An Integrative Genomics Approach Identifies Activation of Thioredoxin/Thioredoxin Reductase-1-Mediated Oxidative Stress Defense Pathway and Inhibition of Angiogenesis in Obese Nondiabetic Human Subjects

Das, Swapan K.; Sharma, Neeraj Kumar; Hasstedt, Sandra J.; Mondal, Ashis; Ma, Lijun; Langberg, Kurt A.; Elbein, Steven C.

doi:10.1210/jc.2011-0101

Cited by 42 publications

(43 citation statements)

References 21 publications

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“…However, results remained consistent; the effect direction of TRIG or HDL-C associated transcripts were completely concordant and effect sizes (β) were strongly correlated (r 2 >0.99) between the overall cohort and the remaining cohort after excluding individuals on statin therapy (Supplementary Figure-1). Studies have shown significant correlation of adipose transcripts with obesity 22, 24 and we found that serum TRIG and HDL-C levels were correlated with BMI. After adjustment for BMI, adipose tissue transcript level of 135 and 79 genes, respectively, remain significantly associated (FDR<1%) with serum TRIG and HDL-C level (Supplementary Table-2).…”

Section: Resultssupporting

confidence: 56%

“…Strong concordance was observed between correlations of adipose tissue transcripts and serum lipids in AAGMEx African Americans (N=250) and non-diabetic European Americans (AREA cohort, N=99) data sets 22 . Among the 580 transcripts significantly correlated with TRIG in both the AAGMEx (p<0.001, Spearman semi-partial correlation coefficients adjusted for age, gender, and ancestry proportion) and AREA cohort (p<0.05, Spearman semi-partial correlation coefficients adjusted for age and gender), 99.31% showed directional concordance.…”

Section: Resultsmentioning

confidence: 80%

“…Serum lipid and insulin sensitivity of participants in this Arkansas cohort was characterized by our laboratory using a similar protocol 22 . To compare results in the Arkansas and AAGMEx cohorts, correlation of triglyceride and HDL-cholesterol with adipose transcripts was evaluated using Spearman semi-partial correlation coefficients adjusted for age and gender or age, gender and ancestry proportion (admixture).…”

Section: Methodsmentioning

confidence: 99%

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Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol

Sajuthi

Sharma

Comeau

et al. 2017

Gene

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Dyslipidemia is a major contributor to the increased cardiovascular disease and mortality associated with obesity and type 2 diabetes. We hypothesized that variation in expression of adipose tissue transcripts is associated with serum lipid concentrations in African Americans (AAs), and common genetic variants regulate expression levels of these transcripts. Fasting serum lipid levels, genome-wide transcript expression profiles of subcutaneous adipose tissue, and genome-wide SNP genotypes were analyzed in a cohort of non-diabetic AAs (N=250). Serum triglyceride (TRIG) and high density lipoprotein-cholesterol (HDL-C) levels were associated (FDR<0.01) with expression level of 1021 and 1875 adipose tissue transcripts, respectively, but none associated with total cholesterol or LDL-C levels. Serum HDL-C-associated transcripts were enriched for salient biological pathways, including branched-chain amino acid degradation, and oxidative phosphorylation. Genes in immuno-inflammatory pathways were activated among individuals with higher serum TRIG levels. We identified significant cis-regulatory SNPs (cis-eSNPs) for 449 serum lipid-associated transcripts in adipose tissue. The cis-eSNPs of 12 genes were nominally associated (p<0.001) with serum lipid level in genome wide association studies in Global Lipids Genetics Consortium (GLGC) cohorts. Allelic effect direction of cis-eSNPs on expression of MARCH2, BEST1 and TMEM258 matched with effect direction of these SNP alleles on serum TRIG or HDL-C levels in GLGC cohorts. These data suggest that expressions of serum lipid-associated transcripts in adipose tissue are dependent on common cis-eSNPs in African Americans. Thus, genetically-mediated transcriptional regulation in adipose tissue may play a role in reducing HDL-C and increasing TRIG in serum.

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

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Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol

Sajuthi

Sharma

Comeau

et al. 2017

Gene

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“…Myeloperoxidase (MPO) generates HOCl, which oxidizes specific tyrosine and methionine residues on apoA-I, thereby impairing apoA-I-mediated cholesterol efflux (31)(32)(33). HDL has been proposed to become oxidized in the milieu of the artery wall (34-36) but might also be oxidized in AT (37)(38)(39). Although the presence of SAA on HDL has been reported to impair HDL's antioxi-HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown.…”

Section: Introductionmentioning

confidence: 99%

Serum amyloid A impairs the antiinflammatory properties of HDL

Han¹,

Tang²,

Guevara³

et al. 2015

Journal of Clinical Investigation

139

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“…We searched our in-house genome-wide gene expression data (Agilent 4X44K array, n ϭ 16 TLs and Illumina HT-12 V4 array, n ϭ 160 TLs) (6,15) and identified 238 expressed genes in this region in TLs. We searched the dbSNP database (v.128) to identify validated transcribed SNPs (cSNP) located in cDNA of expressed genes.…”

Section: Selection Of Snp and Psq Assay Design For Aei Analysismentioning

confidence: 99%

Allelic expression imbalance screening of genes in chromosome 1q21–24 region to identify functional variants for Type 2 diabetes susceptibility

Mondal

Sharma

Elbein

et al. 2013

Physiological Genomics

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Mondal AK, Sharma NK, Elbein SC, Das SK. Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility. Physiol Genomics 45: 509 -520, 2013. First published May 14, 2013 doi:10.1152/physiolgenomics.00048.2013.-Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P Ͻ 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (Ն10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P ϭ 0.027), and IGSF8 (rs1131891, P ϭ 0.02). Examination of published genome-wide association data identified significant associations (P Ͻ 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P ϭ 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P ϭ 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P ϭ 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis. type 2 diabetes; eQTL; allelic expression imbalance; SNP TYPE 2 DIABETES [T2D (MIM 125853)] is a complex metabolic disease for which a genetic contribution is well recognized (2). Since 2007, global efforts to map T2D genetic susceptibility factors have mostly focused on genome-wide association strategies (33). Despite the significant success of these genomewide association studies (GWAS), based on most recent analyses, the 63 T2D-associated loci discovered so far in Caucasian populations together account only for 5.7% of the liabilityscale variance in disease susceptibility, and sibling relative risk ( s ) attributed jointly by these variants is 1.104 (19). Thus, targeted analysis of previously identified genomic intervals representing well-replicated genome-wide significant linkage signals for T2D can be considered as an alternative strategy. Chromosome 1q21-24 is one such region o...

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An Integrative Genomics Approach Identifies Activation of Thioredoxin/Thioredoxin Reductase-1-Mediated Oxidative Stress Defense Pathway and Inhibition of Angiogenesis in Obese Nondiabetic Human Subjects

Cited by 42 publications

References 21 publications

Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol

Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol

Serum amyloid A impairs the antiinflammatory properties of HDL

Allelic expression imbalance screening of genes in chromosome 1q21–24 region to identify functional variants for Type 2 diabetes susceptibility

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