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Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects.

Sadhasivam S, Zhang X, Chidambaran V, Mavi J, Pilipenko V, Mersha TB, Meller J, Kaufman KM, Martin LJ, McAuliffe J - Pharmacogenomics J. (2015)

Bottom Line: Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid.This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy.Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

ABSTRACT
Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

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Missense FAAH SNP, rs324420 and risk of Respiratory Depression and PONVCompared to CA genotype of FAAH polymorphism, rs324420, children with AA genotype had higher risk of PONV [Odds ratio of 2.73 (1.58–4.73), p=0.0003] and RD [Odds ratio of 1.61 (1.01, 2.59), p=0.0473]; on the other hand relatively children with CC genotype had less risk of PONV and RD than children with CA and AA genotypes. PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.
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Figure 3: Missense FAAH SNP, rs324420 and risk of Respiratory Depression and PONVCompared to CA genotype of FAAH polymorphism, rs324420, children with AA genotype had higher risk of PONV [Odds ratio of 2.73 (1.58–4.73), p=0.0003] and RD [Odds ratio of 1.61 (1.01, 2.59), p=0.0473]; on the other hand relatively children with CC genotype had less risk of PONV and RD than children with CA and AA genotypes. PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.

Mentions: The FAAH-1 gene, located on chromosome 1, codes for FAAH which degrades anandamide. After sequencing all 15 exons of the FAAH gene, a human study identified, FAAH SNP, rs324420 as a significant polymorphism; the minor allele of this relatively common missense mutation (385C>A) converts a conserved proline to threonine, resulting in a FAAH variant that has an enhanced sensitivity to proteolytic degradation and reduced cellular stability,27 potentially resulting in high anandamide levels. As can be seen from Supplemental Figure 3, P129 is located in an exposed and highly variable loop, away from the active site and FAAH dimerization interface. This position and the lack of evolutionary conservation make direct functional effect on enzymatic activity unlikely, supporting the alternative hypothesis of a lower number of active copies for the mutant protein with higher sensitivity to proteolytic degradation. In our study population, this particular SNP is in strong linkage disequilibrium with other SNPs of a haploblock of in FAAH gene region (Supplemental Figure 2) and is significant associated with both PONV and respiratory depression (Figure 3). Two different central opioid adverse effects, PONV and respiratory depression, are associated with multiple FAAH SNPs with high linkage; 7 SNPs were associated with PONV and 5 SNPs were associated with RD (Table 2). When sequential modeling (type 1 analysis) in whites was performed to test whether other significantly associated FAAH SNPs would explain PONV and RD in addition to rs324420, no other FAAH provided additional information to the association between rs324420 and PONV or RD.


Novel associations between FAAH genetic variants and postoperative central opioid-related adverse effects.

Sadhasivam S, Zhang X, Chidambaran V, Mavi J, Pilipenko V, Mersha TB, Meller J, Kaufman KM, Martin LJ, McAuliffe J - Pharmacogenomics J. (2015)

Missense FAAH SNP, rs324420 and risk of Respiratory Depression and PONVCompared to CA genotype of FAAH polymorphism, rs324420, children with AA genotype had higher risk of PONV [Odds ratio of 2.73 (1.58–4.73), p=0.0003] and RD [Odds ratio of 1.61 (1.01, 2.59), p=0.0473]; on the other hand relatively children with CC genotype had less risk of PONV and RD than children with CA and AA genotypes. PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492912&req=5

Figure 3: Missense FAAH SNP, rs324420 and risk of Respiratory Depression and PONVCompared to CA genotype of FAAH polymorphism, rs324420, children with AA genotype had higher risk of PONV [Odds ratio of 2.73 (1.58–4.73), p=0.0003] and RD [Odds ratio of 1.61 (1.01, 2.59), p=0.0473]; on the other hand relatively children with CC genotype had less risk of PONV and RD than children with CA and AA genotypes. PONV = Postoperative Nausea and Vomiting; FAAH = Fatty Acid Amide Hydrolase.
Mentions: The FAAH-1 gene, located on chromosome 1, codes for FAAH which degrades anandamide. After sequencing all 15 exons of the FAAH gene, a human study identified, FAAH SNP, rs324420 as a significant polymorphism; the minor allele of this relatively common missense mutation (385C>A) converts a conserved proline to threonine, resulting in a FAAH variant that has an enhanced sensitivity to proteolytic degradation and reduced cellular stability,27 potentially resulting in high anandamide levels. As can be seen from Supplemental Figure 3, P129 is located in an exposed and highly variable loop, away from the active site and FAAH dimerization interface. This position and the lack of evolutionary conservation make direct functional effect on enzymatic activity unlikely, supporting the alternative hypothesis of a lower number of active copies for the mutant protein with higher sensitivity to proteolytic degradation. In our study population, this particular SNP is in strong linkage disequilibrium with other SNPs of a haploblock of in FAAH gene region (Supplemental Figure 2) and is significant associated with both PONV and respiratory depression (Figure 3). Two different central opioid adverse effects, PONV and respiratory depression, are associated with multiple FAAH SNPs with high linkage; 7 SNPs were associated with PONV and 5 SNPs were associated with RD (Table 2). When sequential modeling (type 1 analysis) in whites was performed to test whether other significantly associated FAAH SNPs would explain PONV and RD in addition to rs324420, no other FAAH provided additional information to the association between rs324420 and PONV or RD.

Bottom Line: Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid.This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy.Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

ABSTRACT
Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.

Show MeSH
Related in: MedlinePlus