Background The purpose of this study was to investigate genetic risk factors associated with ischemic heart disease (IHD) in Russian adults, to develop prognostic PRS models for IHD risk stratification, and to gain a better understanding of molecular mechanisms underlying IHD through a transcriptome analysis. Materials and methods The study analyzed data from three independent cohorts: a population sample of 69,500 individuals, a cardiac sample of 5,875 IHD patients, and a sample of 2,870 long-living adults. To identify genomic loci associated with IHD, a GWAS was performed, and its findings were used to develop a PRS model for the IHD phenotype. Additionally, a transcriptome analysis was conducted. Results The GWAS for IHD adjusted for sex, age, and the first ten principal component accounting for population structure identified 75 variants, with 67 located at 9p21.3. Based on the GWAS findings, PRS models were developed and validated for IHD. The risk of IHD adjusted for sex, age, and BMI was the lowest in the sample of long-living adults. The TWAS revealed a significant association between IHD and increased CDKN2B expression in the aorta. According to the DEG results, the CDKN1A gene, a member of the same gene family as CDKN2B, was significantly hypoexpressed in the lower limb veins of patients with IHD. Conclusion PRS models offer great benefits for IHD risk prediction, particularly in individuals at the e tremes of the heritable risk distribution. lncRNAs, such as CDKN2BAS1 and lncRNA-MAP3K4, as well as P2X2 receptors, could be potential therapeutic targets for IHD.
Veronika Daniel, Natalia Romanova, Aleksandra Mamchur et al.· Frontiers in Cardiovascular...· 0 citations
Introduction Congenital heart defects (CHD) constitute a prevalent group of structural birth anomalies, characterised by substantial genetic heterogeneity and diverse clinical phenotypes. Methods To investigate the underlying genetic architecture, we performed whole-genome sequencing (WGS) in a cohort of 50 patients with echocardiographically confirmed CHD, followed by systematic variant identification and functional annotation. Results Our analysis reveals the limited discriminatory capacity of current genomic annotation databases and underscores the necessity of stratifying genetic risk assessments by specific CHD subtypes. By integrating clinical classifications, genomic data, and tissue-specific expression profiles, we identified novel coding and non-coding variants alongside putative regulatory signals that may contribute to CHD pathogenesis. Within cardiac-specific genes, we identified CHD subtype-specific genetic associations, including JARID2 with PDA, GOSR2/TBX18 with VSD, PCDHA9 with ASD, and a multi-gene signature (CREBBP, ZFPM2, SLC27A6, ADAM17, ETS1) with atrioventricular septal defects. Among coding variants in non-CHD-associated genes, we identified COL11A2 and PCOLCE2 as plausible collagen-related candidates for CHD pathogenesis. Discussion These findings reinforce the polygenic architecture of CHD and highlight the value of context-aware, phenotype-driven interpretation of genetic variants. Collectively, this study expands the understanding of the genetic landscape underlying congenital heart anomalies and emphasises the need for larger, deeply phenotyped cohorts to translate these preliminary insights into clinically applicable predictors.
A. Korobeinikova, E. Petriaikina, D. Tychinin et al.· Frontiers in Cardiovascular...· 0 citations
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