Key result
LINC01708 variant linked to ~23% higher risk of congenital left-sided lesions and early-onset AVD.
Why the study?
Congenital heart disease is associated with increased risk of later cardiovascular disease. This study aimed to examine later-onset cardiovascular disease risk in individuals with congenital left-sided lesions and early-onset aortic valve disease and to investigate shared genetic susceptibility with adult cardiovascular phenotypes.
Cohort (n=498,826)
Yes
Congenital left-sided lesions and early-onset aortic valve disease are associated with earlier cardiovascular morbidity and share genetic susceptibility (specifically at the LINC01708 locus) with adult cardiovascular phenotypes such as atrial fibrillation.
Answers are grounded in this paper and cite their sources.
May inform genetic risk models for later CVD in CongHD; leaves open clinical utility pending prospective validation.
Background and aims Congenital heart disease (CongHD) is associated with increased risk of later cardiovascular disease (CVD). We examined later-onset CVD risk among individuals with congenital left-sided lesions (LSL) and early-onset aortic valve disease (AVD) and investigated shared genetic susceptibility between left-sided lesions and adult cardiovascular phenotypes. Methods We studied 500,000 individuals from FinnGen. Clinical analyses evaluated congenital LSL (ICD-10 Q23–Q25) and early-onset AVD (ICD-10 I35 diagnosed <50 years) in relation to risk for atrial fibrillation, hypertension, myocardial infarction and heart failure using Cox proportional hazards models. Genome-wide association analyses for these phenotypes were performed in FinnGen using REGENIE, with replication in the UK Biobank. Associations of lead variants with CVD outcomes in the general population were assessed using Cox models. Results The study included 1,616 individuals with congenital LSL, 1,039 with early-onset AVD, and 496,171 controls in FinnGen. Both groups were associated with earlier cardiovascular morbidity across the studied CVD outcomes. The combined genetic analysis identified two genome-wide significant loci: rs35046143 in LINC01708 (OR 1.23, 95% CI 1.17–1.30), a previously reported cardiovascular locus, and rs9503273 in MYLK4 (OR 0.82, 95% CI 0.76–0.88). The rs35046143 association was replicated in UK Biobank. In the general population, rs35046143 was associated with atrial fibrillation (HR 1.03, 95% CI 1.02–1.05). Conclusion Congenital LSL and early-onset AVD were associated with increased and earlier recorded cardiovascular morbidity. The association of the LINC01708 locus with both CongHD and adult cardiovascular phenotypes in the general population provides evidence compatible with shared genetic susceptibility.
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Selenius et al. (2026) conducted a cohort in Congenital left-sided lesions and early-onset aortic valve disease (n=498,826). Congenital left-sided lesions and early-onset aortic valve disease (and genetic variant rs35046143 in LINC01708) vs. Controls without congenital left-sided lesions or early-onset aortic valve disease was evaluated on Genetic susceptibility to congenital left-sided lesions and early-onset aortic valve disease (lead variant rs35046143 in LINC01708) and cardiovascular morbidity (OR 1.23, 95% CI 1.17-1.30). Congenital LSL and early-onset AVD shared genetic susceptibility via LINC01708 rs35046143, which also increased atrial fibrillation risk.
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