Analiza genov leptin-melanokortinske poti pri pediatričnih pacientih z debelostjo

Kocen, Valentina (author), Trebušak Podkrajšek, Katarina (mentor), Kovač, Jernej (co-mentor)

Debelost je pomemben zdravstveni problem tudi pri otrocih, saj vodi v različne bolezni v odrasli dobi. Gre za stanje pozitivnega energijskega ravnovesja, ko začne kalorični vnos presegati porabo kalorij v daljšem časovnem obdobju. Pri tem se zmanjša delež mišičnega tkiva in poveča delež maščobnega tkiva, ki se kopiči predvsem v obliki podkožnega maščevja ali visceralne maščobe. Po podatkih iz leta 2016 je bilo 40 milijonov otrok pod 5 letom starosti in več kot 330 milijonov otrok med 5. in 19. letom prekomerno prehranjenih ali debelih. Pri nastanku otroške debelosti ima največji vpliv okolje, medtem ko genetske bolezni predstavljajo med 30 in 50 % vzrokov. Pri tem so poligenske bolezni pogostejše. Največ genov, vključenih v uravnavanje apetita in metabolizma, se nahaja v leptin-melanokortinski poti. Ta je sestavljena iz treh rok: aferentne, ki sprejema informacije na periferiji, centralne obdelovalne enote, ki obdeluje informacije v hipotalamusu, in eferentne, ki prek avtonomnih efektorjev regulira vnos energije in energijsko porabo. Leptin in adiponektin pošiljata informacije o periferni količini zaloge adipocitne energije do hipotalamusa, pri zmanjšani zalogi energije se aktivira oreksigena pot prek agoutiju sorodnega peptida in nevropeptida Y. Pri povečani zalogi energije se prek proopiomelanokortina aktivirata melanokortinski receptor 3 in melanokortinski receptor 4, ki delujeta anoreksigeno. Namen magistrske naloge je bilo s sekvenciranjem naslednje generacije ugotoviti prisotnost sprememb v 15 izbranih genih leptin-melanokortinski poti, njihovo frekvenco pri testni in kontrolni skupini ter prepoznati gene s potencialno večjo patogenostjo. V nalogo je bilo vključenih 1544 preiskovancev starih med 2 in 19 let, od tega je bilo 1216 oseb s povečano telesno maso in 328 oseb z normalno telesno maso. Prisotnost sprememb neznanega pomena in patogenih sprememb smo odkrili pri 97 (8 %) osebah v testni skupini in 13 (4 %) osebah v kontrolni skupini, kar prikazuje rahlo višji delež pri testni skupini. Patološke ali spremembe neznanega pomena so bile prisotne v skoraj vseh analiziranih genih leptin-melanokortinske poti, največ jih je bilo v genih LEPR, MC3R, MC4R in POMC. Gre za gene, katerih spremembe znano največkrat povzročajo monogensko debelost. Kot najbolj patogen se je izkazal gen MC4R, v katerem je bilo prisotnih 9 različnih sprememb pri 11 osebah s povečano telesno maso. V genu MC4R je bila prisotna tudi statistično značilna razlika v telesni masi med osebami s patološko spremembo in med osebami brez patološke spremembe.

• Language: Slovenian
• Keywords: Ključne besede: genetika, pediatrična debelost, leptin-melanokortinska pot, sekvenciranje naslednje generacije
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-127586
• Publication date in RUL: 16.06.2021

Secondary language

• Language: English
• Title: Gene analysis of leptin-melanocortin pathway in obese pediatric patients

Abstract

Obesity is currently a significant health problem, as it causes serious health problems in children and can lead to various related disorders in adulthood. It is a condition of a positive energy balance over a prolonged period, at which caloric intake begins to surpass calorie consumption while reducing the amount of muscles and increasing the percentage of adipose tissue, that accumulates in the form of subcutaneous or visceral fat. According to data from 2016, 40 million children under the age of 5 and more than 330 million children between the ages of 5-19 were overweight or obese. Environment factors have a significant impact on the development of childhood obesity, while genetic factors represent between 30 to 50 % of all the causes, polygenic being more common. Most of the genes involved in regulating appetite and metabolism are associated with the leptin-melanocortin pathway. It consists of three arms; the afferent arm receives information from the periphery, the central processing unit, which processes information in the hypothalamus, and the efferent arm, which regulates energy intake and energy consumption through autonomous effectors. Leptin and adiponectin send information about the amount of peripheral adipose energy to the hypothalamus. Orexigenic pathway, agouti-related protein and neuropeptide Y are activated when energy mass is reduced. Anorexigenic pathway, melanocortin 3 and 4 receptor are activated, through proopiomelanocortin, when energy supply is increased. The goal of the study was to determine genetic variants in the selected panel of 15 genes associated with the leptin-melanocortin pathway with next-generation sequencing. Furthermore, we aimed to analysed their frequency in the test and control group and to identify genes with higher pathogenicity. The study included 1544 people between the ages of 2 and 19, among them 1216 in the test and 328 in the control group. The pathogenic and changes of unknown significance were found in 97 (8%) test and 13 (4%) control subjects, indicating a slightly higher percentage in the test group. Pathological and changes of unknown significance were present in almost all genes of the panel, the majority in LEPR, MC3R, MC4R, and POMC, previously associated with monogenetic obesity. MC4R was the most highly pathogenic gene with 9 different pathogenic and changes of unknown significance in 11 subjects from the test group. In addition, in MC4R, a significant increase in body weight was observed in subjects with pathological changes, compared to the subjects without pathological change.

• Keywords: Keywords: genetics, pediatric obesity, leptin-melanocortin pathway, next-generation sequencing