HRZZ uspostavna potpora izv. prof. dr. sc. Vesna Boraska Perica

                                                                                                                          

Naziv HRZZ Uspostavne potpore: Genome-wide association analysis of Hashimoto thyroiditis (Cjelogenomska analiza povezanosti Hashimotovog tiroiditisa)

Trajanje projekta: 15. 9 .2014. - 14. 1. 2018.

Voditelj projekta: Izv. prof. dr. sc. Vesna Boraska Perica
 

Suradnici na projektu: prof. dr. sc. Tatijana Zemunik, prof. dr. sc. Ante Punda, prof. dr. sc. Eleftheria Zeggini, izv. prof. dr. sc. Maja Barbalić, prof. dr. sc. Veselin Škrabić, dr. sc. Vesela Torlak, dr. sc. Stana Tokić, dr. med. Sanda Gračan, dr. med. Ana Barić, Luka Brčić, mag. math., Ivana Gunjača, dipl. ing. mol. bio., Dean Kaličanin, mag. biol. i eko.mora.



Kratki opis projekta:
Bolesti štitnjače pogađaju više od 10% populacije i predstavljaju važan javnozdravstveni problem. U ovom istraživanju će se pokušati odrediti genetske odrednice za razvoj bolesti Hashimotov tiroiditis (HT). U istraživanje će biti uključena skupina pacijenata s HT-om i kontrolni ispitanici. Ispitanicima će se izolirati DNA i odrediti genotipovi na razini čitavog genoma. Usporedbom genetskih varijanti između oboljelih ispitanika prikupljenih u ovom projektu i kontrolnih ispitanika u tzv. analizi cjelokupnog genoma pokušati ćemo odrediti genetske varijante koje su uključene u razvoj bolesti štitnjače. Analiza cjelokupnog genoma je dokazano pouzdana metoda u istraživanju genetske predispozicije složenih bolesti, a bazira se na pretpostavci da sve genomske regije mogu imati jednaki utjecaj na nastanak neke bolesti.  Osnovna ideja ovog projekta je identificirati genetske biljege koji sudjeluju u etiologiji (razvoju) HT-a da bi pomogli u razumijevanju temeljnih bioloških putova povezanih s funkcijom štitnjače i mehanizmima nastanka bolesti štitnjače, a sve u cilju poboljšanja liječenja bolesti i razvoja novih prevencijskih, dijagnostičkih i terapeutičkih metoda.

Osnovni ciljevi projekta:
Formiranje biobanke bioloških uzoraka i fenotipova 500 ispitanika oboljelih od HT-a (cilj 1); cjelogenomsko genotipiziranje i provođenje analize povezanosti (cilj 2); analiza interakcije između genetskih varijanti s okolišnim čimbenicima i analiza bioloških puteva (cilj 3); detaljna fenotipska karakterizacija ispitanika oboljelih od HT-a (cilj 4).

Ostvarene aktivnosti:
Kroz ovo istraživanje ustanovljena je CROHT biobanka, odnosno biobanka DNA/seruma/plazme za 500 ispitanika oboljelih od Hashimotovog tireoiditisa (HT) i njihovih prikupljenih/izmjerenih > 200 fenotipova. Dodatno smo, kroz suradnju, koristili uzorke kontrolnih i oboljelih ispitanika čime je u našoj cjelogenomskoj i replikacijskoj analizi bilo uključeno ukupno 1474 ispitanika (732 ispitanika s HT-om i 742 kontrolna ispitanika). Naša cjelogenomska studija povezanosti bolesti HT je najveća ikada napravljena genetska studija ove bolesti. Glavni rezultat ovog istraživanja jest pronalazak triju novih genetskih varijanti sugestivno povezanih s HT-om (objavljeno u J Endocrinol Invest, IF=3.166). U zasebnoj cjelogenomskoj analizi protutijela protiv štitne žlijezde pronašli smo sugestivnu povezanost dvaju genetskih varijanti s protutijelom na tiroglobulin (TgAb) i jedne s protutijelom na tireoidnu peroksidazu (TPOAb) u ispitanika oboljelih od HT-a (objavljeno u Sci Rep IF=4.122) dok smo u cjelogenomskoj analizi volumena štitnjače pronašli povezanost dviju genetskih varijanti (rad u recenziji u J Clin Endocrinol Metab IF=5.789). Dodatno, kroz ovaj projekt smo proveli i detaljnu fenotipsku karakterizaciju ispitanika s HT-om i glavni rezultat ovog dijela istraživanja, i za svjetsku znanost novi rezultat, je pronalazak povezanosti između protutijela (TgAb) i broja simptoma, ukazujući pritom na kliničku važnost protutijela TgAb u ovoj bolesti (objavljeno u Immunol Invest, IF=2.588). S projekta je proizašlo 7 originalnih znanstvenih radova.
 
Project summary:
Autoimmune thyroid diseases (AITD) are very common and affect 2-5% of the general population. The most frequent form of AITD is Hashimoto thyroiditis (HT) that is characterised by progressive destruction of thyroid tissue. Many studies tried to unravel genetic contribution to HT development in the past few decades but with low success. The breakthrough of the genome-wide association studies (GWAS) tremendously increased the rate of detecting novel associations. However, HT has been unrepresented in the GWAS mostly because of the lack of large cohorts of HT patients and the performance of such study is a matter of urgency. We plan to recruit 500 HT patients and to create a DNA/serum/plasma biobank of deeply phenotyped HT patients that will serve as a powerful resource for current and future investigations. The aim of this study is to identify genetic variants underlying HT by performing the first GWAS focusing on HT exclusively. We will use newly recruited HT patients and 500 existing controls (from the “10,000 Dalmatians” study) in case-control GWAS and validate observed associations in an independent replication cohort. To further help in elucidating genetic contribution to HT we will perform pathway analysis and gene-interaction analysis using a variety of environmental factors and medical records that will be collected from HT patients. We will also perform deep phenotype characterisation of HT patients that may provide additional clues about HT aetiology. This is timely planned study that aims to generate new knowledge that will advance our understanding of the genetic basis and underlying biological mechanisms of HT. This knowledge will be crucial in guiding the development of new prevention, diagnostic and therapeutic methods. Other benefits of this project include the promotion of collaboration, transfer of knowledge, the building of infrastructure and it will help in the establishment of an independent research carrier of a principal investigator.

Activities resulting from this project:
In this project, we have created CROHT biobank, which is a bank of DNA/serum/plasma samples and collected/measured > 200 phenotypes from 500 patients with Hashimoto’s thyroiditis (HT). We have performed genome-wide association analysis (GWAS) and replication analysis using HT patients and control participants, obtained through collaboration. We have included a total of 1474 participants (732 HT patients and 742 controls) which makes our study the largest GWAS analysis of HT to date. We have found three novel suggestively associated genetic variants with HT (published in J Endocrinol Invest, IF=3.166). In the separate GWAS analysis of thyroid antibodies in HT patients, we have found two suggestively associated genetic variants with thyroglobulin antibodies (TgAb) and one with thyroid peroxidase antibodies (TPOAb) (published in Sci Rep IF=4.122), whereas in GWAS analysis of thyroid volume, we observed genome-wide significant associations of two genetic variants with thyroid volume (currently revised in J Clin Endocrinol Metab IF=5.789). Additionally, through this project we have performed detailed phenotypic characterisation of HT patients with the main, and novel, finding of association of TgAb antibodies with symptom burden, suggesting a role of thyroid autoimmunity in clinical manifestations of HT (published in Immunol Invest, IF=2.588). These three papers are already listed under the point 1). However, the total number of original scientific papers that resulted from this project is seven.

Doktorske disertacije:
Doktorand Luka Brčić, mag. math, je 18.12.2018. uspješno obranio svoju doktorsku disertaciju pod naslovom „Hashimotov tireoidits: otkrivanje genetskih varijanti uključenih u razvoj bolesti“ pod mentorstvom izv. prof. Vesne Boraska Perica.

     
Dr. sc. Luka Brčić s ponosnom mentoricom nakon obrane doktorata te s kolegama s Katedre za medicinsku biologiju nakon promocije doktora znanosti 2019.

Nagrade i proznanja:
Ana Barić, dr. med. stipendistica je Nacionalnog programa L'Oreal-UNÉSCO "Za žene u znanosti" 2019. na temelju
znanstvenog istraživanja "Analiza kliničkih karakteristika i fenotipova u bolesnika s Hashimotovim tireoiditisom".

      
Ana Barić, dr. med.

Znanstvena mobilnost:
Warda Kherrour, dobitnica je prestižne ICGEB SMART Fellowship stipendije za znanstveno-istraživačko usavršavanje u našoj grupi. Warda i izv. prof. Boraska Perica osmislile su projekt pod nazivom „Candidate-gene approach in analysis of genetic predisposition to Hashimoto’s thyroiditis in Algerian population“ u kojem će tijekom 5 mjeseci Warda istraživati genetsku pozadinu ove učestale bolesti u populaciji Alžira. Tijekom svog boravka, Warda će izgrađivati svoje laboratorijske vještine, učiti se principima analize genetičkih podataka i interpretacije rezultata istraživanja uz pomoć članova Katedre.

     
Stipendistica Warda s kolegama s Katedre za medicinsku biologiju 

Projekt u medijima:
Gostovanje izv. prof. Vesne Boraska Perica u emisiji OSVRT TV Jadrana
poveznica: http://www.tvjadran.hr/09/osvrt-vesna-boraska-perica-01-08-2018/

Znanstveni radovi:
Brčić L, Barić A, Gračan S, Torlak V, Brekalo M, Škrabić V, Zemunik T, Barbalić M, Punda A, Boraska Perica V. Genome-wide association analysis suggests novel loci underlying thyroid antibodies in Hashimoto’s thyroiditis. Sci Rep. 2019 Mar 29;9(1):5360. doi: 10.1038/s41598-019-41850-6.
 
Barić A, Brčić L, Gračan S, Škrabić V, Brekalo M, Šimunac M, Torlak Lovrić V, Anić I, Barbalić M, Zemunik T, Punda A, Boraska Perica V. Thyroglobulin antibodies are associated with symptom burden in patients with Hashimoto's thyroiditis: a cross-sectional study. Immunological investigations. 2018 Oct 17:1-12 doi: 10.1080/08820139.2018.1529040

Brčić L, Barić A, Gračan S, Brekalo M, Kaličanin D, Gunjača I, Torlak Lovrić V, Tokić S, Radman M, Škrabić V, Miljković A, Kolčić I,  Štefanić M, Glavaš-Obrovac Lj, Lessel D, Polašek O, Zemunik T, Barbalić M, Punda A, Boraska Perica V. Genome-wide association analysis suggests novel loci for Hashimoto’s thyroiditis. Journal of Endocrinological Investigation. 2018 Oct 3. doi: 10.1007/s40618-018-0955-4

Kaličanin D, Brčić L, Barić A, Zlodre S, Barbalić M, Torlak Lovrić V, Punda A, Boraska Perica V. 2018. Evaluation of Correlations Between Food-Specific Antibodies and Clinical Aspects of Hashimoto’s Thyroiditis. Journal of the American College of Nutrition. 2018 Sep 28:1-8 doi: 10.1080/07315724.2018.1503103.

Brčić Luka, Gračan Sanda, Barić Ana, Gunjača Ivana, Torlak Lovrić Vesela, Kolčić Ivana, Zemunik Tatijana, Polašek Ozren, Barbalić Maja, Punda Ante, Boraska Perica Vesna. Association of Established Thyroid-stimulating Hormone and Free Thyroxine Genetic Variants with Hashimoto's Thyroiditis, Immunological Investigations, 2017, Aug;46(6):625-638.
 
Barić Ana, Brčić Luka, Gračan Sanda, Torlak Lovrić Vesela, Gunjača Ivana, Šimunac Marta, Brekalo Marko, Boban Mladen, Polašek Ozren, Barbalić Maja, Zemunik Tatijana, Punda Ante, Boraska Perica Vesna. Association of established hypothyroidism-associated genetic variants with Hashimoto's thyroiditis, Journal of Endocrinological Investigation, 2017, Oct;40(10):1061-1067
 
Brčić L, Barić A, Gračan S, Brdar D, Torlak Lovrić V, Vidan N, Zemunik T, Polašek O, Barbalić M, Punda A, Boraska Perica V. Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto's thyroiditis. Autoimmunity. 2016 Jun 7:1-6.
 

Kongresni sažeci:

Kaličanin D, Brčić L, Barić A, Gračan S, Brekalo M, Torlak Lovrić V, Kolčić I, Polašek O, Zemunik T, Punda A, Boraska Perica V. Food frequency questionnaire analysis in patients with Hashimoto's tyroiditis. 11th International Scientific and Profesional Conference: With food to health, 18.-19.10. 2018, Split, Hrvatska

 Kratka oralna prezentacija - Dean Kaličanin, mag.biol. i eko.mora
 
Brčić L, Barić A, Brekalo M, Gračan S, Škrabić V, Kaličanin D, Novak I, Zemunik T, Barbalić M, Punda A, Boraska Perica V. Apoptosis-antagonizing transcription factor AATF and chromatin-remodeling SMARCA2 are associated with thyroid volume in Hashimoto's thyroiditis patients. 4th Congress of Croatian Geneticists with international participation. 26.-29.9. 2018, Krk, Hrvatska.

 Kratka oralna prezentacija – izv. prof. Vesna Boraska Perica
 
Brčić L*, Barić A, Gračan S,  Torlak Lovrić V, Brekalo M, Škrabić V, Zemunik T, Barbalić M, Punda A, Boraska Perica V. Genome-wide association analysis suggests novel loci underlying thyroid antibodies in Hashimoto's thyroiditis. 4th Congress of Croatian Geneticists with international participation, 26.-29.9. 2018, Krk, Hrvatska.

 Kratka oralna prezentacija - Luka Brčić, mag. math.
 
Barić A, Brčić L, Gračan S, Škrabić V, Brekalo M, Šimunac M, Torlak Lovrić V, Anić I, Barbalić M, Zemunik T, Punda A, Boraska Perica V. Thyroglobulin antibodies are associated with symptom burden in patients with Hashimoto's thyroiditis. 41th Annual Meeting of the European Thyroid Association (ETA), 15.-18.09.2018., Newcastle, Velika Britanija.
Poster

Luka Brčić, Ana Barić, Sanda Gračan, Dean Kaličanin, Ivana Gunjača, Vesela Torlak Lovrić, Marko Brekalo, Marta Radman, Veselin Škrabić, Stana Tokić, Mario Štefanić, Ljubica Glavaš-Obrovac, Tatijana Zemunik, Maja Barbalić, Ante Punda, Vesna Boraska Perica. "Genome-wide association analysis approach in identifying loci for complex diseases, an example for Hashimoto's thyroiditis". Second Adriatic Symposium on Biophysical Approaches in Biomedical Studies, 24.09.2017 - 28.09.2017, Split

  Pozvano predavanje – izv. prof. Vesna Boraska Perica
 

Luka Brčić, Ana Barić, Sanda Gračan, Ivana Gunjača, Vesela Torlak Lovrić, Marko Brekalo, Veselin Škrabić, Tatijana Zemunik, Maja Barbalić, Ante Punda, Vesna Boraska Perica. "Genome-wide association analysis of thyroid volume and thyroid antibodies in Hashimoto's thyroiditis“. Second Adriatic Symposium on Biophysical Approaches in Biomedical Studies, 24.09.2017 - 28.09.2017, Split

 Kratka oralna prezentacija - Luka Brčić, mag. math.


Dean Kaličanin, Luka Brčić, Ana Barić, Sanja Zlodre, Maja Barbalić, Vesela Torlak Lovrić, Ante Punda, Vesna Boraska Perica. Genome-wide association analysis of food intolerance in patients with Hashimoto's thyroiditis. The 10th ISABS Conference in Forensic, Anthropologic and Medical Genetics and Mayo Clinic Lectures in Translational Medicine, Dubrovnik, Croatia

 Kratka oralna prezentacija - Dean Kaličanin, mag.biol. i eko.mora


Vesna Boraska Perica, Luka Brčić, Ana Barić, Sanda Gračan, Dean Kaličanin, Ivana Gunjača, Vesela Torlak Lovrić, Marko Brekalo, Marta Radman, Veselin Škrabić, Ana Miljković, Ivana Kolčić, Stana Tokić, Mario Štefanić, Ljubica Glavaš-Obrovac, Ozren Polašek, Tatijana Zemunik, Maja Barbalić, Ante Punda. „A genome-wide association analysis of Hashimoto’s thyroiditis“. American Society of Human Genetics Annual Meeting, 17-21 listopada 2017., Orlando, Florida, SAD,  

Poster

Brčić L, Barić A, Gračan S, Brdar D, Torlak V, Vidan N, Zemunik T, Polašek O, Barbalić M, Punda A, Boraska Perica V. Hashimoto's thyroiditis and thyroid peroxidase autoantibody levels share genetic background.VI. Hrvatski kongres humane genetike, Split, 5.-7.11.2015.

Poster

Barić A, Brčić L, Gračan S, Torlak Lovrić V, Gunjača I, Šimunac M, Boban M, Zemunik T, Polašek O, Barbalić M, Punda A, Boraska Perica V. Association of established hypothyroidism associated genetic variants with Hashimoto's thyroiditis. Annual Congress of the European Association of Nuclear Medicine, Barcelona, 15.-19.10.2016.

Poster

Promocija projekta:

HRZZ predstavljanje programa „Uspostavni istraživački projekti“, predavanje pod nazivom Cjelogenomska analiza povezanosti Hashimotovog tiroiditisa", Izv. prof. Vesna Boraska Perica.


Diplomski radovi:

Diplomant Mihael Plosnić je 27. lipnja 2019. obranio diplomski rad pod nazivom „Status kalcitonina kod pacijenata s Hashimotovim tireoiditisom“ pod mentorstvom izv. prof. Vesne Boraske Perice.
 Mihael Plosnić, dr.med. i mentorica

Diplomantica Iva Anić je 27. listopada 2017. obranila diplomski rad pod nazivom „Fenotipska karakterizacija ispitanika oboljelih od Hashimotovog tiroiditisa“ pod mentorstvom izv. prof. Vesne Boraske Perice.

 Iva Anić, mag. pharm. i članovi povjerenstva 
 

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