Genome-wide association analysis suggests novel loci for Hashimoto’s thyroiditis

Ljubetić

et al. 2020

Sci Rep

Food is considered as important environmental factor that plays a role in development of Hashimoto's thyroiditis (HT). The goal of our study was to identify food groups, assessed by food frequency questionnaire, that differ in consumption frequency between 491 patients with HT and 433 controls. We also analysed association of food groups with the wealth of HT-related clinical traits and symptoms. We found significantly increased consumption of animal fat (OR 1.55, p < 0.0001) and processed meat (OR 1.16, p = 0.0012) in HT cases, whereas controls consumed significantly more frequently red meat (OR 0.80, p < 0.0001), non-alcoholic beverages (OR 0.82, p < 0.0001), whole grains (OR 0.82, p < 0.0001) and plant oil (OR 0.87, p < 0.0001). We also observed association of plant oil consumption with increased triiodothyronine levels in HT patients (β = 0.07, p < 0.0001), and, association of olive oil consumption with decreased systolic blood pressure (β = − 0.16, p = 0.001) in HT patients on levothyroxine (LT4) therapy. Analysis of food consumption between HT patients with and without LT4 therapy suggest that patients do not tend to modify their diet upon HT diagnosis in our population. Our study may be of relevance to nutritionists, nutritional therapists and clinicians involved in developing dietary recommendations for HT patients. Environmental factors, in addition to genetic factors, play important role in Hashimoto's thyroiditis (HT) development 1. HT is a chronic autoimmune thyroid disorder (AITD) characterized by the production of thyroid autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) 2. Other main characteristics of HT include infiltration of lymphocytes and ruination of thyroid tissue, which usually leads to hypothyroidism 3. This disease predominantly affects female population and is considered as one of the most frequent endocrine disorders 4. The estimated incidence of HT is 350/100,000 for females and 80/100,000 per year for males 5. It is most often diagnosed in women between the age of 30 and 60 6. High iodine intake (median urinary iodine concentration ≥ 300 μg/L) 7 , especially in areas with sufficient iodine supply, is one of the most known factors that increase the incidence of HT 8. Also, low vitamin D levels (below 30 ng/mL) 9 and low selenium intake (bellow 40 µg/day) 10 are proposed to be risk factors for HT development, albeit a role of these factors in HT still needs to be confirmed. Conversely, alcohol intake was proposed to decrease the risk for HT 11. Other dietary factors are also considered as potential environmental modifiers of the clinical appearance of HT 12-15. A diet low in gluten has been recently proposed to have beneficial effects on the disease course in a study of 34 women with HT 13. Another study of 83 patients with HT indicated that restriction of lactose intake in lactose-intolerant HT patients resulted with decreased thyroid-stimulating hormone (TSH) levels 14. However, the current knowledge of this topic is scarce and only the following two studies ...

Section: Methodsmentioning

confidence: 99%

Differences in food consumption between patients with Hashimoto’s thyroiditis and healthy individuals

Kaličanin

Ljubetić

et al. 2020

Sci Rep

“…As we have previously performed GWAS study of 405 HT cases and 430 controls 26 , we were able to check allele frequencies of the most associated AATF genetic variant (rs7212416) in both groups. We do not observe difference in allele frequency distribution of this SNP between HT patients and controls implying that an effect of this SNP on thyroid volume may be triggered by pathologic conditions in thyroid of HT patients.…”

Section: Discussionmentioning

confidence: 99%

“…We additionally involved patients with previously diagnosed HT that came to physicians on follow-up. All HT patients that were recruited through our study are part of "Croatian biobank of patients with Hashimoto's thyroiditis" (CROHT) that was established with principal aim of identifying genetic variants associated with HT 26 and HT-related traits, such as thyroid antibodies 27 and thyroid volume.…”

mentioning

confidence: 99%

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

Barić

Benzon

et al. 2020

Sci Rep

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.

“…Importantly, there was only one GWAS that focused exclusively on HT to date. That study was performed in the Croatian population and included 405 cases and 433 controls, followed up by replication in 303 cases and 302 controls from two replication cohorts [23]. That study suggested an association of three novel HT variants: rs12944194 located 206 kb from SDK2, rs791903 inside IP6K3, and rs75201096 inside GNA14 [23].…”

Section: Introductionmentioning

confidence: 99%

Genotype association of IP6K3 gene with Hashimoto’s thyroiditis in Algerian population (Aures region)

Kherrour

Kaličanin

et al. 2020

Egypt J Med Hum Genet

Background Hashimoto’s thyroiditis (HT) is a chronic autoimmune disease of the thyroid gland and is also the main cause of hypothyroidism. A recent genome-wide association study (GWAS) suggested an association of three novel genetic variants with HT in a population of Caucasian origin (Croatian). A case-control study was performed to investigate the association of these three newly suggested genetic variants with HT in a non-Caucasian ethnic group, an Arab-Berber from Algeria. Three variants (rs12944194 located 206 kb from SDK2, rs791903 inside IP6K3, and rs75201096 inside GNA14) were genotyped using real-time PCR. Results There were no significant differences in allele frequencies of the three genetic variants between HT cases and controls. However, the present study showed nominal significance in the genotype distribution of rs791903 (IP6K3 gene) between HT patients and the control group (P = 0.024); we observed a decrease in the frequency of rs791903 recessive homozygotes (CC) in HT cases versus controls (OR = 0.476, P = 0.025). Conclusion This is the first study that showed the genotypic association of IP6K3 intronic variant with decreased risk for HT in non-Caucasian, Algerian, population, whereas we did not confirm the association of SDK2 and GNA14 genetic variants with HT. The IP6K3 gene (inositol hexaphosphate kinase 3), located near major histocompatibility complex (MHC), has previously been associated with other common autoimmune diseases beside HT, such as Graves’s disease and rheumatoid arthritis, which is providing more evidence of a good candidacy for the genetic contribution to the development of HT and autoimmunity.