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

Küçük, Uğur; Akşit, Ercan

doi:10.1590/1806-9282.20260404

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Original Article • Rev. Assoc. Med. Bras. 72 (8) • 2026 • https://doi.org/10.1590/1806-9282.20260404 linkcopy

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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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.

KEYWORDS:
HLA-DQ2; HLA-DQ8; Atrial remodeling; Inflammation; Genetic susceptibility

Variable		Heart failure group (n=50)	Control group (n=50)	p-value
Age (years)		62.2±15.0	59.7±13.6	0.375
Male sex, n (%)		36 (72.0%)	28 (56.0%)	0.145
BMI (kg/m²)		28.10±1.32	27.68±1.87	0.198
Echocardiographic data
	LVEF (%)	28.3±8.0	57.7±5.5	<0.001
	LVEDV (mL)	135.12±8.15	88.37±3.26	<0.001
	LVESV (mL)	91.68±3.18	61.3±4.1	<0.001
	LA (mm)	38.2±4.1	33.2±2.8	<0.001
	LAVi (mL/m²)	38.4±2.3	29.8±2.7	<0.001
	Heart rate (bpm)	83.4±12.2	81.2±11.8	0.362
	Systolic BP (mmHg)	119.4±20.5	125.6±12.9	0.076
	Diastolic BP (mmHg)	72.4±8.2	72.8±8.3	0.837
	HLA-DQ2/DQ8 positivity, n (%)	20 (40.0%)	23 (46.0%)	0.686
	Incident atrial fibrillation, n (%)	8 (16.0%)	1 (2.0%)	0.031

Group	AF (+) n (%)	AF (-) n (%)	Total (n)	p-value*
HF+HLA-DQ2/DQ8 positive	8 (40.0%)	12 (60.0%)	20	0.0002
HF+HLA-DQ2/DQ8 negative	0 (0.0%)	30 (100.0%)	30	Reference
Total HF cohort	8 (16.0%)	42 (84.0%)	50	-
Control group	1 (2.0%)	49 (98.0%)	50	0.0309

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[TFN1] BMI: body mass index; LVEF: left ventricular ejection fraction; LVEDV: left ventricular end-diastolic volume; LVESV: left ventricular end-systolic volume; LA: left atrium; LAVi: left atrial volume index; BP: blood pressure; HLA: human leukocyte antigen.