Association of Heme Oxygenase-1 Promoter Polymorphisms and Plasma Heme Oxygenase-1 Levels with Atrial Septal Defect–Associated Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a serious complication of atrial septal defect driven by oxidative stress and vascular remodelling. Heme oxygenase-1 (HO-1), encoded by the HMOX1 gene, exerts antioxidant and cytoprotective effects, and its expression is influenced by promoter polymorphisms. This study investigated the association of (GT)n repeats, rs2071746, and plasma HO-1 levels with atrial septal defect-pulmonary arterial hypertension (ASD-PAH) in the Javanese population. A total of 101 participants from Dr. Sardjito Hospital, Indonesia, were enrolled, including 51 ASD-PAH and 50 ASD patients non-PAH. Hemodynamic parameters were assessed by echocardiography and right heart catheterization. Plasma HO-1 and endothelin-1 levels were measured using ELISA. HMOX1 polymorphisms were analyzed using PCR-based methods, and associations were evaluated by logistic regression. ASD-PAH patients showed significantly higher pulmonary vascular resistance (8.15 ± 6.36 vs. 4.41 ± 6.72 Wood units; p = 0.0014), mean pulmonary arterial pressure (48.57 ± 16.67 vs. 37.55 ± 19.00 mmHg; p = 0.01), and endothelin-1 levels (p = 0.04). Plasma HO-1 levels did not differ significantly. The L allele of (GT)n repeats increased ASD-PAH risk (OR = 2.04; p = 0.015), while the rs2071746 T allele showed a strong association (OR = 4.61; p < 0.001), with AT+TT genotypes conferring >10-fold risk. Multivariate analysis confirmed that the S allele and higher HO-1 levels reduced ASD-PAH risk. HMOX1 polymorphisms and HO-1 expression influenced ASD-PAH susceptibility. The S allele and elevated HO-1 are protective, while the L and T alleles increase disease risk, supporting their potential as complementary biomarkers.