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.