Association between human leukocyte antigen-DQ2/DQ8 positivity and incident atrial fibrillation in patients with heart failure with reduced ejection fraction

Q: What are the key findings of this study?

HLA-DQ2/DQ8 positivity in patients with heart failure with reduced ejection fraction was associated with a markedly increased risk of incident atrial fibrillation (OR 41.48).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Heart failure with reduced ejection fraction (HFrEF) (n=100). Intervention: HLA-DQ2/DQ8 positivity vs. HLA-DQ2/DQ8 negativity. Primary outcome: Incident atrial fibrillation (OR 41.48, 95% CI 2.22-774.64, p=0.0002).

Q: What does this research mean for the field?

HLA-DQ2/DQ8 positivity in patients with heart failure with reduced ejection fraction is strongly associated with a markedly increased risk of incident atrial fibrillation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Uğur Küçük; Ercan Akşıt

doi:10.1590/1806-9282.20260404

January 1, 2026Revista da Associação Médica BrasileiraOpen Access

Association between human leukocyte antigen-DQ2/DQ8 positivity and incident atrial fibrillation in patients with heart failure with reduced ejection fraction

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Key result

HLA-DQ2/DQ8 positivity linked to ~41.5-fold higher odds of incident AF in HFrEF.

OR 41.48
95% CI 2.22-774.64
P=0.0002
n=100

Figures

Why the study?

Human leukocyte antigen-DQ2 and DQ8 alleles are established markers of immune-genetic dysregulation and chronic inflammation, but their association with incident atrial fibrillation in HFrEF patients was unclear.

Does HLA-DQ2/DQ8 positivity increase the risk of incident atrial fibrillation in patients with heart failure with reduced ejection fraction?

Key Points

To investigate whether human leukocyte antigen (HLA)-DQ2 and HLA-DQ8 allele positivity is associated with incident atrial fibrillation in patients with heart failure with reduced ejection fraction.
Retrospectively analyzed a prospectively followed cohort of 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction <40%) and 50 age- and sex-matched controls.
Screened participants for HLA-DQ2/DQ8 alleles, confirmed sinus rhythm at baseline, and followed patients for up to 24 months with regular outpatient visits every 3–6 months and 12-lead electrocardiograms.
Incident atrial fibrillation occurred in 16% (n=8) of the heart failure group compared to 2% (n=1) of the control group (p=0.031).
Within the heart failure cohort, all 8 incident atrial fibrillation cases occurred exclusively among HLA-DQ2/DQ8-positive patients (40.0% vs. 0.0% in HLA-negative patients, p=0.0002; p=0.031 in abstract).
HLA positivity in heart failure patients was associated with an increased risk of incident atrial fibrillation with a corrected odds ratio of 41.48 (95% CI 2.22–774.64) after applying the Haldane-Anscombe correction.

Study Design

Type

Cohort (n=100)

Multicenter

No

Structured PICO

Does HLA-DQ2/DQ8 positivity increase the risk of incident atrial fibrillation in patients with heart failure with reduced ejection fraction?

P

Population

100 adults (mean age 61, 36% female), comprising 50 patients with heart failure with reduced ejection fraction and 50 matched healthy controls, all in sinus rhythm at baseline, followed for 24 months.

E

Exposure

Human leukocyte antigen (HLA)-DQ2/DQ8 allele positivity (exposure)

C

Comparator

Human leukocyte antigen (HLA)-DQ2/DQ8 allele negativity (unexposed)

O

Outcome

Incident atrial fibrillation (first documented episode by 12-lead ECG, ≥30 s on Holter/telemetry, or device-detected) over 24-month follow-uphard clinical

Main Result

Odds Ratio: 41.48 (95% CI 2.22–774.64)

Absolute Event Rate: 40% vs 0%

p-value: p=0.0002

HLA-DQ2/DQ8 allele positivity identifies a subset of HFrEF patients with a markedly increased risk of incident atrial fibrillation, suggesting a significant role for immune-genetic susceptibility in atrial arrhythmogenesis.

Limitations

Single-center, small-sample design yielding low statistical power.
Selection bias due to requiring prior clinical indications for HLA testing.
Standard rhythm monitoring without continuous ambulatory monitoring may underestimate short or asymptomatic AF episodes.
Unmeasured confounders such as undiagnosed obstructive sleep apnea, dynamic inflammation, and autonomic imbalance could not be excluded.
Single-time HLA assessment misses potential dynamic immune changes over time.
Single-center, small-sample design yielding low statistical power
Selection bias due to requiring prior HLA testing for clinical indications
Standard rhythm monitoring may underestimate short or asymptomatic AF episodes
Unmeasured confounders like undiagnosed OSAS or dynamic inflammation
Single-time HLA assessment missing potential dynamic immune changes

Implication

HLA-DQ2/DQ8 positivity should not yet guide AF screening in HFrEF; hypothesis-generating for immune-genetic susceptibility and needs prospective validation.

Abstract

OBJECTIVE: Genetic susceptibility is increasingly recognized in cardiac arrhythmias. human leukocyte antigen-DQ2 and human leukocyte antigen-DQ8 alleles are established markers of immune-genetic dysregulation and chronic inflammation. This study investigated the association between human leukocyte antigen-DQ2/DQ8 positivity and incident atrial fibrillation in patients with heart failure with reduced ejection fraction. METHODS: This study was based on a prospectively followed cohort; the present retrospective analysis evaluated 50 heart failure with reduced ejection fraction patients (left ventricular ejection fraction <40%) and 50 age- and sex-matched controls. Participants were screened for human leukocyte antigen-DQ2/DQ8 alleles. All subjects were in sinus rhythm at baseline and followed for 24 months for the primary endpoint of incident atrial fibrillation. RESULTS: Incident atrial fibrillation occurred in 16% (n=8) of the heart failure with reduced ejection fraction group and 2% (n=1) of the control group. Among heart failure with reduced ejection fraction patients, human leukocyte antigen-positive status (positivity for DQ2 and/or DQ8) was found in 20 patients. Interestingly, all eight incident atrial fibrillation cases in the heart failure with reduced ejection fraction group occurred within the human leukocyte antigen-positive subgroup (40 vs. 0% in human leukocyte antigen-negative heart failure with reduced ejection fraction, p=0.031). human leukocyte antigen-positive heart failure with reduced ejection fraction patients exhibited a significantly higher atrial fibrillation risk compared to human leukocyte antigen-positive controls (p=0.0069), suggesting that structural heart disease and genetic predisposition synergistically increase arrhythmic risk. CONCLUSION: Human leukocyte antigen-DQ2/DQ8 positivity is significantly associated with incident atrial fibrillation in heart failure with reduced ejection fraction patients. These findings suggest human leukocyte antigen-related immune-genetic susceptibility contributes to atrial electrical vulnerability, positioning human leukocyte antigen typing as a potential novel biomarker for arrhythmic risk stratification in heart failure.

Discussion

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Cite This Study

Küçük et al. (2026) conducted a cohort in Heart failure with reduced ejection fraction (HFrEF) (n=100). HLA-DQ2/DQ8 positivity vs. HLA-DQ2/DQ8 negativity was evaluated on Incident atrial fibrillation (OR 41.48, 95% CI 2.22-774.64, p=0.0002). HLA-DQ2/DQ8 positivity in patients with heart failure with reduced ejection fraction was associated with a markedly increased risk of incident atrial fibrillation (OR 41.48).

synapsesocial.com/papers/6ad0fcc53afa093ea9acff83 https://doi.org/10.1590/1806-9282.20260404

Topics

HFrEF treatment

Atrial fibrillation

Persistent AF management

Heart failure

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Association between human leukocyte antigen-DQ2/DQ8 positivity and incident atrial fibrillation in patients with heart failure with reduced ejection fraction

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Topics

Association between human leukocyte antigen-DQ2/DQ8 positivity and incident atrial fibrillation in patients with heart failure with reduced ejection fraction

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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