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Glucagon-like peptide-1 receptor gene polymorphism (Leu260Phe) is associated with morning cortisol in preschoolers.

ABSTRACT: Glucagon-like peptide-1 (GLP-1) has been shown to be a potent stress-regulating neuropeptide in animal models, but little is known about whether genetic polymorphisms that influence this peptide influence stress responses in humans. We therefore explored whether a missense mutation (rs1042044) in the GLP-1 receptor was associated with morning and evening salivary cortisol levels in preschool aged children. Morning and evening saliva samples and individual buccal swabs for DNA extraction were collected from seventy-seven preschool aged children. Salivary cortisol was assayed using a time-resolved fluorescence immunoassay with fluorometric end-point detection (DELFIA), and the rs1042044 single nucleotide polymorphism (SNP) was genotyped using allele specific TaqMan probes. Children homozygous for the phenylalanine (C) substitution in the GLP-1R gene had significantly higher morning salivary cortisol levels than children with other GLP-1R genotypes (p=0.029). Additionally, children with one or two copies of the phenylalanine (C) allele had significantly higher morning cortisol levels compared to children homozygous for the leucine (A) allele (p=0.008). Our results identify associations between a novel genetic variant of GLP-1R and hypothalamus-pituitary-adrenal (HPA) axis regulation. This polymorphism may have functional significance in stress-related psychiatric disorders.

SUBMITTER: Sheikh HI

PROVIDER: S-EPMC2910171 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Glucagon-like peptide-1 receptor gene polymorphism (Leu260Phe) is associated with morning cortisol in preschoolers.

Sheikh Haroon I HI Dougherty Lea R LR Hayden Elizabeth P EP Klein Daniel N DN Singh Shiva M SM

Progress in neuro-psychopharmacology & biological psychiatry 20100516 6

Glucagon-like peptide-1 (GLP-1) has been shown to be a potent stress-regulating neuropeptide in animal models, but little is known about whether genetic polymorphisms that influence this peptide influence stress responses in humans. We therefore explored whether a missense mutation (rs1042044) in the GLP-1 receptor was associated with morning and evening salivary cortisol levels in preschool aged children. Morning and evening saliva samples and individual buccal swabs for DNA extraction were col ...[more]

PMID: 20483198

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Project description:BackgroundCommon genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression.AimsTo determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women.MethodWe recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva.ResultsThere were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U-shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels.ConclusionsMorning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression.

Project description:OBJECTIVES:The cortisol response during critical illness varies widely among patients. Our objective was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the cortisol response among critically ill children. DESIGN:This was a prospective observational study employing tag single nucleotide polymorphism methodology to examine genetic contributions to the variability of the cortisol response in critical illness. Thirty-one candidate genes and 31 ancestry markers were examined. SETTING:Patients were enrolled from seven pediatric critical care units that constitute the Eunice Kennedy Shriver Collaborative Pediatric Critical Care Research Network. SUBJECTS:Critically ill children (n = 92), age 40 weeks gestation to 18 years old, were enrolled. INTERVENTIONS:Blood samples were obtained from all patients for serum cortisol measurements and DNA isolation. Demographic and illness severity data were collected. MEASUREMENTS AND MAIN RESULTS:Single nucleotide polymorphisms were tested for association with serum free cortisol concentrations in context of higher illness severity as quantified by Pediatric Risk of Mortality III score greater than 7. A single nucleotide polymorphism (rs1941088) in the MC2R gene was strongly associated (p = 0.0005) with a low free cortisol response to critical illness. Patients with the AA genotype were over seven times more likely to have a low free cortisol response to critical illness than those with a GG genotype. Patients with the GA genotype exhibited an intermediate free cortisol response to critical illness. CONCLUSIONS:The A allele at rs1941088 in the MC2R gene, which encodes the adrenocorticotropic hormone (corticotropin, ACTH) receptor, is associated with a low cortisol response in critically ill children. These data provide evidence for a genetic basis for a portion of the variability in cortisol production during critical illness. Independent replication of these findings will be important and could facilitate development of personalized treatment for patients with a low cortisol response to severe illness.

Project description:ObjectiveClinical reports link use of the glucagon-like peptide-1 receptor (GLP-1R) agonists exenatide and liraglutide to pancreatitis. However, whether these agents act on the exocrine pancreas is poorly understood.Research design and methodsWe assessed whether the antidiabetic agents exendin (Ex)-4, liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or the biguanide metformin were associated with changes in expression of genes associated with the development of experimental pancreatitis. The effects of Ex-4 when administered before or after the initiation of caerulein-induced experimental pancreatitis were determined. The importance of endogenous GLP-1R signaling for gene expression in the exocrine pancreas and the severity of pancreatitis was assessed in Glp1r(-/-) mice.ResultsAcute administration of Ex-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of Ex-4 or liraglutide for 1 week increased pancreas weight and induced expression of mRNA transcripts encoding the anti-inflammatory proteins pancreatitis-associated protein (PAP) (RegIIIbeta) and RegIIIalpha. Chronic Ex-4 treatment of high-fat-fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory monocyte chemotactic protein-1, tumor necrosis factor-alpha, and signal transducer and activator of transcription-3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Ex-4 administered before or after caerulein did not modify the severity of experimental pancreatitis, and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r(-/-) versus Glp1r(+/+) mice.ConclusionsThese findings demonstrate that GLP-1 receptor activation increases pancreatic mass and selectively modulates the expression of genes associated with pancreatitis. However, activation or genetic elimination of GLP-1R signaling does not modify the severity of experimental pancreatitis in mice.

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Glucagon-like peptide-1 receptor gene polymorphism (Leu260Phe) is associated with morning cortisol in preschoolers.

Publications

Glucagon-like peptide-1 receptor gene polymorphism (Leu260Phe) is associated with morning cortisol in preschoolers.

Similar Datasets

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