| Abstract | Uvod: Hashimotov tireoiditis (HT) je jedan od najučestalijih endokrinoloških poremećaja i
najučestalija autoimunosna bolesti štitnjače. Okolišni čimbenici zajedno s genetskim
čimbenicima igraju vrlo važnu ulogu u razvoju ove kronične upale štitnjače. Prehrambeni
čimbenici su potencijalno značajni okolišni modifikatori koji mogu doprinijeti razvoju HT-a.
Možemo reći da je trenutno znanje o ovoj temi vrlo ograničeno i da je vrlo mali broj studija
proveden do sada. Naš cilj je istražiti utjecaj povezanosti prehrane s HT-om i fenotipovima
karakterističnim za HT putem dva različita pristupa: analizirajući upitnik o prehrambenim
navikama (FFQ) i istražujući imunološki odgovor putem IgG protutijela na antigene iz hrane.
Dodatno planiramo odrediti i genetske varijante koje utječu na razinu povišenih IgG protutijela
na antigene iz hrane u ispitanika s HT-om.
Ispitanici i metode: U prvom dijelu istraživanja smo usporedili tjedni unos skupina namirnica
deriviranih iz FFQ-a između 491 ispitanika s HT-om i 433 zdrava ispitanika te testirali
povezanost konzumacije skupina namirnica s fenotipovima i simptomima karakterističnim za
HT modelima logističke i linearne regresije. U drugom dijelu istraživanja smo istraživali
razlike između IgG protutijela na 125 antigena iz hrane između 74 ispitanika s HT-om i 245
kontrolnih ispitanika neparametrijskim Mann-Whitney U testom te smo Spearmanovim testom
analizirali korelacije između povišenih IgG protutijela na antigene iz hrane s kliničkim
fenotipovima. Također smo istraživali povezanost razina povišenih IgG protutijela sa
simptomima hipotireoze u ispitanika s HT-om neparametrijskim Mann-Whitney U testom.
Dodatno smo proveli cjelogenomsku analizu povezanosti (GWAS) na razine povišenih IgG
protutijela na antigene iz hrane u 74 ispitanika s HT-om.
Rezultati: Naš najznačajniji rezultat je pronalazak učestalije konzumacije životinjskih
masnoća (OR 1,55, P<0,0001) i mesnih prerađevina u ispitanika s HT-om (OR 1,16,
P=0,0012), kao i učestalije konzumacije nekoliko skupina namirnica (crveno meso, sokovi,
cjelovite žitarice, biljno ulje, maslinovo ulje, žestoka alkoholna pića, plava riba i voće) u
kontrolnih ispitanika. Testirane skupine namirnica iz FFQ općenito nisu povezane sa
simptomima hipotireoze u ispitanika s HT-om koji nisu primali terapiju levotiroksinom.
Pronašli smo povišene IgG razine na antigene iz sveukupno 12 namirnica u skupini ispitanika
s HT-om i/ili kontrolnih ispitanika. Od ovih 12 namirnica, ispitanici s HT-om su imali značajno
više razine IgG protutijela na anigene iz šljive (P=1,70x10-8
), dok su IgG protutijela na badem
bila značajno smanjena (P=8,11x10-5
). Jedan od naših glavnih rezultata je nepostojanje
značajnih korelacija između povišenih IgG protutijela i IgG protutijela za glijadin s klinički
važnim fenotipovima za HT te njihove povezanosti sa simptomima hipotireoze. Pronašli smo
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dvije genetske varijante na cjelogenomskoj razini značajnosti na razine IgG protutijela na
antigene iz badema: rs1268150 kraj FOXO3 gena (P=4,04×10-9
, β=0,971, SE=0,145) i
rs7160273 unutar INF2 gena (P=3,32×10-8
, β=-1,046, SE=0,169) i sugestivno povezanu
varijantu rs4870456 kraj IYD gena (P=2,53×10-7
, β=-1,052, SE=0,185) na razinu IgG
protutijela na antigene iz šljive.
Zaključci: Sveukupni cilj našeg istraživanja je doprinijeti razumijevanju odnosa prehrane i
HT-a s obzirom na vrlo ograničena sadašnja znanja. Naši rezultati mogu biti od koristi za
nutricioniste i liječnike uključene u razvijanje prehrambenih smjernica za pacijente s HT-om.
Nismo pronašli dokaze da su povišene razine IgG protutijela na antigene iz hrane povezane s
kliničkim aspektima HT-a, što ukazuje da test intolerancije na hranu ne donosi veću korist
ispitanicima s HT-om u odnosu na opću populaciju. Naši rezultati također sugeriraju postojanje
povezanosti između biološki zanimljivih genetskih varijanti i imunološkog odgovora putem
IgG protutijela na antigene iz badema i šljive u ispitanika s HT-om. |
| Abstract (english) | Introduction: Hashimoto's thyroiditis (HT) is one of the most common endocrine disorders
and the most common form of autoimmune thyroid disorders. Environmental factors, along
with genetic factors, play important role in the development of this chronic thyroid
inflammation disease. Dietary factors are considered as potential environmental modifiers that
may contribute to the development of HT. However, the current knowledge of this topic is
scarce and only few studies have been conducted to date. Our goal is to investigate the effects
of diet with HT and HT-related phenotypes by using two different approaches: investigation of
self-reported food frequency questionnaire (FFQ) and analysis of immunologic response to
specific food antigens mediated by IgG antibodies. Additionally, we plan to determine genetic
variants that are associated with increased food specific IgG antibody levels in patients with
HT.
Subjects and methods: In the first part of the research, we compared weekly intake of food
groups, assesed through self-reported FFQ, between 491 patients with HT and 433 controls
using logistic regression model. Additionally, we tested the association of weeky intake of food
groups with HT-related phenotypes and symptoms using linear regression model. In the second
part of our research, we compared the difference between IgG levels to 125 food specific
antigens between 74 patients with HT and 245 controls using the Mann-Whitney U test. We
tested correlations between elevated food specific IgG levels and HT-related clinical
phenotypes using Spearman’s correlation test. We also tested association between elevated
food specific IgG levels and symptoms of hypothyroidism in patients with HT using MannWhitney U test. Additionally, we performed a genome-wide association study (GWAS) on
elevated food specific IgG levels in 74 patients with HT.
Results: The most significant result of our study is significantly increased consumption of
animal fat (OR 1.55, P<0.0001) and processed meat (OR 1.16, P=0.0012) in HT patients and
significantly increased consumption of several food groups (red meat, non-alcoholic beverages,
whole grains, plant oil, olive oil, liquor, oily fish and fruits) in control participants. Another
interesting observation is the lack of association between symptoms of hypothyroidism with
food groups in the group of HT patients without levothyroxine therapy. We also found
increased IgG levels to 12 different food antigens in either HT cases or control group of which
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plum-specific were significantly higher (P=1.70x10-8
), and almond-specific were significantly
lower (P=8.11x10-5
) in HT patients than in controls. One of our main results is the absence of
significant correlation and association between any of 12 increased food-specific IgG
antibodies, along with gluten-specific IgG, with clinically relevant HT phenotypes and
symptoms of hypothyroidism. We have detected two genome-wide significant associations for
almond specific IgG levels: rs1268150 located near FOXO3 gene (P=4.04×10-9
, β=0.971,
SE=0.145) and rs7160273 inside INF2 gene (P=3.32×10-8
, β=-1.046, SE=0.169). Also, we
have detected one suggestively associated variant for plum specific IgG levels: rs4870456
located near IYD gene (P=2.53×10-7
, β=-1.052, SE=0.185).
Conclusions: The overall aim of our research is to contribute to the currently limited
knowledge related to diet and HT which may be of relevance to nutritionists and clinicians
involved in developing dietary recommendations for patients with HT. We found no evidence
that elevated food specific IgG antibodies are associated with clinical aspects of HT, pointing
out that the test of food intolerance does not bring greater benefit to HT patients in comparison
to the general population. Our results also suggest an association between biologically
interesting genetic variants with immunologic response to almond and plum specific IgG
levels. |
