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Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease.

ABSTRACT: Coronary artery disease (CAD) is one of the leading threats to global health. Previous research has proven that metabolic pathway disorders, such as high blood lipids and diabetes, are one of the risk factors that mostly cause CAD. However, the crosstalk between metabolic pathways and CAD was mostly studied on physiology processes by analyzing a single gene function. A canonical correlation analysis was used to identify the metabolic pathways, which were integrated as a unit to coexpress with CAD susceptibility genes, and to resolve additional metabolic factors that are related to CAD. Seven pathways, including citrate cycle, ubiquinone, terpenoid quinone biosynthesis, and N-glycan biosynthesis, were identified as an integrated unit coexpressed with CAD genes. These pathways could not be revealed as a coexpressed pathway through traditional methods as each single gene has weak correlation. Furthermore, sets of genes in these pathways were candidate markers for diagnosis and detection from patients' serum.

SUBMITTER: Lu H

PROVIDER: S-EPMC5828413 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease.

Lu Heng H Chen Yi Y Li Linlin L

International journal of genomics 20180211

Coronary artery disease (CAD) is one of the leading threats to global health. Previous research has proven that metabolic pathway disorders, such as high blood lipids and diabetes, are one of the risk factors that mostly cause CAD. However, the crosstalk between metabolic pathways and CAD was mostly studied on physiology processes by analyzing a single gene function. A canonical correlation analysis was used to identify the metabolic pathways, which were integrated as a unit to coexpress with CA ...[more]

PMID: 29607312

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Project description:Coronary artery disease (CAD) is the principal cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate whether NAFLD is causally involved in the pathogenesis of CAD. For this, previously reported NAFLD susceptibility genes were clustered and tested for an association with CAD in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis plus the Coronary Artery Disease Genetics (CARDIoGRAMplusC4D) Consortium data set. The role of plasma lipids as a potential mediator was explored by using data from the Global Lipids Genetics Consortium. Statistical analyses revealed that the combination of 12 NAFLD genes was not associated with CAD in 60,801 CAD cases and 123,504 controls (odds ratio [OR] per NAFLD risk allele, 1.0; 95% confidence interval [CI], 0.99-1.00). In a subsequent sensitivity analysis, a positive relationship was observed after exclusion of gene variants that are implicated in NAFLD through impaired very low-density lipoprotein secretion (i.e., microsomal triglyceride transfer protein [MTTP], patatin-like phospholipase domain containing 3 [PNPLA3], phosphatidylethanolamine N-methyltransferase [PEMT], and transmembrane 6 superfamily member 2 [TM6SF2]) (OR, 1.01; 95% CI, 1.00-1.02). Clustering of the excluded genes showed a significant negative relationship with CAD (OR, 0.97; 95% CI, 0.96-0.99). A substantial proportion of the observed heterogeneity between the individual NAFLD genes in relation to CAD could be explained by plasma lipids, as reflected by a strong relationship between plasma lipids and CAD risk conferred by the NAFLD susceptibility genes (r = 0.76; P = 0.004 for low-density lipoprotein cholesterol). Conclusion: NAFLD susceptibility genes do not cause CAD per se. The relationship between these genes and CAD appears to depend to a large extent on plasma lipids. These observations strongly suggest taking plasma lipids into account when designing a new drug to target NAFLD.

Project description:An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

Dataset Information

Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease.

Publications

Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease.

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