PPARγ Variant rs10865710 and Mortality in Pediatric Septic Shock Stratified by Corticosteroid Exposure.

OBJECTIVES

To determine whether genetic variation in peroxisome proliferator-activated receptor gamma (PPARγ) is associated with mortality across corticosteroid exposure strata in pediatric septic shock.

DESIGN

Multicenter prospective observational study.

SETTING

PICUs at multiple U.S. hospitals.

PATIENTS: Children 1 week to 10 years old meeting consensus criteria for septic shock.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN

RESULTS

Genomic DNA was genotyped for two PPARγ single nucleotide variants (SNVs; rs10865710 and rs1801282) using TaqMan assays. Associations with 28-day mortality were evaluated using multivariable logistic regression and Cox proportional hazards models, with analyses stratified by systemic corticosteroid exposure within 72 hours. In a subset with whole-blood RNA sequencing, expression quantitative trait locus (eQTL) analyses assessed genotype effects on candidate transcripts. Among 381 patients, both SNVs were in Hardy-Weinberg equilibrium. Carriage of the rs10865710 mutant allele was associated with higher 28-day mortality (10.2% vs. 3.5%; p = 0.009), whereas rs1801282 showed no association. In stratified analyses, rs10865710 carriage was associated with increased mortality among corticosteroid-treated patients (adjusted odds ratio, 5.85; 95% CI, 1.62-30.44; p = 0.015) but not corticosteroid-naive patients. Similarly, in stratified Cox models, rs10865710 carriage was associated with increased hazard of death among corticosteroid-treated patients (hazard ratio, 5.33; 95% CI, 1.43-19.83; p = 0.013). Genotype was not associated with established mortality risk strata or transcriptomic endotype. In eQTL analyses (n = 81), rs10865710 carriage was not associated with PPARγ expression; however, a trend toward lower glucocorticoid receptor (NR3C1) expression was noted (p = 0.07).

CONCLUSIONS

The intronic PPARγ variant rs10865710 is associated with increased mortality in pediatric septic shock, with the association most apparent among corticosteroid-treated patients. Although no cis-eQTL effect on PPARγ expression was detected, exploratory data suggest potential differences in glucocorticoid receptor signaling. Prospective validation and mechanistic studies are warranted.