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Type One Diabetes Associated Autoantibodies, Genetical and Environmental Risk Factors in Estonia
Hanna Sepp
Summary
Diabetes mellitus is a group of metabolic diseases characterized by continuous increased plasma glucose levels resulting from defects in insulin secretion and/or function. Three major types of diabetes are type 1 diabetes (T1D), type 2 diabetes (T2D) and gestation diabetes (GDM). Most cases of T1D (~95%) result from a cellular-mediated autoimmune destruction of the β-cells of the pancreas (2). The trigger of the disease is still unknown but several associations with human leukocyte antigen (HLA) and some environmental factors, for instance enteroviruses, have been described. Also, common characteristic features of autoimmunity are autoantibodies against islet cells, insulin, GAD65 and ZnT8.
Type 1 diabetes can be diagnosed at any age, however, it is more common among those who are under 30-years old. At the same time, during last decade the incidence and prevalence of T1D have been increased, especially among children under 5-years old (19). According to the National Institute of Health Development of Estonia, the incidence rate of T1D in Estonia in 2016 was 43.0 per 100 000 persons. Distribution of incidence between age groups 1–4, 5–9, 10–14, 15–19, 20–24 and 25–34 years old was 10.7, 41.7, 44.3, 38.5, 40.0 and 39.5 per 100 000 persons, respectively (18).
This Master’s Thesis introduces a case-control study with the aim to describe and compare the spectrum of autoantibodies, HLA risk alleles and enterovirus antibodies of patients with newly diagnosed T1D based on the data from study of “Immune Mechanisms in Diabetes”.
A study population of these Master’s Thesis was formed during the period of 1 October 2004 until 31 October 2018. In total, 480 volunteers were involved in the study. Cases included (n=209) patients with newly diagnosed T1D who joined the study within two months of diagnose. They attended a medical appointment in one of the following clinical centers: Internal Medicine Clinic of Tartu University Hospital, Children’s Clinic of Tartu University Hospital, North Estonia Medical Centre, East Tallinn Central Hospital, Tallinn Children´s Hospital and Kuressaare Hospital. The control group (n=271) was formed as a convenient sample of volunteered persons without T1D, including employees and students of Tartu University, and patients who received microsurgical surgery in Children’s Clinic of Tartu University Hospital.
The data analysis included comparing T1D associated characteristics; 1) between cases vs. controls; and 2) between younger (age of under 19-years old) vs. older cases (age of
19-42
years old and older). Data analysis methods like the Mann-Whitney test, χ2-test or Fisher’s exact test and logistic regression modelling were conducted using statistical software STATA/IC 14.2.
In our study, those participants whose first-degree relatives had T1D had higher risk to T1D. These cases also had a higher risk of autoimmune endocrine comorbidities (OR=13,02 95% CI 2,83–59,78) and non-autoimmune endocrine comorbidities (OR=2,31 95% CI 0,38–
14,93). The odd ratio to have enterovirus antibodies was 2,82 times higher among cases than controls.
While comparing the distribution of HLA haplotypes between younger and older cases we found that risk-conferring HLA haplotype (DR3/DR4) was more frequent among younger than older cases, with prevalence of 33% and 18%, respectively. At the same time all types of autoantibodies were presented more commonly among younger than older cases. Moreover, for younger cases, the risk of single autoantibody was 4,36 (95% CI 1,09–17,37) times higher, the risk of two autoantibodies was 12,86 (95% CI 3,41–48,49) times higher and the risk of three autoantibodies was 18,00 (95% CI 4,86–67,26) times higher than for older cases.
In conclusion, both autoimmune and non-autoimmune comorbidities were more frequent among cases than controls. They also had higher probability for enterovirus antibodies.
All type of autoantibodies, as well as the tendency to have a different type of autoantibody at the same time, were more characteristic to younger cases. Risk-conferring HLA haplotype (DR3/DR4) was more frequent among younger than older cases.
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Tänuavaldus
Käesoleva magistritöö autor soovib tänada:
Juhendajaid immunoloogia professor Raivo Uibot ja biostatistika assistenti Heti Pisarevi
Eelretsensenti Ene Indermittet
Tartu Ülikooli bio- ja siirdemeditsiini instituudi immunoloogia osakonna spetsialisti Kaja Metsküla autoantikehade määramise eest
Tartu Ülikooli bio- ja siirdemeditsiini instituudi immunoloogia osakonna spetsialisti Ija Talja enteroviiruste vastaste antikehade määramise eest
Teisi TÜ bio- ja siirdemeditsiini instituudi immunoloogia õppetooli labori spetsialiste (sh Kristi Alnek, Helis Janson-Tasa, Astrid Oras, Katrin Pruul jt)
Teisi TÜ bio- ja siirdemeditsiini instituudi immunoloogia õppetooli töötajaid abi ja mõistmise eest nii magistritöö kui kogu magistri õpingute jooksul
Tänan koostöö eest:
kõiki uuringus osalenud vabatahtlikke, arste ja kliinikuid
SA TÜK Sisekliinik (Dr Gusseva, Dr Tuisk, Dr Matjus, Dr Salu, Dr Tammiksaar, Dr Reppo, Dr Lubi)
SA TÜK Kirurgiakliinik (Dr Varik)
ITK endokrinoloogiakeskus (Dr Jakovlev, Dr Merandi, Dr Verrev) SA PERH (Dr Rudenko, Dr Ambos)
Kuressaare Haigla SA (Dr Nemvalts) SA TLA (Dr Einberg, Dr Heilman)
SA TÜK Lastekliinik (Dr Peet, Dr Heilman).
Tänan oma lähedasi kannatlikkuse, toetuse ja mõistmise eest magistriõpingute jooksul
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Elulugu
I. Üldandmed 1. Ees- ja perekonnanimi: Hanna Sepp
2. Sünniaeg ja -koht: 26.11.1992, Põlva 3. Kodakondsus: Eesti
4. E-post: hanna.sepp@gmail.com 5. Haridus:
2017– … Tartu Ülikool, rahvatervishoiu magistriõpe
2013–2017 Tartu Tervishoiu Kõrgkool, bioanalüütika, rakenduskõrgharidus 2009–2010 Põlva Ühisgümnaasium
2000–2009 Põlva Keskkool 6. Keelteoskus:
eesti keel emakeel inglise keel kesktase 7. Töökogemus:
2017 veebruar–… Spetsialist, Tartu Ülikooli bio- ja siirdemeditsiini instituut, immunoloogia õppetool,
2019 veebruar–mai Praktikant, Maailma Terviseorganisatsioon (World Health Organization – WHO)
2016 juuli–august Abilaborant, SA Pärnu Haigla 2015 august Nooremõde, AS Põlva Haigla 2014 juuli–august Nooremõde, AS Põlva Haigla
II. Teaduslik ja arendustegevus
1. Sepp H. „Uriini mikrobioloogilise analüüsi juhend Tartu Tervishoiu Kõrgkooli mikrobioloogia laboris kasutamiseks“ Eesti Bioanalüütikute Ühingu 25. aastapäeva konverents, 11.11.2017; Tartu, Eesti.
2. Osalemine projektis IUT20-43 Diabeedi immuunmehhanismid, spetsialist, 2017–…
III. Erialane enesetäiendus
1. Osalemine koolitusel „Data Carpentry Workshop“, Elixir Estonia, 19–20.11.2018 2. Osalemine Eesti Bioanalüütikute Ühingu 25. aastapäeva konverentsil, 11.11.2017 3. Osalemine Tartu Ülikooli immunoloogia õppetooli teadusseminaridel.
Kuupäev: 15.05.2019
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