AATF and SMARCA2 are associated with thyroid volume in Hashimoto’s thyroiditis patients

Thyroid volume of Hashimoto’s thyroiditis (HT) patients varies in size over the course of disease and it may reflect changes in biological function of thyroid gland. Patients with subclinical hypothyroidism predominantly have increased thyroid volume whereas patients with more pronounced hypothyroid...

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Veröffentlicht in:Scientific reports Jg. 10; H. 1; S. 1754
Hauptverfasser: Brčić, Luka, Barić, Ana, Benzon, Benjamin, Brekalo, Marko, Gračan, Sanda, Kaličanin, Dean, Škrabić, Veselin, Zemunik, Tatijana, Barbalić, Maja, Novak, Ivana, Pešutić Pisac, Valdi, Punda, Ante, Boraska Perica, Vesna
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 04.02.2020
Nature Publishing Group
Schlagworte:
45/43
631/208/205/2138
692/163/2743/1841
Adult
Apoptosis
Apoptosis - genetics
Apoptosis Regulatory Proteins - genetics
Atrophy
Case-Control Studies
Chromatin remodeling
Female
Genetic diversity
Genetic variance
Genome-wide association studies
Genome-Wide Association Study - methods
Genomes
Genotype
Genotypes
Hashimoto Disease - genetics
Hashimoto Disease - pathology
Heterozygote
Humanities and Social Sciences
Humans
Hypothyroidism
Hypothyroidism - genetics
Hypothyroidism - pathology
Male
Middle Aged
multidisciplinary
Polymorphism, Single Nucleotide - genetics
Repressor Proteins - genetics
Science
Science (multidisciplinary)
Thyroid
Thyroid gland
Thyroid Gland - pathology
Thyroiditis
Thyroxine
Thyroxine - genetics
Transcription Factors - genetics
ISSN:2045-2322, 2045-2322
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Zusammenfassung:Thyroid volume of Hashimoto’s thyroiditis (HT) patients varies in size over the course of disease and it may reflect changes in biological function of thyroid gland. Patients with subclinical hypothyroidism predominantly have increased thyroid volume whereas patients with more pronounced hypothyroidism have smaller thyroid volumes. Suggested mechanism for thyroid atrophy is thyrocyte death due to apoptosis. We performed the first genome-wide association study (GWAS) of thyroid volume in two groups of HT patients, depending on levothyroxine (LT4) therapy, and then meta-analysed across. Study included 345 HT patients in total and 6 007 322 common autosomal genetic variants. Underlying hypothesis was that genetic components that are involved in regulation of thyroid volume display their effect in specific pathophysiologic conditions of thyroid gland of HT patients. We additionally performed immunohistochemical analysis using thyroid tissues and analysed differences in expression levels of identified proteins and apoptotic marker between HT patients and controls. We found genome-wide significant association of two loci, both involved in apoptosis, with thyroid volume of HT patients: rs7212416 inside apoptosis-antagonizing transcription factor AATF (P = 8.95 × 10 −9 ) and rs10738556 near chromatin-remodeling SMARCA2 (P = 2.83 × 10 −8 ). In immunohistochemical analysis we observed that HT patients with homozygous AATF risk genotypes have decreased AATF expression (0.46-fold, P < 0.0001) and increased apoptosis (3.99-fold, P = 0.0001) in comparison to controls. HT patients with heterozygous SMARCA2 genotypes have decreased SMARCA2 expression, albeit without reaching statistical significance (1.07-fold, P = 0.5876), and significantly increased apoptosis (4.11-fold, P < 0.0001). By two lines of evidence we show that two highly plausible genetic loci, AATF and SMARCA2 , may be involved in determining the thyroid volume of HT patients. The results of our study significantly add to the current knowledge of disturbed biological mechanisms in thyroid gland of HT patients.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-58457-x