Title Hashimotov tireoiditis : otkrivanje genetskih varijanti uključenih u razvoj bolesti Title (english) Hashimoto thyroiditis : discovery of genetic variants involved in the development of the disease Author Luka Brčić Mentor Vesna Boraska Perica (mentor)Committee member Dragan Ljutić (predsjednik povjerenstva)Committee member Irena Drmić-Hofman (član povjerenstva)Committee member Zvonko Kusić (član povjerenstva)Granter University of Split Defense date and country 2018, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 616 - Pathology. Clinical medicine Abstract Hashimotov tireoiditis (HT) najčešći je oblik autoimune bolesti štitnjače. Glavno obilježje HTa
jest kronična upala i smanjena funkcija štitnjače. Trenutno znanje o genetskim čimbenicima
uključenim u razvoj HT-a je ograničeno, te dosad nije provedena nijjedna cjelogenomska
studija povezanosti fokusirana isključivo na HT. S ciljem otkrivanja genetičkih odrednica HT-a,
proveli smo prvu cjelogenomsku analizu povezanosti HT-a praćenu replikacijom u ukupno
1443 ispitanika iz Hrvatske, uključujući 708 ispitanika oboljelih od HT-a i 735 ispitanika iz
kontrolne skupine.
Početna skupina sastojala se od 430 ispitanika oboljelih od HT-a i 439 kontrola koji pripadaju
splitskoj regiji. Dijagnoza bolesti prvenstveno je postavljena na osnovi kliničkog pregleda,
karakteristične ultrazvučne slike štitnjače (nehomogeno i često hipoehogeno tkivo štitnjače) i
krvnih koncentracija hormona i protutijela štitnjače (TPOAt i TgAt), slijedeći preporuke i
smjernice Europske udruge za štitnjaču. Analiza povezanosti između 8.6 milijuna genetskih
varijanti i HT-a provedena je uporabom modela linearne regresije sa slučajnim učincima, gdje
je status bolesti tretiran kao kvantitativna varijabla. Trinaest najznačajnijih nezavisnih
genetskih varijanti (P<10-5) odabrano je za genotipizaciju u dvije nezavisne replikacijske
skupine koje su uključile ukupno 303 ispitanika oboljela od HT-a i 302 kontrole koji pripadaju
osiječkoj regiji, odnosno splitskoj regiji. U završnom koraku, provedena je meta-analiza
rezultata za odabrane varijante između početne skupine i replikacijskih skupina.
Otkrivene su tri nove genetske varijante povezane s HT-om: rs12944194 udaljen 206 kb od
SDK2 gena (P=1.8×10-6, β=-0.088, SE=0.018), rs75201096 smješten unutar GNA14 gena
(P=2.41×10-5, β=-0.252, SE=0.06) i rs791903 smješten unutar IP6K3 gena (P=3.16×10-5,
β=0.07, SE=0.017). Genetski rizični skor (GRS), izračunat uporabom rizičnih alela otkrivenih
lokusa, objašnjava 4.82% ukupne varijabilnosti u HT-u, a ispitanici iz gornjeg GRS kvartila
imaju 2.76 puta veće izglede za razvoj HT-a u usporedbi s ispitanicima iz donjeg GRS kvartila.
Sva tri otkrivena lokusa po prvi put su povezana s nastankom HT-a, međutim poznato je da
su genomske regije koje okružuju navedene lokuse uključene u regulaciju funkcije štitnjače i
razvoj različitih autoimunih bolesti. Dodatno, uočena je zajednička genetska pozadina
između HT-a i nekoliko drugih fenotipova, posebice hipotireoze, Gravesove bolesti i TPOAt-a.
Zaključno, ovo istraživanje donosi nova saznanja o genetskoj podlozi HT-a i postavlja čvrste
temelje za daljnja genetska istraživanja ove učestale, ali slabo istražene bolesti.
Abstract (english) Hashimoto’s thyroiditis (HT) is the most common form of autoimmune thyroid disease
characterized by chronic inflammation and reduced function of the thyroid gland. Current
knowledge of HT genetics is very limited, and not a single genome-wide association study
(GWAS) focusing exclusively on HT has been performed to date. In order to decipher genetic
determinants of HT, we performed the first GWAS followed by replication in a total of 1443
individuals from Croatia, including 708 HT cases and 735 controls.
The discovery dataset included 430 HT cases and 439 controls from the region of Split (South
Croatia). Diagnosis of HT was primarily based on clinical examination, characteristic thyroid
ultrasound image (unhomogenic and/or hypoechogenic thyroid tissue) and evaluation of
thyroid hormones and antibodies (TPOAb and TgAb), according to ETA (European Thyroid
Association) recommendations and guidelines. Association analysis between 8.6 million
genetic variants and HT was performed using univariate linear model with random effects,
by treating binary disease status as quantitative trait. Thirteen most significant independent
genetic variants (P<10-5) were selected for genotyping in 303 HT cases and 302 controls from
two independent replication cohorts from the region of Osijek (East Croatia) and region of
Split (South Croatia). As the final step, we performed meta-analysis across discovery and
replication cohorts for selected variants.
We identified three suggestive associations of novel variants with HT: rs12944194 located
206 kb from SDK2 gene (P=1.8×10-6, β=-0.088, SE=0.018), rs75201096 inside GNA14 gene
(P=2.41×10-5, β=-0.252, SE=0.06) and rs791903 inside IP6K3 gene (P=3.16×10-5, β=0.07,
SE=0.017). Genetic risk score (GRS), calculated using risk alleles of these three loci,
accounted for 4.82% of the total HT variance, and individuals from the top GRS quartile had
2.76 times higher odds for HT than individuals from the lowest GRS quartile.
These three loci are implicated with susceptibility to HT for the first time. Nevertheless,
genomic regions harboring these loci exhibit good biological candidacy for HT development,
due to their involvement in the regulation of the thyroid gland function and autoimmunity.
Additionally, we observe genetic overlap between HT and several related traits, such as
hypothyroidism, Graves’ disease and TPOAb. In conclusion, this study adds a new knowledge
of underlying HT genetics and sets a firm basis for further research of this common, yet
poorly investigated disease.
Keywords
Hashimotova bolest
Keywords (english)
Hashimoto Disease
Language croatian URN:NBN urn:nbn:hr:171:159020 Project Number: UIP-2013-11-4950 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 2023-05-11 11:03:27
