Dataset Information

Network-based association of hypoxia-responsive genes with cardiovascular diseases.

ABSTRACT: Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct an hypoxia-CVD bipartite network and find several interesting hypoxia-CVD modules with significant Gene Ontology (GO) similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology.

SUBMITTER: Wang RS

PROVIDER: S-EPMC4270352 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Network-based association of hypoxia-responsive genes with cardiovascular diseases.

Wang Rui-Sheng RS Oldham William M WM Loscalzo Joseph J

New journal of physics 20141001 10

Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung disea ...[more]

PMID: 25530704

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Project description:Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.

Dataset Information

Network-based association of hypoxia-responsive genes with cardiovascular diseases.

Publications

Network-based association of hypoxia-responsive genes with cardiovascular diseases.

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