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Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans.

ABSTRACT: African Americans (AA) have more pronounced insulin resistance and higher insulin secretion than European Americans (Caucasians or CA) when matched for age, gender, and body mass index (BMI). We hypothesize that physiological differences (including insulin sensitivity [SI]) between CAs and AAs can be explained by co-regulated gene networks in tissues involved in glucose homeostasis.We performed integrative gene network analyses of transcriptomic data in subcutaneous adipose tissue of 99 CA and 37 AA subjects metabolically characterized as non-diabetic, with a range of SI and BMI values.Transcripts negatively correlated with SI in only the CA or AA subjects were enriched for inflammatory response genes and integrin-signaling genes, respectively. A sub-network (module) with TYROBP as a hub enriched for genes involved in inflammatory response (corrected p?=?1.7E-26) was negatively correlated with SI (r?=?-0.426, p?=?4.95E-04) in CA subjects. SI was positively correlated with transcript modules enriched for mitochondrial metabolism in both groups. Several SI-associated co-expressed modules were enriched for genes differentially expressed between groups. Two modules involved in immune response to viral infections and function of adherens junction, are significantly correlated with SI only in CAs. Five modules involved in drug/intracellular transport and oxidoreductase activity, among other activities, are correlated with SI only in AAs. Furthermore, we identified driver genes of these race-specific SI-associated modules.SI-associated transcriptional networks that were deranged predominantly in one ethnic group may explain the distinctive physiological features of glucose homeostasis among AA subjects.

SUBMITTER: Das SK

PROVIDER: S-EPMC4351975 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans.

Das Swapan Kumar SK Sharma Neeraj Kumar NK Zhang Bin B

BMC medical genomics 20150207

<h4>Background</h4>African Americans (AA) have more pronounced insulin resistance and higher insulin secretion than European Americans (Caucasians or CA) when matched for age, gender, and body mass index (BMI). We hypothesize that physiological differences (including insulin sensitivity [SI]) between CAs and AAs can be explained by co-regulated gene networks in tissues involved in glucose homeostasis.<h4>Methods</h4>We performed integrative gene network analyses of transcriptomic data in subcuta ...[more]

PMID: 25868721

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Project description:Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1, ATR, POLQ, NEIL3, ERCC6, BRCA2, BRCA1, XPC, JAG1, RPA1, POLE, ATM, and LIG1 in African American men, and POLQ, NEIL3, POLB, BRCA2, EXO1, ERCC6, ATR, RBBP8, BRCA1, ATM, JAG1, XPC, and POLE in Caucasians. We found that 89% of tumors had at least one mutation in nucleotide excision repair pathway genes in African Americans, whereas >40% of tumors had mutations in base excision repair pathway genes in Caucasians. We further identified a marginal increase in mutation rate in tumors in African Americans with increasing age. Tumors in Caucasians did not show a correlation with age, but a progressive increase in the mutation rate was observed at higher Gleason scores. Our data reveal significant differences in the molecular signatures in the DNA repairome in prostate cancer between African Americans and Caucasians. These data also have substantial implications regarding the well-known health disparities in prostate cancer, such as the higher mortality in African Americans than Caucasians.

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Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans.

Publications

Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans.

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