Title Host genetics in susceptibility to respiratory infectious diseases Title (croatian) Genetika domaćina u osjetljivosti na respiratorne zarazne bolesti Author Andrea Gelemanović Mentor Ozren Polašek (mentor)Committee member Janoš Terzić (predsjednik povjerenstva)Committee member Vjekoslav Krželj (član povjerenstva)Committee member Alemka Markotić (član povjerenstva)Granter University of Split Defense date and country 2019, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 61 - Medical sciences Abstract Background and aim: With substantial global burden of respiratory infectious diseases on human health, it is important to elucidate all the factors involved in their susceptibility and pathogenesis. Frequently used approach is to study host genetic polymorphisms, but results of such studies were often inconsistent. The aim of this Thesis was to provide the most comprehensive and up to date field synopsis on involvement of host genetics to respiratory infections (tuberculosis, influenza, pneumonia, RSV, SARS) susceptibility.
Methods: 425 studies were identified as relevant and meta-analysed from the total of 30,307 studies identified in a systematic search of four bibliographic databases and stringently assessed for risk of bias using the novel Confounding-Selection-Information risk of bias scale.
Results: In random-effects meta-analysis four genes retained their significance after multiple testing correction: IL4 for RSV (rs2070874, OR [95% CI] = 0.69 [0.58, 0.81]; rs2243250, OR [95% CI] = 0.76 [0.66, 0.87]) and pooled respiratory infections (rs2070874, OR [95% CI] = 0.75 [0.65, 0.87]), TLR2 for tuberculosis (rs5743708, OR [95% CI] = 3.21 [2.05, 5.02]) and pooled respiratory infections (rs3804099, OR [95% CI] = 1.40 [1.18, 1.65]), IFNG for tuberculosis (rs2430561, OR [95% CI] = 1.31 [1.19, 1.46]) and pooled respiratory infections (rs2430561, OR [95% CI] = 1.34 [1.19, 1.51]), and within a subset analysis of methodologically better studies CCL2 was significant for tuberculosis (rs1024611, OR [95% CI] = 0.71 [0.62, 0.82]).
Conclusion: The IFNG-IL4-TLR2-CCL2 axis could represent a highly interesting target for translation towards clinical use. However, this conclusion is based on a very low credibility of evidence with almost 95% of identified studies showed a string risk of bias or confounding. Recommendations for future studies in this field are to build upon large-scale collaborations, but also to substantially improve primary study design, in order to produce reproducible and clinically translatable evidence.
Abstract (croatian) Uvod i cilj: Kako zarazne bolesti dišnog sustava i dalje predstavljaju ogroman teret na globalno ljudsko zdravlje, neophodno je istražiti sve čimbenike koji pridonose podložnosti i patogenezi. Analiza genetskih čimbenika je čest pristup, no rezultati takvih studija su većinom nedosljedni. Stoga je cilj ove doktorske disertacije provesti najopsežniji i najrecentniji pregled literature o ulozi ljudskih genetskih čimbenika na podložnost zaraznim bolestima dišnog sustava (tuberkuloza, gripa, upala pluća, RSV, SARS).
Metode: 425 studija se pokazalo značajnima te su uključene u meta-analizu od ukupno 30,307 studija pronađenih prilikom sustavnog pregleda četiri bibliografske baze podataka, te je njihov rizik od pristranosti strogo procijenjen uporabom nove ljestvice za procjenu rizika od pristranosti (Confounding-Selection-Information risk of bias scale).
Rezultati: Rezultati meta-analize nasumičnog učinka pokazali su kako su četiri gena zadržali svoju značajnost nakon ispravka statističke značajnosti zbog problema višestrukog testiranja: IL4 za RSV (rs2070874, OR [95% CI] = 0.69 [0.58, 0.81]; rs2243250, OR [95% CI] = 0.76 [0.66, 0.87]) i u udruženom modelu (svih pet bolesti zajedno) (rs2070874, OR [95% CI] = 0.75 [0.65, 0.87]), TLR2 za tuberkulozu (rs5743708, OR [95% CI] = 3.21 [2.05, 5.02]) i u udruženom modelu (rs3804099, OR [95% CI] = 1.40 [1.18, 1.65]), IFNG za tuberkulozu (rs2430561, OR [95% CI] = 1.31 [1.19, 1.46]) i u udruženom modelu (rs2430561, OR [95% CI] = 1.34 [1.19, 1.51]), te unutar metodološki boljih studija CCL2 se pokazao značajnim za tuberkulozu (rs1024611, OR [95% CI] = 0.71 [0.62, 0.82]).
Zaključak: IFNG-IL4-TLR2-CCL2 os bi mogla predstavljati značajnu metu za translaciju prema kliničkoj upotrebi. No, rezultati ovog rada se temelje na veoma niskoj vjerodostojnosti dokaza budući da skoro 95% uključenih studija pokazuju snažan rizik od pristranosti. Smjernice za buduća istraživanja u ovom području uključuju udruživanje u veće kolaboracijske centre, no također je potrebno značajno poboljšati ustroj primarnih istraživanja, kako bi se proizveli dokazi koji su ponovljivi, te se mogu prenijeti u kliničku upotrebu.
Keywords
Respiratory Tract Infections -- genetics
Keywords (croatian)
Infekcije respiratornog trakta -- genetika
Language english URN:NBN urn:nbn:hr:171:574158 Project Number: 602525 Project Number: 212111 Project Number: IP-2013-11-8875 Study programme Title: Translational Research in Biomedicine - TRIBE Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2023-05-10 12:59:21
