Whole-exome sequencing reveals genetic variations in humans with differential sensitivity to sevoflurane: A prospective observational study

Background: The anesthesia sensitivity is heterogeneous both in animals and humans, while the underlying molecular mechanism has not yet been determined. Here, for the first time, we conducted a prospective observational study to test whether genetic variations contribute to the differential sensitivity to sevoflurane in humans. Methods: Five hundred patients who underwent abdominal surgeries were included. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain Bispectral index (BIS) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. These patients were further divided into high sensitivity group (mean - SD, H group) and low sensitivity group (mean + SD, L group) to investigate the genetic variants related to the differential sensitivity to sevoflurane by whole-exome sequencing (WES) and genome-wide association study (GWAS) in karyocyte from peripheral blood. Results: The mean ETsevo of these 500 patients was 1.60% +/- 0.34%. After pairing, 55 patients from H group and 59 patients from L group were selected for WES (ETsevo of H group: 1.06% +/- 0.13% vs. ETsevo of L group: 2.17% +/- 0.16%, P < 0.001), respectively. Finally, FAT atypical cadherin 2 (FAT2, SNP rs174272, rs174271, and rs174261), acireductone dioxygenase 1 (ADI1, SNP rs117278), NEDD4 E3 ubiquitin protein ligase (NEDD4, SNP rs70048, rs70049, and rs70056), and FAD dependent oxidoreductase domain containing 2 (FOXRED2, SNP rs144281) were found to be associated with sevoflurane sensitivity. Conclusions: Genetic variations may contribute to the differential sensitivity to sevoflurane among humans.

Automated summary

This study is the first prospective observational study to investigate the genetic variations associated with the differential sensitivity to sevoflurane in humans using whole-exome sequencing and genome-wide association study.