Varijante u genima za editovanje RNK, serotoninski receptor 2C i triptofan-hidroksilazu 2 kao faktori rizika za pokušaj samoubistva kod psihijatrijskih bolesnika

Abstract

Samoubilačko ponašanje predstavlja globalni zdravstveni problem s obzirom da oko milion ljudi godišnje izvrši samoubistvo, a efikasne mere prevencije ili lečenja ne postoje. Kao i drugi složeni fenotipovi, etiologija samoubilačkog ponašanja vezuje se za brojne genetičke i sredinske faktore rizika i njihove međusobne interakcije. Pokušaj samoubistva je često, ali ne i nužno, povezan sa psihijatrijskim oboljenjima i stresnim događajima tokom života, kao što su stresni događaji iz detinjstva i akutni stresni događaji. Neurobiološka istraživanja ukazuju na hipofunkciju serotoninskog sistema kod osoba sa samoubilačkim ponašanjem. Editovanje RNK deaminacijom adenozina u inozin, katalizovan enzimima ADAR i ADARB1, doprinosi finoj i dinamičnoj regulaciji i održavanju optimalne serotoninske transmisije kroz editovanje transkripata za triptofanhidroksilazu 2 (TPH2), enzima koji katalizuje sintezu serotonina u mozgu, i transkripata za postsinaptički serotoninski receptor 2C (HTR2C). Cilj ove doktorske teze je identifikacija varijanti u genima TPH2, HTR2C, ADAR i ADARB1, stresnih životnih događaja i njihovih međusobnih interakcija koje mogu napraviti razliku između psihijatrijskih bolesnika koji su pokušali samoubistvo i onih koji to nikada nisu uradili. Studija je uključila 353 psihijatrijska bolesnika sa dijagnozom depresivnog poremećaja, bipolarnog afektivnog poremećaja i shizofrenije, od kojih je 165 pokušalo samoubistvo, dok njih 188 nije. Stresni događaji iz detinjstva i akutni stresni događaji procenjeni su korišćenjem upitnika Early Trauma Inventory–Self Report i List of Threatening Experiences Questionnaire, redom. Primenom Pirsonovog 2–testa i logističke regresije testirane su potencijalne pojedinačne asocijacije stresnih događaja tokom detinjstva, akutnih stresnih događaja, 23 tag varijante gena ADAR i ADARB1, varijanta rs6318 gena HTR2C i varijante rs7305115 i rs4290270 gena TPH2 sa pokušajem samoubistva. Generalizovani linearni modeli i selekcija unazad primenjeni su za ispitivanje udruženih efekata pojedinačnih faktora i njihovih interakcija na rizik za pokušaj samoubistva, uključujući psihijatrijske dijagnoze, pol i starost bolesnika kao konfaunderi...

Suicidal behavior is a global health problem since about one million people per year commit suicide and there is no effective prevention or treatment. Like other complex phenotypes, etiology of suicidal behavior is associated with numerous genetic and environmental risk factors and their interactions. A suicide attempt is often, although not necessarily, associated with psychiatric disorders and stressful life events, such as childhood abuse and acute stressful life events. Neurobiological studies have indicated a hypofunction of the serotonin system in patients with suicidal behavior. RNA editing by deamination of adenosine to inosine, catalysed by ADAR and ADARB1 enzymes, contributes to fine and dynamic tuning and maintenance of an optimal serotonin transmission through the editing of transcripts encoded by the tryptophan-hydroxylase 2 (TPH2) and serotonin receptor 2C (HTR2C) genes. TPH2 is a rate limiting enzyme for serotonin synthesis in the brain, while HTR2C is a postsynaptic receptor. The aim of this doctoral thesis was to identify variants in the TPH2, HTR2C, ADAR and ADARB1 genes, individual stressful life events, and possible interaction among these factors that might help to differentiate between psychiatric patients who attempted suicide and those who did not. The study included 353 patients diagnosed with major depressive disorder, bipolar affective disorder and schizophrenia, of which 165 attempted suicide, while 188 did not. Childhood abuse and acute stressful life events were evaluated using the Early Trauma Inventory Self-Report questionnaire and the List of Threatening Experiences Questionnaire, respectively. Pearson’s 2–test and logistic regression were performed to test potential individual association of various domains of child abuse, acute stressful events, 23 ADAR and ADARB1 tag variants, HTR2C variant rs6318 and TPH2 variants rs7305115 and rs4290270 with attempted suicide. Generalized linear models and backward selection were applied to test the joint effect of individual and interacting effects of examined factors on suicide attempt, including psychiatric diagnoses, patients’ gender and age as potential confounders...