Systems Genetics Analysis of Gene-by-Environment Interactions in Human Cells

Romanoski, Casey E.; Lee, Sangderk; Kim, Michelle; Ingram‐Drake, Leslie; Plaisier, Christopher L.; Yordanova, Roumyana; Tilford, Charles; Guan, Bo; He, Aiqing; Gargalovic, Peter S.; Kirchgessner, Todd G.; Berliner, Judith A.; Lusis, Aldons J.

doi:10.1016/j.ajhg.2010.02.002

Cited by 105 publications

(108 citation statements)

References 56 publications

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“…A number of studies surveyed transcriptional genotype-byenvironment interactions in humans and reported dozens of response eQTLs in vitro under a variety of environmental challenges such as radiation (26) and treatment with various agents (27)(28)(29). The number of interacting loci in response to malaria infection in our in vivo study is lower than the number of response eQTLs reported in these studies despite the fact that similar sample sizes were used.…”

Section: Resultscontrasting

confidence: 52%

Evidence for additive and interaction effects of host genotype and infection in malaria

Idaghdour

Quinlan

Goulet

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

124

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The host mechanisms responsible for protection against malaria remain poorly understood, with only a few protective genetic effects mapped in humans. Here, we characterize a host-specific genome-wide signature in whole-blood transcriptomes of Plasmodium falciparum-infected West African children and report a demonstration of genotype-by-infection interactions in vivo. Several associations involve transcripts sensitive to infection and implicate complement system, antigen processing and presentation, and T-cell activation (i.e., SLC39A8, C3AR1, FCGR3B, RAD21, RETN, LRRC25, SLC3A2, and TAPBP), including one association that validated a genome-wide association candidate gene (SCO1), implicating binding variation within a noncoding regulatory element. Gene expression profiles in mice infected with Plasmodium chabaudi revealed and validated similar responses and highlighted specific pathways and genes that are likely important responders in both hosts. These results suggest that host variation and its interplay with infection affect children's ability to cope with infection and suggest a polygenic model mounted at the transcriptional level for susceptibility.host response | parasite load | eQTL | eSNP | genotype-by-environment interactions

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Section: Resultscontrasting

confidence: 52%

Evidence for additive and interaction effects of host genotype and infection in malaria

Idaghdour

Quinlan

Goulet

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

124

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“…However, when the cells were stimulated with oxidized lipids, all cells reached a similar level of HO-1 mRNA, regardless of basal levels of HMOX1 transcript (43). We propose that miRNAs may be serving as a rheostat to titrate the levels of HO-1 expression to a physiologic set point (Fig.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Heme Oxygenase-1 Protein Expression by miR-377 in Combination with miR-217

Beckman¹,

Chen

Nguyen³

et al. 2011

Journal of Biological Chemistry

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Heme oxygenase-1 (HO-1) enzyme plays a critical role in metabolizing the excess heme generated during hemolysis. Our previous studies suggested that during intravascular hemolysis the expression of HO-1 protein is not sufficient to reduce the oxidative burden of free heme in the vasculature. This led us to hypothesize that a post-translational mechanism of control exists for HO-1 expression. Micro-RNAs (miRNA) affect gene expression by post-transcriptional gene regulation of transcripts. We performed in silico analysis for the human HMOX1-3 untranslated region (3 UTR) and identified candidate miRNA binding sites. Two candidate miRNAs, miR-377 and miR-217, were cloned and co-transfected with a luciferase vector containing the human HMOX1-3UTR region. The combination of miR-377 and miR-217 produced a 58% reduction in HMOX1-3UTR luciferase reporter expression compared with controls. The same constructs were then used to assess how overexpression of miR-217 and miR-377 affected HO-1 levels after induction with hemin. Cells transfected with the combination of miR-377 and miR-217 exhibited no change in HMOX1 mRNA levels, but a significant reduction in HMOX1 (HO-1) protein expression and enzyme activity compared with non-transfected hemin-stimulated controls. Transfection with either miR-377 or miR-217 alone did not produce a significant decrease in HO-1 protein expression or enzyme activity. Knockdown of miR-217 and miR-377 in combination leads to up-regulation of HO-1 protein. Exposure to hemin induced a significant reduction in miR-217 expression and a trend toward decreased miR-377 expression in two different cells lines. In summary, these data suggests that the combination of miR-377 and miR-217 help regulate HO-1 protein expression in the presence of hemin.During hemolysis, up to 20 M of free heme can be released leading to the breakdown of heme detoxification systems and subsequent damage to lipids, proteins, and DNA primarily through the ability of heme to generate reactive oxygen species (1). Free heme is quite hydrophobic in nature and readily enters cell membranes and increases cellular susceptibility to oxidant-mediated killing (1). Heme oxygenase-1 (HO-1) 2 is a 32-kDa microsomal/mitochondrial (2) enzyme, which oxidizes protoheme to biliverdin IX␣ in a three-step process, which requires oxygen and reducing equivalents from NADPH. In the process, this enzyme releases the antioxidant molecules carbon monoxide and biliverdin (2). Transcription of HO-1 is induced by a variety of agents, such as heme, oxidants, hypoxia, and cytokines and leads to induction of the enzyme and protection of tissues and cells against ischemiareperfusion injury and oxidative stress (3, 4). As illustrated in patients and HMOX1 Ϫ/Ϫ mice, HO-1 deficiency leads to oxidant-mediated injury, highlighting that the control and regulation of HO-1 expression is critical to protect cells from oxidative stress and damage (5-7).To date several hundred microRNA (miRNA) genes have been identified in the human genome and it is proposed that at least...

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“…SNP genotyping was performed using the Affymetrix SNP 6.0 microarray platform as described previously ( 15 ). Microarray images were processed using the Affymetrix Genotyping Console 4.1 to make the SNP calls.…”

Section: Genotyping and Association Analysismentioning

confidence: 99%

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

Erbilgin

Civelek²,

Romanoski³

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org provided insight into the many different genetic factors that contribute to the disease ( 3-7 ). Using data acquired from thousands of patients and healthy controls, these studies have collectively identifi ed 35 genetic loci associated with CAD ( 8, 9 ). Although 10 of the recently identifi ed CAD risk loci work through known risk factors, such as lipids and blood pressure, this is not the case for the majority of loci ( 3 ), implying that key pathways leading to coronary atherosclerosis are yet to be discovered. Given their fi rm association with disease risk, novel CAD loci provide a solid foundation to unravel disease networks.As GWAS results do not provide functional information on the loci identifi ed, additional studies are needed to determine the candidate genes and their role in disease. The immediate challenges associated with the validation of GWAS candidate genes include identifying the likely cell types in which the risk variants and genes function, determining which of the multiple candidate genes represented by each CAD locus contribute to disease, and defi ning the functions of poorly annotated candidate genes. Expression analyses of candidate genes under defi ned conditions in model organisms and their associations with risk variants in human samples provide a powerful way to address these issues and predict the causal candidate genes.It is likely that at least some of the novel genes (that is, those not affecting known risk factors, such as plasma lipids or blood pressure) are perturbing vessel wall or infl ammatory cell functions. Endothelial cells (EC) play a critical role in the initiation and progression of atherosclerosis. Abstract Recent genome-wide association studies (GWAS)have identifi ed 35 loci that signifi cantly associate with coronary artery disease (CAD) susceptibility. The majority of the genes represented in these loci have not previously been studied in the context of atherosclerosis. To characterize the roles of these candidate genes in the vessel wall, we determined their expression levels in endothelial, smooth muscle, and macrophage cells isolated from healthy, prelesioned, and lesioned mouse aortas. We also performed expression quantitative locus (eQTL) mapping of these genes in human endothelial cells under control and proatherogenic conditions. Of the 57 genes studied, 31 were differentially expressed in one or more cell types in disease state in mice, and the expression levels of 8 were signifi cantly associated with the CAD SNPs in human cells, 7 of which were also differentially expressed in mice. By integrating human and mouse results, we predict that PPAP2B , GALNT4 , MAPKAPK5 , TCTN1 , SRR , SNF8 , and ICAM1 play a causal role in the susceptibility to atherosclerosis through a role in the vasculature. Additionally, we highlight the genetic complexity of a subset of CAD loci through the differential expression of multiple candidate genes per locus and the involvement of genes that lie outside linkage disequilib...

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Systems Genetics Analysis of Gene-by-Environment Interactions in Human Cells

Cited by 105 publications

References 56 publications

Evidence for additive and interaction effects of host genotype and infection in malaria

Evidence for additive and interaction effects of host genotype and infection in malaria

Regulation of Heme Oxygenase-1 Protein Expression by miR-377 in Combination with miR-217

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

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