IMPACT OF ABCC8 AND TRPM4 GENETIC VARIATION IN CENTRAL NERVOUS SYSTEM DYSFUNCTION ASSOCIATED WITH PEDIATRIC SEPSIS

Area of Science:

• Neuroscience
• Genetics
• Pediatrics

Background:

• Sepsis-associated brain injury (SABI) leads to cognitive impairment and increased morbidity in children.
• The SUR1/TRPM4 channel, upregulated in CNS injury, facilitates sodium influx, depolarization, and cellular swelling, contributing to secondary injury.
• Understanding genetic factors influencing SABI is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the association between genetic variations in ABCC8 (SUR1 gene) and TRPM4 and the occurrence of central nervous system (CNS) dysfunction in severe pediatric sepsis.
• To explore the potential protective role of rare variants in ABCC8 and TRPM4 against CNS dysfunction in this population.

Main Methods:

• Whole exome sequencing was performed on 326 children with severe sepsis.
• Children were compared based on the presence or absence of CNS dysfunction (Glasgow Coma Scale <12).
• Rare variants in ABCC8 and TRPM4 were pooled and analyzed for association with CNS dysfunction, with adjustments for clinical factors. Protein structures were analyzed to map variant locations.

Main Results:

• Pooled rare variants in ABCC8 or TRPM4 were associated with significantly decreased odds of CNS dysfunction in severe pediatric sepsis (OR 0.14, P=0.025).
• This protective association remained significant after adjusting for covariates (aOR 0.11, P=0.038).
• Rare variants were found to cluster in functionally important domains of the ABCC8 and TRPM4 proteins.

Conclusions:

• The ABCC8/TRPM4 channel plays a potential role in the pathophysiology of CNS dysfunction during severe pediatric sepsis.
• Rare variants in ABCC8/TRPM4 may confer a protective effect against CNS dysfunction.
• Further research is warranted to elucidate the mechanisms and confirm the therapeutic potential of these findings for preventing and mitigating SABI.