Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits

Vaura, Felix; Palmu, Joonatan; Aittokallio, Jenni; Kauko, Anni; Niiranen, Teemu J.

doi:10.1161/circresaha.121.319891

Cited by 28 publications

(20 citation statements)

References 239 publications

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“…Because the markers we identified in this study were based on sex-adjusted models such that the markers share similar biology between sex, we did not observe significant sex susceptibility for CAC across the CVHassociated markers. Given the evident sex differences in CVD traits reported in the literature, 64 this topic should be further investigated using a targeted approach, focusing on sex-chromosome methylation and methylation markers in sex hormone receptors and signaling pathways. 65 Similar to genetic risk scores, the MRS allowed us to aggregate relevant epigenetic information that could be clinically meaningful for risk stratification.…”

Section: Discussionmentioning

confidence: 99%

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study

et al. 2022

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Background: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual’s future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. Methods: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25–45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. Results: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 ( P =4.7E-7–5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A , ABCG1 , and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1 , SOCS3 , and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly ( P =0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P =9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P =1.22E-05). Conclusions: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.

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Section: Discussionmentioning

confidence: 99%

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study

et al. 2022

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“…Greater diversity can even lead to novel insights into disease biology, as a GWAS of coronary artery disease identified ancestry-specific genetic risk loci and an enrichment of genes expressed in the adrenal cortex among Japanese individuals [10]. Similarly, studies should carefully consider sex differences as many diseases exhibit sex-specific differences in rates of disease, which may be partially explained by sex hormones or other biological differences in each sex [127][128][129]. For instance, a study of atherosclerotic plaques found differences in gene regulatory networks across sexes where male samples expressed immune and inflammation genes while female samples expressed genes related to phenotype switching in smooth muscle cells [129].…”

Section: Challenges and Limitations Of Multi-omics Technologiesmentioning

confidence: 99%

From ‘Omics to Multi-omics Technologies: the Discovery of Novel Causal Mediators

Mohammadi-Shemirani

Sood

Paré

2023

Curr Atheroscler Rep

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Purpose of Review ‘Omics studies provide a comprehensive characterisation of a biological entity, such as the genome, epigenome, transcriptome, proteome, metabolome, or microbiome. This review covers the unique properties of these types of ‘omics and their roles as causal mediators in cardiovascular disease. Moreover, applications and challenges of integrating multiple types of ‘omics data to increase predictive power, improve causal inference, and elucidate biological mechanisms are discussed. Recent Findings Multi-omics approaches are growing in adoption as they provide orthogonal evidence and overcome the limitations of individual types of ‘omics data. Studies with multiple types of ‘omics data have improved the diagnosis and prediction of disease states and afforded a deeper understanding of underlying pathophysiological mechanisms, beyond any single type of ‘omics data. For instance, disease-associated loci in the genome can be supplemented with other ‘omics to prioritise causal genes and understand the function of non-coding variants. Alternatively, techniques, such as Mendelian randomisation, can leverage genetics to provide evidence supporting a causal role for disease-associated molecules, and elucidate their role in disease pathogenesis. Summary As technologies improve, costs for ‘omics studies will continue to fall and datasets will become increasingly accessible to researchers. The intrinsically unbiased nature of ‘omics data is well-suited to exploratory analyses that discover causal mediators of disease, and multi-omics is an emerging discipline that leverages the strengths of each type of ‘omics data to provide insights greater than the sum of its parts.

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“…Other GWAS have found evidence for sexspeci c associations in and visceral fat [46], renal cell carcinoma [47] and longevity [48]. Literature in heterogeneity between sexes and sex-speci c differences in pQTLs are limited [49].…”

Section: Meta-analysismentioning

confidence: 99%

Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases

Carland

Png

Mälarstig

et al. 2023

Preprint

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Background: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. Methods: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. Results: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). Conclusion: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.

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Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits

Cited by 28 publications

References 239 publications

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study

From ‘Omics to Multi-omics Technologies: the Discovery of Novel Causal Mediators

Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases

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