Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome:A multicenter retrospective study

BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

genetic studies in irritable bowel syndrome-status quo

AIM To evaluate the most common studied genetic polymorphisms that may have an etiological role in irritable bowel syndrome (IBS).METHODS The data base Pub Med was searched for studies analyzing the association between gene polymorphisms and IBS. All original full papers, written in English, were retained for further analysis. The retrieved papers were further systematized according to those polymorphisms that have been detected in IBS.RESULTS Considering these criteria, our literature search found 12 polymorphisms, residing in 10 genes, which were reported to be consistently associated with IBS. The initial search identified 189 articles, out of which 48 potentially appropriate articles were reviewed. Of these 48 articles, 41 articles were included in the review. These articles were published between 2002 and 2016. Out of these 41 studies, 17 reported analysis of the serotonin transporter (SERT) gene (SLC6A4), eight on guanine nucleotide-binding protein subunit beta-3 (GNbeta3), six on the serotonin type 3 receptor genes (HTR3A), four on (HTR3E), three on (HTR2A), three the tumor necrosis factor superfamily member TL1A gene (TNFSF15), and ten on genetic polymorphisms with limited evidence.CONCLUSION Current evidence for the relation between genetic polymorphisms and IBS is limited owing to the fact that high-quality prospective studies and detailed phenotyping of patients suffering from IBS and matched controls were lacking in the past.

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

The interplay between keratinocytes and immune cells,especially T cells,plays an important role in the pathogenesis of chronic inflammatory skin diseases.During psoriasis,keratinocytes attract T cells by releasing chemokines,while skin-infiltrating selfreactive T cells secrete proinflammatory cytokines,e.g.,IFN γand IL-17A,that cause epidermal hyperplasia.Similarly,in chronic graftversus-host disease,allogenic IFN γ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin.However,whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown.Here,we demonstrate that under proinflammatory conditions,primary human keratinocytes indeed activate naive human T cells.This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1.Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells.In particular,keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2.The latter molecule initiated STAT1 signaling and IFN γproduction in T cells.Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease.Consequently,local interference with T cell–keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.