Genomics Inform.  2014 Dec;12(4):195-202. 10.5808/GI.2014.12.4.195.

Pathway Analysis of Metabolic Syndrome Using a Genome-Wide Association Study of Korea Associated Resource (KARE) Cohorts

• Shim U
• Kim HN
• Sung YA
• Kim HL

• KMID: 2391496
• DOI: http://doi.org/10.5808/GI.2014.12.4.195

Abstract

Metabolic syndrome (MetS) is a complex disorder related to insulin resistance, obesity, and inflammation. Genetic and environmental factors also contribute to the development of MetS, and through genome-wide association studies (GWASs), important susceptibility loci have been identified. However, GWASs focus more on individual single-nucleotide polymorphisms (SNPs), explaining only a small portion of genetic heritability. To overcome this limitation, pathway analyses are being applied to GWAS datasets. The aim of this study is to elucidate the biological pathways involved in the pathogenesis of MetS through pathway analysis. Cohort data from the Korea Associated Resource (KARE) was used for analysis, which include 8,842 individuals (age, 52.2 +/- 8.9 years; body mass index, 24.6 +/- 3.2 kg/m2). A total of 312,121 autosomal SNPs were obtained after quality control. Pathway analysis was conducted using Meta-analysis Gene-Set Enrichment of Variant Associations (MAGENTA) to discover the biological pathways associated with MetS. In the discovery phase, SNPs from chromosome 12, including rs11066280, rs2074356, and rs12229654, were associated with MetS (p < 5 x 10(-6)), and rs11066280 satisfied the Bonferroni-corrected cutoff (unadjusted p < 1.38 x 10(-7), Bonferroni-adjusted p < 0.05). Through pathway analysis, biological pathways, including electron carrier activity, signaling by platelet-derived growth factor (PDGF), the mitogen-activated protein kinase kinase kinase cascade, PDGF binding, peroxisome proliferator-activated receptor (PPAR) signaling, and DNA repair, were associated with MetS. Through pathway analysis of MetS, pathways related with PDGF, mitogen-activated protein kinase, and PPAR signaling, as well as nucleic acid binding, protein secretion, and DNA repair, were identified. Further studies will be needed to clarify the genetic pathogenesis leading to MetS.

Keyword

genome-wide association studies; metabolic cardiovascular syndrome

MeSH Terms

Body Mass Index
Chromosomes, Human, Pair 12
Cohort Studies*
Dataset
DNA Repair
Genome-Wide Association Study*
Inflammation
Insulin Resistance
Korea
Metabolic Syndrome X
Obesity
Peroxisome Proliferator-Activated Receptors
Peroxisomes
Phosphotransferases
Platelet-Derived Growth Factor
Polymorphism, Single Nucleotide
Protein Binding
Protein Kinases
Quality Control
Peroxisome Proliferator-Activated Receptors
Phosphotransferases
Platelet-Derived Growth Factor
Protein Kinases