RESUMO
BACKGROUND: High serum triglyceride (TG) levels is an established risk factor for coronary heart disease (CHD). Fat is stored in the form of TGs in human adipose tissue. We hypothesized that gene co-expression networks in human adipose tissue may be correlated with serum TG levels and help reveal novel genes involved in TG regulation. METHODS: Gene co-expression networks were constructed from two Finnish and one Mexican study sample using the blockwiseModules R function in Weighted Gene Co-expression Network Analysis (WGCNA). Overlap between TG-associated networks from each of the three study samples were calculated using a Fisher's Exact test. Gene ontology was used to determine known pathways enriched in each TG-associated network. RESULTS: We measured gene expression in adipose samples from two Finnish and one Mexican study sample. In each study sample, we observed a gene co-expression network that was significantly associated with serum TG levels. The TG modules observed in Finns and Mexicans significantly overlapped and shared 34 genes. Seven of the 34 genes (ARHGAP30, CCR1, CXCL16, FERMT3, HCST, RNASET2, SELPG) were identified as the key hub genes of all three TG modules. Furthermore, two of the 34 genes (ARHGAP9, LST1) reside in previous TG GWAS regions, suggesting them as the regional candidates underlying the GWAS signals. CONCLUSIONS: This study presents a novel adipose gene co-expression network with 34 genes significantly correlated with serum TG across populations.
Assuntos
Tecido Adiposo/metabolismo , Regulação da Expressão Gênica , Redes Reguladoras de Genes/genética , Triglicerídeos/genética , Estudos de Casos e Controles , Finlândia , Perfilação da Expressão Gênica , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Imunidade/genética , Inflamação/sangue , Inflamação/genética , México , Polimorfismo de Nucleotídeo Único/genética , Triglicerídeos/sangue , Gêmeos/genéticaRESUMO
OBJECTIVE: Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism. METHODS AND RESULTS: Our data show that rs7575840 is associated with serum apoB levels (P=4.85×10(-10)) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (P=2×10(-5) to 9×10(-7)) in the Finnish Metabolic Syndrome in Men study sample (n=7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (n=2666, P=3.33×10(-5)). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (P=1.13×10(-10)) and a regional noncoding RNA (BU630349) (P=7.86×10(-6)) in adipose tissue. CONCLUSIONS: It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels.