Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

Abstract

IntroductionPatients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium.MethodsNinety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism.ResultsGenotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050.ConclusionThis observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments.

KIBRA, MTNR1B, and FKBP5 genotypes are associated with decreased odds of incident delirium in elderly post-surgical patients

“…Just as individuals at risk for delirium are provided with supplemental melatonin, it is possible that having elevated and prolonged levels of melatonin can be helpful in a hospital environment where disrupted sleep is common. Interestingly, our finding is opposite the only known study investigating this gene in relation to delirium, specifically in a small population of subjects undergoing cardiac surgery 10 . Despite the observed association between melatonin dysregulation and delirium, trials of exogenous melatonin or the melatonin agonist ramelteon yielded mixed results 10 .…”

“…Interestingly, our finding is opposite the only known study investigating this gene in relation to delirium, specifically in a small population of subjects undergoing cardiac surgery 10 . Despite the observed association between melatonin dysregulation and delirium, trials of exogenous melatonin or the melatonin agonist ramelteon yielded mixed results 10 . It is possible that classifying the presence of MTNR1B genotype in participants of these trials may provide a role in understanding who may benefit from these delirium prevention therapies.…”

“…There is significant interest in improving sleep for hospitalized patients to reduce the risk of delirium, including care pathways providing non-pharmacologic means for improving sleep (e.g., ear plugs, eye masks), or the use of supplemental melatonin, which is a regulator of the circadian rhythm 29 . The MTNR1B gene encodes the melatonin receptor MT2, a G protein-coupled receptor that is expressed in many tissues and acts as a receptor for melatonin, a hormone released from the pineal gland that is important for regulation of circadian rhythms 10 . The MTNR1B G allele of the SNP rs10830963, which was found to be more common in adults without delirium in our study, is associated with altered melatonin signaling, specifically both a longer duration of elevated melatonin levels and a delayed off time 30 .…”

“…Based on the current literature, we focused on specific single nucleotide polymorphisms (SNPs) of four candidate genes associated with reduced rates or acceleration of cognitive impairment but never studied in delirium: (1) KIdney and BRAin expressed protein ( KIBRA ; rs17070145; C/T), (2) KLOTHO (rs9536314; T/G), (3) Sirtuin 1 ( SIRT1 ; rs7896005; A/G), and (4) FK506 binding protein 51 ( FKBP5 ; rs1360780; C/T). We also investigated the Melatonin Receptor-1B ( MTNR1B ) SNP rs10830963 (C/G), which was recently demonstrated in a single cardiac surgery population to be associated with reduced odds of developing delirium 10 . We sought to understand whether the absence of delirium was independently associated with increased odds of having genotypes that are associated with resiliency to cognitive impairment.…”

The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders

“…Postoperative pain is inevitable following major surgery, and improper management of pain not only decreases the total sleep duration 78 but also impacts the cognitive scores. 79 The secretion of melatonin, an important regulator of circadian rhythm, is delayed during anesthesia and surgery, [80][81][82] and the delay lasts up to the first night following surgery. 73 Postoperative supplementation with melatonin prevents related sleep disturbances 83,84 but fails to reduce the incidence of POD in elderly patients with nosocomial hip fractures.…”