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

Autor: Lian-Yang Zhang, Jianxin Jiang, Hongxiang Lu, Ding-yuan Du, Jin Deng, Juan Du, Ling Zeng, Jianhui Sun, Anqiang Zhang, Dalin Wen
Rok vydání: 2019
Předmět:
Oncology
Adult
Male
medicine.medical_specialty
Genotype
Critical Care and Intensive Care Medicine
Polymorphism
Single Nucleotide
Trauma
Sepsis
Cohort Studies
03 medical and health sciences
0302 clinical medicine
Transcriptional regulation
Polymorphism (computer science)
Internal medicine
medicine
Humans
Electrophoretic mobility shift assay
Genetic Predisposition to Disease
Peroxisome proliferator-activated receptor gamma
Allele
Enhancer
Transcription factor
Genetic Association Studies
030304 developmental biology
0303 health sciences
business.industry
Research
lcsh:Medical emergencies. Critical care. Intensive care. First aid
030208 emergency & critical care medicine
lcsh:RC86-88.9
Middle Aged
medicine.disease
PPAR gamma
Gene Expression Regulation
Expression quantitative trait loci
Wounds and Injuries
Female
rs10865710
business
Transcription Factors
Zdroj: Critical Care
Critical Care, Vol 23, Iss 1, Pp 1-9 (2019)
ISSN: 1466-609X
Popis: Background 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. 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 PPARγ 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 P P = 0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPARγ expression (P = 9.2 × 10−5 for dominant effect and P = 0.005 for recessive effect). Conclusions Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPARγ expression, thus conferring susceptibility to traumatic sepsis. Trial registration ClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.
Databáze: OpenAIRE
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