RESUMO
Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p < 1E-14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women's Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.
Assuntos
Doenças Cardiovasculares , Metilação de DNA , Humanos , Feminino , Locos de Características Quantitativas , Regulação da Expressão Gênica , Estudos Longitudinais , Doenças Cardiovasculares/genética , Ilhas de CpG/genética , Estudo de Associação Genômica AmplaRESUMO
Purpose: Assessing an individual's systemic inflammatory state is vital to understand inflammation's role in cardiometabolic diseases and identify those at the greatest risk of disease. We generated global inflammation scores and investigated their associations with cardiometabolic risk factors and adverse outcomes. Patients and Methods: Aggregate Inflammation Scores (AIS) and Principal Component Analysis (PCA) scores were generated for 7287 Framingham Heart Study participants using up to 26 inflammation-related proteins, with higher scores reflecting a pro-inflammatory milieu. Multivariable regression and proportional hazards analyses were conducted to investigate the associations of inflammation with cardiometabolic risk factors and outcomes. The primary outcomes for cross-sectional analyses included age, cigarette smoking, fasting lipid and glucose levels, blood pressure, body mass index (BMI), and hypertension, diabetes, and obesity. For prospective analyses, new-onset hypertension, diabetes, obesity, cardiovascular disease and all-cause mortality were investigated. Results: Higher inflammation scores were associated with smoking and older age, higher BMI, systolic blood pressure, lipids, and glucose levels, and with greater odds of hypertension and diabetes after adjusting for age, sex, cohort, and BMI (all p < 0.001). Higher baseline scores were associated with greater odds of new-onset hypertension after adjusting for traditional risk factors (OR [95% CI] per one standard deviation [1-SD] increase, AIS: 1.33 [1.21-1.47], PCA score: 1.26 [1.12-1.42], p < 0.001). The AIS also was associated with new-onset diabetes (1.32 [1.14-1.52], p < 0.001). Proportional hazards analyses revealed greater risk of new-onset cardiovascular disease events and all-cause mortality (HR [95% CI] per 1-SD, AIS: 1.25 [1.14-1.37] and 1.32 [1.23-1.42], PCA score: 1.22 [1.13-1.33] and 1.40 [1.31-1.49], p < 0.001). Conclusion: Global inflammation scores encompassing an array of pro- and anti-inflammatory proteins and pathways may enhance risk assessment for cardiometabolic diseases. The AIS and PCA scores provide further opportunities to investigate the mechanisms of inflammation-related risk of disease.
RESUMO
[This corrects the article DOI: 10.1016/j.isci.2022.105077.].
RESUMO
APOBEC3 family members are cytidine deaminases catalyzing conversion of cytidine to uracil. Many studies have established a link between APOBEC3 expression and cancer development and progression, especially APOBEC3A (A3A) and APOBEC3B (A3B). Preclinical studies with human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) and clinical trial specimens revealed induction of A3B, but not A3A expression after demethylation. We examined the kinetic features of the cytidine deaminase activity for full length A3B and found that longer substrates and a purine at -2 position favored by A3B, whereas A3A prefers shorter substrates and an adenine or thymine at -2 position. The importance and biological significance of A3B catalytic activity rather than A3A and a preference for purine at the -2 position was also established in HPV+ HNSCCs. Our study explored factors influencing formation of A3A and A3B-related cancer mutations that are essential for understanding APOBEC3-related carcinogenesis and facilitating drug discovery.
RESUMO
DNA methylation commonly occurs at cytosine-phosphate-guanine sites (CpGs) that can serve as biomarkers for many diseases. We analyzed whole genome sequencing data to identify DNA methylation quantitative trait loci (mQTLs) in 4126 Framingham Heart Study participants. Our mQTL mapping identified 94,362,817 cis-mQTLvariant-CpG pairs (for 210,156 unique autosomal CpGs) at P < 1e-7 and 33,572,145 trans-mQTL variant-CpG pairs (for 213,606 unique autosomal CpGs) at P < 1e-14. Using cis-mQTL variants for 1258 CpGs associated with seven cardiovascular disease (CVD) risk factors, we found 104 unique CpGs that colocalized with at least one CVD trait. For example, cg11554650 (PPP1R18) colocalized with type 2 diabetes, and was driven by a single nucleotide polymorphism (rs2516396). We performed Mendelian randomization (MR) analysis and demonstrated 58 putatively causal relations of CVD risk factor-associated CpGs to one or more risk factors (e.g., cg05337441 [APOB] with LDL; MR P = 1.2e-99, and 17 causal associations with coronary artery disease (e.g. cg08129017 [SREBF1] with coronary artery disease; MR P = 5e-13). We also showed that three CpGs, e.g., cg14893161 (PM20D1), are putatively causally associated with COVID-19 severity. To assist in future analyses of the role of DNA methylation in disease pathogenesis, we have posted a comprehensive summary data set in the National Heart, Lung, and Blood Institute's BioData Catalyst.
Assuntos
COVID-19 , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Humanos , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Doença da Artéria Coronariana/genética , Locos de Características Quantitativas , Polimorfismo de Nucleotídeo Único , Citosina , Ilhas de CpG/genética , Estudo de Associação Genômica AmplaRESUMO
To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis -eQTL variant-gene transcript (eGene) pairs at p < 5x10 - 8 (2,855,111 unique cis -eQTL variants and 15,982 unique eGenes) and 1,469,754 trans -eQTL variant-eGene pairs at p < 1e-12 (526,056 unique trans -eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis -eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis- eGenes are enriched for immune functions (FDR < 0.05). The cis -eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.
RESUMO
To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis -eQTL variant-gene transcript (eGene) pairs at p <5×10 -8 (2,855,111 unique cis -eQTL variants and 15,982 unique eGenes) and 1,469,754 trans -eQTL variant-eGene pairs at p <1e-12 (526,056 unique trans -eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis -eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis- eGenes are enriched for immune functions (FDR <0.05). The cis -eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.
RESUMO
To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis-eQTL variant-gene transcript (eGene) pairs at p < 5 × 10-8 (2,855,111 unique cis-eQTL variants and 15,982 unique eGenes) and 1,469,754 trans-eQTL variant-eGene pairs at p < 1e-12 (526,056 unique trans-eQTL variants and 7233 unique eGenes). In addition, 442,379 cis-eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis-eGenes are enriched for immune functions (FDR < 0.05). The cis-eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.