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Wei W.-H.,University of Edinburgh | Hemani G.,Roslin Institute | Gyenesei A.,Finnish Microarray and Sequencing Center | Vitart V.,University of Edinburgh | And 18 more authors.
European Journal of Human Genetics | Year: 2012

We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E08) and a Bonferroni corrected threshold (P=1.1E12), respectively. Next we compared sub genome-wide significant SNP interactions (P5.0E08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings. © 2012 Macmillan Publishers Limited All rights reserved.

Babu M.,University of Eastern Finland | Devi T.D.,University of Eastern Finland | Makinen P.,University of Eastern Finland | Kaikkonen M.,University of Eastern Finland | And 7 more authors.
Circulation Research | Year: 2015

Rationale: Hyperlipidemia and type 2 diabetes mellitus (T2DM) severely impair adaptive vascular growth responses in ischemic muscles. This is largely attributed to dysregulated gene expression, although details of the changes are unknown. Objective: To define the role of promoter methylation in adaptive vascular growth in hyperlipidemia (LDLR-/- ApoB100/100) and T2DM (IGF-II/LDLR-/- ApoB100/100) mouse models of hindlimb ischemia. Methods and Results: Unilateral hindlimb ischemia was induced by ligating femoral artery. Perfusion was assessed using ultrasound, and capillary and arteriole parameters were assessed using immunohistochemistry. Genome-wide methylated DNA sequencing was performed with DNA isolated from ischemic muscle, tissue macrophages (Mφs), and endothelial cells. Compared with the controls, hyperlipidemia and T2DM mice showed impaired perfusion recovery, which was associated with impaired angiogenesis and arteriogenesis. Genome-wide proximal promoter DNA methylation analysis suggested differential patterns of methylation in Mφ genes in ischemic muscles. Classically activated M1-Mφ gene promoters, including Cfb, Serping1, and Tnfsf15, were significantly hypomethylated, whereas alternatively activated M2-Mφ gene promoters, including Nrp1, Cxcr4, Plxnd1, Arg1, Cdk18, and Fes, were significantly hypermethylated in Mφs isolated from hyperlipidemia and T2DM ischemic muscles compared with controls. These results combined with mRNA expression and immunohistochemistry showed the predominance of proinflammatory M1-Mφs, compared with anti-inflammatory and proangiogenic M2-Mφs in hyperlipidemia and T2DM ischemic muscles. Conclusions: We found significant promoter hypomethylation of genes typical for proinflammatory M1-Mφs and hypermethylation of anti-inflammatory, proangiogenic M2-Mφ genes in hyperlipidemia and T2DM ischemic muscles. Epigenetic alterations modify Mφ phenotype toward proinflammatory M1 as opposed to anti-inflammatory, proangiogenic, and tissue repair M2 phenotype, which may contribute to the impaired adaptive vascular growth under these pathological conditions. © 2015 American Heart Association, Inc.

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