Gene expression profiling in whole blood identifies distinct biological pathways associated with obesity

Ghosh, Sujoy; Dent, Robert; Harper, Mary‐Ellen; Gorman, Shelby A.; Stuart, Joan S.; McPherson, Ruth

doi:10.1186/1755-8794-3-56

Cited by 67 publications

(77 citation statements)

References 58 publications

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“…The black module was dominated by a ribosome and proteasome-related gene signature. Interestingly, similar signatures have been reported in two blood expression studies of obesity unrelated to asthma: a ribosome pathway signature defined in peripheral whole blood samples was also associated with obesity in a small gene expression study in 17 obese and 17 non-obese subjects [38], and a second study by the same group showed a proteasome signature in whole blood comparing nine diet-sensitive and nine diet-resistant obese subjects [39]. Given that both these biological processes are of fundamental importance to cellular function generally, it is unclear whether their implication in our study is specific to asthma and obesity together (perhaps reflecting fundamental differences in cellular metabolic demands in these patients) [40,41], or whether these associations reflect more generic patterns of cellular activity or stress seen in obese patients [42,43].…”

Section: Discussionsupporting

confidence: 71%

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

Croteau‐Chonka

Chen

Barnes

et al. 2017

Preprint

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Asthmatic children who develop obesity have poorer outcomes compared to those that do not, including poorer control, more severe symptoms, and greater resistance to standard treatment. The aim of this study was to characterize the biology of childhood asthma complicated by adult obesity. Gene expression networks are powerful statistical tools for characterizing the underpinnings of human disease that leverage the putative co-regulatory relationships of genes to infer biological pathways altered in disease states. We performed weighted gene co-expression network analysis (WGCNA) of adult gene expression data in whole blood from 514 subjects from the Childhood Asthma Management Program (CAMP). We identified a multivariate model in which four gene coexpression network modules were associated with incident obesity in CAMP (each P < 0.05). The module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult). The network structures of each of the four obese asthma modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in obese subjects in both replication cohorts (each P < 0.05). Our gene co-expression network profiles thus implicate multiple inflammatory pathways in the biology of an important endotype of obese asthma.

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Section: Discussionsupporting

confidence: 71%

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

Croteau‐Chonka

Chen

Barnes

et al. 2017

Preprint

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“…Transcriptional profiling studies in peripheral blood leukocytes may provide some evidence on the relationship between LY86 gene methylation and gene expression. We searched the Gene Expression Omnibus (GEO) database and identified a dataset (Ghosh et al, 2010; GSE18897) that included genome-wide gene expression data in peripheral blood samples from 20 obese and 20 lean adults. In line with our findings that obese cases had higher methylation levels of the LY86 gene, in this gene expression dataset, the expression level of LY86 gene was lower in the obese cases than in the lean controls, although the difference did not reach significance (309 ± 78 vs. 340 ± 75, p = .18).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation of the LY86 Gene is Associated With Obesity, Insulin Resistance, and Inflammation

Zhu

et al. 2014

Twin Res Hum Genet

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Background Previous genome-wide association studies (GWAS) have identified a large number of genetic variants for obesity and its related traits, representing a group of potential key genes in the etiology of obesity. Emerging evidence suggests that epigenetics may play an important role in obesity. It has not been explored whether the GWAS-identified loci contribute to obesity through epigenetics (e.g., DNA (deoxyribonucleic acid) methylation) in addition to genetics. Method A multi-stage cross-sectional study was designed. We did a literature search and identified 117 genes discovered by GWAS for obesity and its related traits. Then we analyzed whether the methylation levels of these genes were also associated with obesity in two genome-wide methylation panels. We examined an initial panel of seven adolescent obese cases and seven age-matched lean controls, followed by a second panel of 48 adolescent obese cases and 48 age- and gender-matched lean controls. The validated CpG sites were further replicated in two independent replication panels of youth (46 vs. 46 and 230 cases vs. 413 controls, respectively) and a general population of youth, including 703 healthy subjects. Results One CpG site in the lymphocyte antigen 86 (LY86) gene, which showed higher methylation in the obese in both the initial (p = .009) and second genome-wide DNA methylation panel (p = .008), was further validated in both replication panels (meta p = .00016). Moreover, in the general population of youth, the methylation levels of this region were significantly correlated with adiposity indices (p ≤.02), insulin resistance (p = .001), and inflammatory markers (p < .001). Conclusion By focusing on recent GWAS findings in genome-wide methylation profiles, we identified a solid association between LY86 gene DNA methylation and obesity.

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“…This is further highlighted by the complex patterns and variability in magnitude of expression changes for a transcript in different tissues. Analysis of the effects of the GWAS SNPs on gene expression in lymphocytes has been suggested since this is a readily accessible source of RNA, and differences in lymphocyte gene expression between lean and obese individuals have been detected [35]. This may be useful if the SNPs affect basal transcription of a gene, but will not be useful if the SNPs affect enhancer elements.…”

Section: Discussionmentioning

confidence: 99%

Nutritional regulation of genome-wide association obesity genes in a tissue-dependent manner

Yoganathan

Karunakaran

et al. 2012

Nutr Metab (Lond)

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BackgroundGenome-wide association studies (GWAS) have recently identified several new genetic variants associated with obesity. The majority of the variants are within introns or between genes, suggesting they affect gene expression, although it is not clear which of the nearby genes they affect. Understanding the regulation of these genes will be key to determining the role of these variants in the development of obesity and will provide support for a role of these genes in the development of obesity.MethodsWe examined the expression of 19 GWAS obesity genes in the brain and specifically the hypothalamus, adipose tissue and liver of mice by real-time quantitative PCR. To determine whether these genes are nutritionally regulated, as may be expected for genes affecting obesity, we compared tissues from fasting and non-fasting animals and tissues from mice consuming a high fat high sucrose diet in comparison to standard rodent chow.ResultsWe found complex, tissue-dependent patterns of nutritional regulation of most of these genes. For example, Bat2 expression was increased ~10-fold in the brain of fed mice but was lower or unchanged in the hypothalamus and adipose tissue. Kctd15 expression was upregulated in the hypothalamus, brain and adipose tissue of fed mice and downregulated by high fat feeding in liver, adipose tissue and the hypothalamus but not the remainder of the brain. Sh2b1 expression in the brain and Faim2 expression in adipose tissue were specifically increased >20-fold in fed mice. Tmem18 expression in adipose tissue but not the brain was reduced 80% by high fat feeding. Few changes in the expression of these genes were observed in liver.ConclusionsThese data show nutritional regulation of nearly all these GWAS obesity genes, particularly in the brain and adipose tissue, and provide support for their role in the development of obesity. The complex patterns of nutritional and tissue-dependent regulation also highlight the difficulty that may be encountered in determining how the GWAS genetic variants affect gene expression and consequent obesity risk in humans where access to tissues is constrained.

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Gene expression profiling in whole blood identifies distinct biological pathways associated with obesity

Cited by 67 publications

References 58 publications

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

DNA Methylation of the LY86 Gene is Associated With Obesity, Insulin Resistance, and Inflammation

Nutritional regulation of genome-wide association obesity genes in a tissue-dependent manner

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