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Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression.

ABSTRACT: BACKGROUND:Peroxisome proliferator-activated receptor gamma (PPAR?) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis. METHODS:Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPAR? was assessed by expression quantitative trait locus (e-QTL) and western blot analyses. RESULTS:The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR?=?1.41 (1.11-1.79), P?=?0.004 and OR?=?1.45 (1.01-2.09), P?=?0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR?=?1.41 (1.17-1.71), P?=?0.0004 for the dominant model, OR?=?1.78 (1.34-2.36), P?

SUBMITTER: Lu H

PROVIDER: S-EPMC6938012 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression.

Lu Hongxiang H Wen Dalin D Sun Jianhui J Zeng Ling L Du Juan J Du Dingyuan D Zhang Lianyang L Deng Jin J Jiang Jianxin J Zhang Anqiang A

Critical care (London, England) 20191230 1

<h4>Background</h4>Peroxisome proliferator-activated receptor gamma (PPARγ) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis.<h4>Methods</h4>Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 ...[more]

PMID: 31888703

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Project description:BACKGROUND:Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer's disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops. METHODS:To characterize AD SNPs within non-coding regions, we extracted 406?AD SNPs with GWAS p-values of less than 1.00?×?10-?6 from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments. RESULTS:We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes. CONCLUSION:Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.

Dataset Information

Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression.

Publications

Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression.

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