance threshold (P < .05) increasing Type I error risk.
Potential residual unmeasured horizontal pleiotropy.
MR reflects lifelong genetic predisposition rather than direct biological causality.
Limited number of instrumental SNPs available for DCM in reverse MR analysis.
GWAS datasets restricted to European and East Asian populations.
Small sample sizes of some original GWAS cohorts.
Lack of validation from in vivo or in vitro functional experiments.
Limited overall sample size and statistical power of East Asian subsets compared with European cohorts
False discovery rate correction was not adopted as the primary threshold

Implication

This bidirectional Mendelian randomization study provides genetic evidence for a reciprocal causal relationship between specific immunocyte phenotypes and dilated cardiomyopathy.

Abstract

The association between immunocyte phenotypes and dilated cardiomyopathy (DCM) has been explored, however the exact pathogenesis of the relationship between immune cells and DCM is unclear. This bidirectional two-sample Mendelian randomization (MR) research aims to further validate the causal link between 731 immunocyte phenotypes and DCM. Summary statistics from a genome-wide association study data of individuals with European ancestry were utilized, including 1444 DCM cases and 353,937 controls, as well as 3757 European adults for the 731 immunocyte phenotypes. Causal effects were estimated using inverse variance weighted, MR-Egger regression, weight median estimator, weighted mode, and simple mode. Sensitivity analysis was conducted to confirm data robustness and feasibility. Based on the inverse variance weighted findings, 14 immunocyte phenotypes were risk factors for DCM ( P < .05, odds ratio [OR] > 1), while 15 immunocyte phenotypes exhibited a protective effect on DCM ( P < .05, OR < 1). The results of reverse MR analysis suggested evidence that DCM occurrence might elevate the levels of 17 immunocyte phenotypes ( P < .05, OR > 1) and decrease the levels of 9 immunocyte phenotypes ( P < .05, OR < 1). Our research indicated that CD28 on secreting regulatory T cell could mitigate the occurrence of DCM, and reciprocally, the progression of DCM could reduce the level of CD28 on secreting regulatory T cell. This study confirmed the bidirectional genetic predictive relationship between immunocyte phenotypes and DCM, underscoring the complex interplay between DCM and the immune system.

Discussion

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Cite This Study

Feng et al. (2026) conducted an observational in Dilated cardiomyopathy (n=359,138). Immunocyte phenotypes (CD28 on secreting regulatory T cells) vs. Genetic predisposition to lower levels was evaluated on Risk of dilated cardiomyopathy (OR 0.928, 95% CI 0.872-0.988, p=<.05). Genetically predicted higher levels of CD28 on secreting regulatory T cells were associated with a reduced risk of dilated cardiomyopathy (OR 0.928), with a reciprocal effect observed.

synapsesocial.com/papers/6a5b39118167787360d24f2c https://doi.org/10.1097/md.0000000000049691

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The bidirectional genetic causality between immunocyte phenotypes and dilated cardiomyopathy: A bidirectional Mendelian randomization study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

The bidirectional genetic causality between immunocyte phenotypes and dilated cardiomyopathy: A bidirectional Mendelian randomization study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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