Interaction between HTR2A rs3125 and negative life events in suicide attempts among patients with major depressive disorder: a cross-sectional study.

BACKGROUND: Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. METHODS: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. RESULTS: Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071-2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515-3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264-4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264-5.131, P = 0.009). CONCLUSION: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD.

Association of serotonin receptor gene polymorphisms with anorexia nervosa: a systematic review and meta-analysis.

PURPOSE: Several studies have investigated the association between anorexia nervosa and polymorphisms of genes regulating serotonin neurotransmission, with a focus on the rs6311 polymorphism of 5-HTR2A. However, inconsistent results of these studies and conflicting conclusions of existing meta-analyses complicate the understanding of a possible association. We have updated these results and evaluated the involvement of other serotonin receptor gene polymorphisms in anorexia nervosa. METHODS: Adhering to PRISMA guidelines, we have searched studies on anorexia nervosa and serotonin-regulating genes published from 1997 to 2022, selected those concerning receptor genes and meta-analyzed the results from twenty candidate gene studies on the 5-HTR2A rs6311 polymorphism and the 5-HTR2C rs6318 polymorphism. RESULTS: Present analyses reveal an association for the 5-HTR2A rs6311 polymorphism, with G and A alleles, across eighteen studies (2049 patients, 2877 controls; A vs. G allele, Odds Ratio = 1.24; 95% Confidence Interval = 1.06-1.47; p = 0.009). However, after geographic subgrouping, an association emerged only in a Southern European area, involving five studies (722 patients, 773 controls; A vs. G allele, Odds Ratio = 1.82; 95% Confidence Interval = 1.41-2.37; p < 0.00001). No association was observed for the 5-HTR2C rs6318 polymorphism across three studies. CONCLUSIONS: To date, the involvement in the pathophysiology of anorexia nervosa of the 5-HTR2A rs6311 polymorphism appears limited to a specific genetic and/or environmental context, while that of the 5-HTR2C rs6318 polymorphism seems excluded. Genome-wide association studies and epigenetic studies will likely offer deeper insights of genetic and environmental factors possibly contributing to the disorder. LEVEL OF EVIDENCE: III Evidence obtained from well-designed cohort or case-control analytic studies. Clinical trial registration PROSPERO registration number: CRD42021246122.

Revealing receptor-ligand interactions of atypical antipsychotic drugs and screening anti-schizophrenia ingredients in Magnolia officinalis based on 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models.

Schizophrenia is a serious mental illness with unknown etiology, and shows increasing incidence and high lifetime prevalence rate. The main receptors related to the disease are DRD2 and 5-HTR2A. Thus, a comprehensive understanding of the interaction mode between antipsychotic drugs with relevant receptors is very important for developing more effective drugs. 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models constructed in this work provided a new method for studying the interaction between atypical antipsychotics and the two receptors. The results of comparative experiments showed that the new models not only met the high selectivity and specificity of the screening requirements but were also more stable and long-lasting than the traditional CMC model. Binding assays showed that the effects of three atypical antipsychotics (including clozapine, olanzapine, and quetiapine) on 5-HTR2A were stronger than their effects on DRD2. Additionally, two potentially active components, magnolol and honokiol, were screened in Magnolia officinalis methanol extract using the 5-HTR2A-SNAP-Tag/CMCHPLC-MS system. Nonlinear chromatographic analysis and molecular docking were conducted to study the interactions between screened compounds and the two receptors. The binding constants (KA) of magnolol and honokiol with 5-HTR2A were 17,854 ± 1,117 M-1 and 38,858 ± 4,964 M-1, respectively, and KA values with DRD2 were 4,872 ± 1,618 M-1 and 20,692 ± 10,267 M-1, respectively. We concluded that the established models are reliable for studying receptor-ligand interactions and screening antagonists of schizophrenia.

BDNF, DRD4, and HTR2A Gene Allele Frequency Distribution and Association with Mental Illnesses in the European Part of Russia.

The prevalence of mental disorders and how they are diagnosed represent some of the major problems in psychiatry. Modern genetic tools offer the potential to reduce the complications concerning diagnosis. However, the vast genetic diversity in the world population requires a closer investigation of any selected populations. In the current research, four polymorphisms, namely rs6265 in BDNF, rs10835210 in BDNF, rs6313 in HTR2A, and rs1800955 in DRD4, were analyzed in a case-control study of 2393 individuals (1639 patients with mental disorders (F20-F29, F30-F48) and 754 controls) from the European part of Russia using the TaqMan SNP genotyping method. Significant associations between rs6265 BDNF and rs1800955 DRD4 and mental impairments were detected when comparing the general group of patients with mental disorders (without separation into diagnoses) to the control group. Associations of rs6265 in BDNF, rs1800955 in DRD4, and rs6313 in HTR2A with schizophrenia in patients from the schizophrenia group separately compared to the control group were also found. The obtained results can extend the concept of a genetic basis for mental disorders in the Russian population and provide a basis for the future improvement in psychiatric diagnostics.

Regulation of headache response and transcriptomic network by the trigeminal ganglion clock.

OBJECTIVE: To characterize the circadian features of the trigeminal ganglion in a mouse model of headache. BACKGROUND: Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood. METHODS: We examined trigeminal ganglion ex vivo and single-cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross-referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy. RESULTS: The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single-cell cultures, with core circadian proteins found in both neuronal and non-neuronal cells. Using our novel behavioral model, we showed that nitroglycerin-treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA-sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock-regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia. CONCLUSION: Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology. PLAIN LANGUAGE SUMMARY: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24-hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day.

CX3CR1 mediates motor dysfunction in mice through 5-HTR2a.

CX3CR1 knockout could induce motor dysfunction in several neurological disease models mainly through regulating microglia's function. While CX3CR1 was expressed on neurons in a few reports, whether neuronal CX3CR1 could affect the function of neurons and mediate motor dysfunction under physiological conditions is unknown. To elucidate the roles of neuronal CX3CR1 on motor dysfunction, CX3CR1 knockout mice were created. Rotarod test and Open field test found that the CX3CR1-/- mice's motor capacity was reduced. Immunofluorescence staining detected the expression of CX3CR1 in neurons both in vivo and in vitro. Immunohistochemistry and West blot found that knockout of CX3CR1 did not affect the neurons' number in both spinal cord and brain of mice. While inhibiting the function of CX3CR1 by AZD8797 could decrease the expression of 5-Hydroxytryptamine receptor(5-HTR2a), which involved in the regulation of motor function. Further investigation revealed that CX3CR1 regulated the expression of HTR2a through the NF-κB pathway. For the first time, we reported that neuronal CXCR1 mediates motor dysfunction. Our results suggest that modulating CXCR1 activity offers a novel therapeutic strategy for motor dysfunction.

Association between the rs6313 polymorphism in the 5-HTR2A gene and the efficacy of antipsychotic drugs.

BACKGROUND: Prescribing the optimal antipsychotic treatment to schizophrenia is very important as it is well established that patients have different sensitivity to the available antipsychotic drugs. The genotype of the HTR2A T102C (rs6313) polymorphism has been suggested to affect the efficacy of antipsychotic drugs, but the results of different studies have been inconsistent METHODS: In this study, a meta-analysis was used to ascertain the association between allele and genotype polymorphism of rs6313 and the efficacy of antipsychotic drugs. Related studies publicated from January 1995 to December 2021 were retrieved from PubMed, Embase, ScienceDirect, and Web of Science databases. The correlations between allele and genotype polymorphism of rs6313 and the responder rate and scale score reduction rate of antipsychotics were analyzed. In addition, subgroup analyses were performed on time, drug, and ethnicity. RESULTS: A total of 18 studies were included. The meta-analysis showed that allele and genotype polymorphisms at the rs6313 locus overall were not associated with antipsychotic drug responder rate or scale score reduction rate. Ethnicity subgroup analysis showed that antipsychotic drugs were more effective in patients with allele T in the Caucasian population. Indian patients with the TT genotype had the lowest scale score reduction rate and poor drug treatment effect. East Asian patients with the TC genotype had better treatment effect, whereas in patients with the CC genotype, the treatment was less effective. Drug subgroup analysis showed that patients with the TC genotype treated with clozapine had the highest responder rate and score reduction rate. CONCLUSIONS: The association between rs6313 polymorphism and the efficacy of antipsychotic drugs is mainly influenced by drug and ethnicity. Caucasian patients with the T allele respond better to drug therapy, and Asian patients with TC genotype. The TC genotype was also a good predictor of the efficacy of clozapine treatment.

Prognostic and immunomodulatory roles of schizophrenia-associated genes HTR2A, COMT, and PRODH in pan-cancer analysis and glioma survival prediction model.

Background: The shortened life expectancy in schizophrenia (SCZ) patients may be correlated with most cancers, yet there is heterogeneity in the studies examining these correlations. This study explored the expression of SCZ-related genes (HTR2A, COMT, and PRODH) in pan-cancer analysis. It helped to enhance the mechanistic understanding of the SCZ-cancer relationship and their immune mechanisms at the genetic level. Additionally, this study established a survival prediction model for glioblastoma and low-grade glioma (GBMLGG). Methods and results: SCZ-associated genes (HTR2A, COMT, and PRODH) were subjected to pan-cancer analysis. COX regression analysis and survival analysis were carried out for differentially expressed genes in multiple cancers, and finally, GBMLGG was derived as the focus for further detailed analysis. The immune scores and immune cell infiltration analyses were performed. All three genes were considerably linked with immune infiltration in GBMLGG, consistent with survival analysis. Based on the immunocyte analysis, it was observed that CD8+ T cells might be critically involved in the survival of GBMLGG. Genomic heterogeneity studies identified correlations of three genes with GBMLGG in tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH). HTR2A and COMT were significantly negatively correlated in TMB. Furthermore, it was found that HTR2A had a significant positive correlation with MATH, whereas PRODH had a significant negative correlation with MATH. Accordingly, a survival prediction model was constructed for GBMLGG using these three genes and clinical data, with better results obtained when evaluated in two separate datasets. Finally, gene expression validation and further immunocyte analysis were carried out in the single-cell RNA sequencing (scRNA-seq) data of glioma. Conclusion: SCZ-associated genes (HTR2A, COMT, and PRODH) were significantly differentially expressed in the carcinogenesis and survival of multiple cancers. The up or downregulation of gene expression varied across cancer types. In the GBMLGG analysis, upregulation of HTR2A and COMT was significantly positively correlated with carcinogenesis, while the opposite was noted for PRODH. Furthermore, a negative correlation was found between the upregulation of HTR2A and COMT and the survival of GBMLGG, and the opposite was also noted for PRODH. As reflected in the immunocyte analysis, abnormal expression of the three genes might be linked with CD8+ T cell infiltration, which might be critically involved in the survival of GBMLGG patients. The expression of HTR2A and COMT may inversely affect the efficacy of immunotherapy through the TMB pathway and further affect the prognosis of patient survival. The expression of HTR2A might positively indicate the degree of tumor heterogeneity through MATH and further affect the survival and prognosis of patients. The negative correlation of PRODH led to the opposite effect. Finally, the constructed survival prediction model demonstrated good predictive value, which was well validated in scRNA-seq analysis.

Effects of serotonin transporter and receptor polymorphisms on depression.

INTRODUCTION: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. OBJECTIVE: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. METHODS: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). CONCLUSIONS: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.

Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats.

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC.

Association between single-nucleotide polymorphisms in serotonin receptor 2A and melatonin receptor 1A genes and pain after root canal treatment.

AIM: This study aimed to investigate whether single-nucleotide polymorphisms (SNPs) in the genes encoding 5-HTR2A (5-Hydroxytryptamine (serotonin) receptor 2A) and MTNR1A (melatonin receptor 1A) may contribute to postoperative pain perception after root canal treatment. We hypothesised that SNPs in HTR2A and MTNR1A genes were associated with postoperative pain after root canal treatment. METHODOLOGY: This genetic cohort study enrolled patients with single-rooted teeth diagnosed with pulp necrosis and asymptomatic apical periodontitis before root canal treatment. Root canal treatment was performed in one session using a standardized protocol. Postoperative pain and tenderness were assessed using a visual analogue scale (recorded every day for 7 days and on the 14th and 30th days after root canal treatment). Genomic DNA was extracted from saliva and used to genotype the SNPs in HTR2A (rs4941573 and rs6313) and MTNR1A (rs6553010, rs6847693 and rs13140012) using real-time polymerase chain reaction. Genotypes were compared using univariate and multivariate Poisson regression with generalized estimating equations (p < .05). RESULTS: In total, 108 patients were enrolled in this study. The SNPs rs6553010 (MTNR1A), rs4941573 and rs6313 (HTR2A) were associated with an increased risk of developing pain after root canal treatment (p < .05). CONCLUSIONS: This study suggests that SNPs in HTR2A and MTNR1A influence pain response after root canal treatment.

Development of a Novel Senolysis Approach Targeting the Senescent Fibroblast Marker HTR2A via Antibody-Dependent Cellular Cytotoxicity.

Abnormal remodeling of collagen and extracellular matrix caused by the accumulation of senescent fibroblasts in the dermis is the most likely cause of skin aging. Therefore, the application of "senolysis," in which only senescent cells are cleared from the body, has a potential in the development of antiaging treatments for skin. However, markers that label senescent fibroblasts only reflect the state of senescence, and it is important to develop markers as therapeutic targets to aid senolysis application. We investigated the potential of serotonin 2A receptor (HTR2A), which is involved in melanin production in response to ultraviolet light, as a senescent cell marker. The results showed that HTR2A is upregulated in aging dermal fibroblasts but is expressed at low levels in proliferating young cells. Flow cytometry demonstrated the presence of many HTR2A-positive cells in the aging cell population and few in the young cells. Furthermore, antibody-dependent cytotoxicity assays revealed that HTR2A preferentially sensitizes senescent fibroblasts and specifically damages only senescent cells by natural killer cells that recognize it. In conclusion, selective labeling of the novel senescent cell marker, HTR2A, could preferentially eliminate senescent cells and may contribute to the future development of novel skin senolysis approaches.

Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice.

The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RA gene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood-brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction.

Efectos de los Polimorfismos del Transportador y de los Receptores de Serotonina en la Depresión

Introducción: La serotonina tiene gran implicación en la regulación del estado emocional y la ejecución de tareas cognitivas, de modo que los genes del transportador de serotonina (5-HTT, SLC6A4) y de los receptores de serotonina (HTR1A, HTR1B, HTR2A) se convierten en candidatos adecuados para estudiar los efectos de estos genes y sus variaciones polimórficas en las características de la depresión. Objetivo: Revisión de reportes de investigación que hayan estudiado los efectos de las variantes de los genes del transportador y de los receptores de serotonina en las diferentes características clínicas de la depresión. Métodos: Se realizó una búsqueda en las bases de datos Scopus, Web of Science y PubMed con las palabras clave "depression", AND "polymorphism". Conclusiones: Según la revisión de 54 artículos, se encontró que el alelo corto del polimorfismo de 5-HTTLPR es el factor de riesgo más reportado en relación con el desarrollo de depresión y su gravedad. Las variantes de los genes estudiados (SLC6A4, HTR1A, HTR1B y HTR2A) pueden generar alteraciones morfológicas de estructuras cerebrales.

Introduction: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. Objective: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. Methods: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). Conclusions: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.

Association of GABRG3, GABRB3, HTR2A gene variants with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental and neurobehavioral disorder characterized by impaired social communication, repetitive and restricted patterns of behavior, activity, or interest, and altered emotional processing. Reported prevalence is 4 times higher in men and it has increased in recent years. Immunological, environmental, epigenetic, and genetic factors play a role in the pathophysiology of autism. Many neurochemical pathways and neuroanatomical events are effective in determining the disease. It is still unclear how the main symptoms of autism occur because of this complex and heterogeneous situation. In this study, we focused on gamma amino butyric acid (GABA) and serotonin, which are thought to contribute to the etiology of autism; it is aimed to elucidate the mechanism of the disease by investigating variant changes in the GABA receptor subunit genes GABRB3, GABRG3 and the HTR2A gene, which encodes one of the serotonin receptors. 200 patients with ASD between the ages of 3-9 and 100 healthy volunteers were included in the study. Genomic DNA isolation was performed from peripheral blood samples taken from volunteers. Genotyping was performed using the RFLP method with PCR specific for specific variants. Data were analyzed with SPSS v25.0 program. According to the data obtained in our study; In terms of HTR2A (rs6313 T102C) genotypes, the homozygous C genotype carrying frequency in the patient group and the homozygous T genotype carrying frequency in the GABRG3 (rs140679 C/T) genotypes were found to be significantly higher in the patient group compared to the control group (*p: 0.0001, p: 0.0001). It was determined that the frequency of individuals with homozygous genotype was significantly higher in the patient group compared to the control group and having homozygous genotypes increased the disease risk approximately 1.8 times. In terms of GABRB3 (rs2081648 T/C) genotypes, it was determined that there was no statistically significant difference in the frequency of carrying homozygous C genotype in the patient group compared to the control group (p: 0.36). According to the results of our study, we think that the HTR2A (rs6313 T102C) polymorphism is effective in modulating the empathic and autistic characteristics of individuals, and that the HTR2A (rs6313 T102C) polymorphism is more distributed in the post-synaptic membranes in individuals with a higher number of C alleles. We believe that this situation can be attributed to the spontaneous stimulatory distribution of the HTR2A gene in the postsynaptic membranes because of T102C transformation. In genetically based autism cases, carrying the point mutation in the rs6313 variant of the HTR2A gene and the C allele and the point mutation in the rs140679 variant of the GABRG3 gene and accordingly carrying the T allele provide a predisposition to the disease.

Nano Parthenolide Improves Intestinal Barrier Function of Sepsis by Inhibiting Apoptosis and ROS via 5-HTR2A.

Background: Intestinal barrier dysfunction is an important complication of sepsis, while the treatment is limited. Recently, parthenolide (PTL) has attracted much attention as a strategy of sepsis, but whether nano parthenolide (Nano PTL) is therapeutic in sepsis-induced intestinal barrier dysfunction is obscured. Methods: In this study, cecal ligation and puncture (CLP)-induced sepsis rats and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells (IECs) were used to investigate the effect of PTL on intestinal barrier dysfunction. Meanwhile, we synthesized Nano PTL and compared the protective effect of Nano PTL with ordinary PTL on intestinal barrier function in septic rats and IECs. Network pharmacology and serotonin 2A (5-HTR2A) inhibitor were used to explore the mechanism of PTL on the intestinal barrier function of sepsis. Results: The encapsulation rate of Nano PTL was 95±1.5%, the drug loading rate was 11±0.5%, and the average uptake rate of intestinal epithelial cells was 94%. Ordinary PTL and Nano PTL improved the survival rate and survival time of septic rats, reduced the mean arterial pressure and the serum level of inflammatory cytokines, and protected the liver and kidney functions in vivo, and increased the value of transmembrane resistance (TEER) reduced the reactive oxygen species (ROS) and apoptosis in IECs in vitro through 5-HTR2A. Nano PTL had better effect than ordinary PTL. Conclusion: Ordinary PTL and Nano PTL can protect the intestinal barrier function of septic rats by inhibiting apoptosis and ROS through up-regulating 5-HTR2A, Nano PTL is better than ordinary PTL.

HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation.

Group 2 innate lymphoid cells (ILC2s) are a category of heterogeneous cells that produce the cytokines IL-5 and IL-13, which mediate the type 2 immune response. However, specific drug targets on lung ILC2s have rarely been reported. Previous studies have shown that type 2 cytokines, such as IL-5 and IL-13, are related to depression. Here, we demonstrated the negative correlation between the depression-associated monoamine neurotransmitter serotonin and secretion of the cytokines IL-5 and IL-13 by ILC2s in individuals with depression. Interestingly, serotonin ameliorates papain-induced lung inflammation by suppressing ILC2 activation. Our data showed that the serotonin receptor HTR2A was highly expressed on ILC2s from mouse lungs and human PBMCs. Furthermore, an HTR2A selective agonist (DOI) impaired ILC2 activation and alleviated the type 2 immune response in vivo and in vitro. Mice with ILC2-specific depletion of HTR2A (Il5cre/+·Htr2aflox/flox mice) abolished the DOI-mediated inhibition of ILC2s in a papain-induced mouse model of inflammation. In conclusion, serotonin and DOI could restrict the type 2 lung immune response, indicating a potential treatment strategy for type 2 lung inflammation by targeting HTR2A on ST2+ ILC2s.

The contribution of the 5-hydroxytryptamine receptor 2 A gene polymorphisms rs6311 and rs6313 to Schizophrenia in Iran.

OBJECTIVE: Schizophrenia is an acute mental disorder with an undefined etiology. Its high heritability suggests that several genetic variants and polymorphisms may contribute to the severity and emergence of its symptoms. Former molecular evidence has shed some light on the association of serotonergic pathway genetic polymorphisms with schizophrenia. This study aimed to investigate the association between schizophrenia and two SNPs from one haplotype block, which lies in the 5-hydroxytryptamine receptor 2 A (5-HTR2A) gene in the Iranian population. MATERIAL AND METHODS: Blood samples were collected from one-hundred and fifty-two patients diagnosed with schizophrenia and one-hundred and fifty-eight cases of the healthy control, who were matched in terms of age and gender. The participants were genotyped for rs6311 and rs6313 using PCR-RFLP. R programming language and Haploview software were respectively leveraged for statistical and haplotype inferencing. RESULTS: The results showed that there was no significant association between rs6313 and schizophrenia. However, the rs6311 T allele was independently associated with schizophrenia, and it was significantly associated with SCZ in an rs6311-rs6313 haplotype. Moreover, the general linear model confirmed the potential predictor role of rs6311 for schizophrenia and the C allele of rs6313 demonstrated a higher frequency among females compared to males. CONCLUSION: The findings of this study indicated the association of rs6311 and rs6311-rs6313 haplotype with schizophrenia in the Iranian population and also suggested a potential schizophrenia risk predictor role for rs6311.

Circulating methylation level of HTR2A is associated with inflammation and disease activity in rheumatoid arthritis.

Objectives: HTR2A is previously identified as a susceptibility gene for rheumatoid arthritis (RA). In this study, we performed the association analysis between DNA methylation of HTR2A with RA within peripheral blood samples. Methods: We enrolled peripheral blood samples from 235 patients with RA, 30 osteoarthritis (OA) patients, and 30 healthy controls. The DNA methylation levels of about 218 bp from chr13: 46898190 to chr13: 46897973 (GRCh38/hg38) around HTR2A cg15692052 from patients were analyzed by targeted methylation sequencing. Results: We measured methylation status for 7 CpGs in the promoter region of HTR2A and obseved overall methylation status are signficantly increased in RA compared with normal inviduals (FDR= 9.05 x 10-5). The average cg15692052 methylation levels (methylation score) showed a positive correlation with CRP (r=0.15, P=0.023). Compared with the OA group or HC group, the proportion of haplotypes CCCCCCC (FDR=0.02 and 2.81 x 10-6) is signficantly increased while TTTTTCC (FDR =0.01) and TTTTTTT(FDR =6.92 x 10-3) are significantly decreased in RA. We find methylation haplotypes combining with RF and CCP could signficantly enhance the performance of the diagnosing RA and its comorbidities (hypertension, interstitial lung disease, and osteoporosis), especially in interstitial lung disease. Conclusions: In our study, we found signficant hypermethylation of promoter region of HTR2A which indicates the potential clinical diagnostic role in rheumatoid arthritis.

Peer victimization, depression, and non-suicidal self-injury among Chinese adolescents: the moderating role of the 5-HTR2A gene rs6313 polymorphism.

BACKGROUND: Peer victimization is a crucial risk predictor for adolescent non-suicidal self-injury (NSSI). However, adolescent NSSI reactions to peer victimization exhibit large individual differences. This study explored whether depression mediated the association between peer victimization and adolescent NSSI, and whether this mediating path was moderated by the 5-HTR2A gene rs6313 polymorphism. METHODS: A total of 667 adolescents (Meanage = 12.81, SD = 0.48) completed questionnaires regarding peer victimization, depression, and NSSI. Genomic DNA was extracted from saliva and buccal cells from each participant. RESULTS: The results showed that the positive relation between peer victimization and adolescent NSSI was mediated by depression. Moreover, the triple interaction between peer victimization, rs6313 polymorphism, and gender on adolescent depression was significant. And the triple interaction between depression, rs6313 polymorphism, and gender on adolescent NSSI was also significant. Specifically, the risk effect of peer victimization on adolescent NSSI through increased depression was stronger for female adolescents with CC genotype than for female adolescents with CT or TT genotype, and male adolescents with CT or TT genotype. However, the indirect effect was nonsignificant for male adolescents with CC genotype. CONCLUSIONS: These findings promote the etiological understanding of adolescent NSSI, highlighting the mediating and moderating effect between peer victimization and NSSI, and adding evidence supporting the relationship between the 5-HTR2A gene rs6313 polymorphism, depression and adolescent NSSI.