The aims of this study were to evaluate: (1) associations of vitamin D with the presence/severity of Hashimoto’s thyroiditis (HT) and (2) correlations of vitamin D with thyroid-related phenotypes. ...Total 25(OH)D (vitamin D in the text) was measured from stored serum samples of 461 HT patients and 176 controls from a Croatian Biobank of HT patients (CROHT). (1) Vitamin D levels, and proportions of vitamin D deficiency, were compared between HT cases and controls. HT patients were additionally divided into two groups (MILD and OVERT) to take into account HT severity. (2) Correlations between vitamin D and 10 clinical phenotypes in all HT patients and two subgroups of HT patients were tested using the Spearman correlation test. Our analyses were adjusted for age, gender, BMI, smoking status and seasonality of blood sampling. (1) No significant differences in vitamin D levels, or proportions of vitamin D deficiency, were detected between HT patients of all disease stages and controls. However, a nominally significant difference in vitamin D levels between MILD and OVERT subgroups (OR = 1.038, p = 0.023) was observed. Proportions of individuals with vitamin D deficiency during winter–spring were high: all HT cases (64.69%), MILD (60.64%), OVERT (68.7%), controls (60.79%). (2) A nominally significant negative correlation between vitamin D and TSH in all HT patients (r = −0.113, p = 0.029) and a positive correlation between vitamin D and systolic blood pressure in OVERT HT patients (r = 0.205, p = 0.025) were identified. Our study indicates that there is no association between vitamin D and HT; however, there may be a subtle decrease in vitamin D levels associated with overt hypothyroidism.
Although environmental factors induce development of type 1 diabetes mellitus (T1DM) in genetically susceptible individuals, many of those factors have been uncovered. Therefore, the aim of the ...present study was to analyze associations of T1DM with a wide range of environmental factors.
A case-control study was conducted on 249 diabetic and 255 healthy individuals from the Dalmatian region of South Croatia. Data regarding risk factors during pregnancy and early life period of the child were evaluated.
History of antihypertensive intake (
=0.04) and frequency of stressful life events during pregnancy (
=0.01) were associated with higher risk of T1DM, while hypertension was associated with lower risk of T1DM (
=0.01). Maternal age<25 years at delivery was associated with a higher risk of T1DM (
=0.01).Diabetic patients had a positive family history of T1DM or T2DM (
=0.002) more frequently than controls, while history of infectious diseases was inversely associated with the risk of T1DM (
=0.03). A higher risk of T1DM was significantly associated with earlier introduction of cow's milk (
=0.001), higher number of meals consumed per day (
=0.02), higher frequency of carbohydrate (
=0.001) and meat (
=0.01) consumption and stressful life events during childhood (
=0.02) while earlier introduction of fruit was associated with a lower risk of T1DM (
=0.03)
This case-control study confirmed associations of a large number of environmental factors with development of T1DM with emphasis on the association of mother's antihypertensive intake during pregnancy, which extends our knowledge about environmental factors related with development of T1DM.
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.
Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are ...almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10
). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10
) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.
Vitamin D insufficiency is a global health problem affecting healthy and diseased individuals, including patients with Hashimoto's thyroiditis (HT). Identifying dietary factors that may affect ...vitamin D levels and providing dietary guidelines accordingly can alleviate this problem. We therefore aimed to identify still unknown associations of dietary patterns, assessed through the Food Frequency Questionnaire (FFQ) with vitamin D blood levels.
FFQ was collected from 459 patients from Croatian Biobank of Patients with Hashimoto's thyroiditis (CROHT), while total 25(OH)D was measured from their stored serum samples. We performed linear regression analysis between vitamin D levels and weekly intake of 24 food groups in 459 patients with HT (ALL), and in two disease-severity groups (MILD and OVERT).
The main results of our study are observations of: (1) an inverse association between vitamin D levels and coffee consumption (ALL:
= -0.433,
= 0.005; OVERT:
= -0.62,
= 0.008); (2) an inverse association between vitamin D levels and sweets consumption (ALL:
= -0.195,
= 0.034; OVERT:
= -0.431,
= 0.006); (3) positive association between vitamin D levels and vegetable consumption (ALL:
= 0.182,
= 0.019; OVERT,
= 0.311,
= 0.009). Importantly, effect sizes of all three associations were more prominent in HT patients with prolonged and more severe disease (OVERT).
Further research into the functional and causal relationships of the observed associations is important to provide guidance regarding coffee/sugar intake on vitamin D status. A well-balanced diet can help prevent vitamin D deficiency and improve the quality of life of patients with HT, especially those in later stages of disease characterized by greater metabolic imbalance.
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
) and rs10738556 near chromatin-remodeling SMARCA2 (P = 2.83 × 10
). 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.
To analyze the association of thyroid function and hormone levels with metabolic syndrome (MetS) and its components.
This cross-sectional population-based study involved 2183 Croatian individuals ...with no history of thyroid disease, hypertension, diabetes, and hyperlipidemia. MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III criteria.
We found no association between thyroid function groups and the prevalence of MetS and its components. Clinically hypothyroid participants showed significantly higher triceps skinfold measurements than subclinically hypothyroid and euthyroid participants. Furthermore, clinically hypothyroid participants had higher abdominal skinfold thickness than subclinically hypothyroid participants. Otherwise, suprailiac and abdominal skinfold measurements were higher in the subclinically and clinically hyperthyroid group of participants compared with euthyroid and subclinically hypothyroid participants. A strong positive association of thyroid-stimulating hormone (TSH) and strong negative association of free triiodothyronine (fT3) and free thyroxine (fT4) levels with HOMA-IR and cholesterol levels were found. Furthermore, the fT4 level also showed a strong negative association with HDL and triceps skinfold thickness.
This study supports the standing that TSH, fT3, and fT4 levels are important variables to determine the association of thyroid function with MetS.
Parathyroid hormone (PTH) is one of the principal regulators of calcium homeostasis. Although serum PTH level is mostly accounted by genetic factors, genetic background underlying PTH level is ...insufficiently known. Therefore, the aim of this study was to identify novel genetic variants associated with PTH levels.
We performed GWAS meta-analysis within two genetically isolated Croatian populations followed by replication analysis in a Croatian mainland population and we also combined results across all three analyzed populations. The analyses included 2596 individuals. A total of 7,411,206 variants, imputed using the 1000 Genomes reference panel, were analysed for the association. In addition, a sex-specific GWAS meta-analyses were performed.
Polymorphisms with the lowest P-values were located on chromosome 4 approximately 84 kb of the 5' of RASGEF1B gene. The most significant SNP was rs11099476 (P = 1.15 × 10
). Sex-specific analysis identified genome-wide significant association of the variant rs77178854, located within DPP10 gene in females only (P = 2.21 × 10
). There were no genome-wide significant findings in the meta-analysis of males.
We identified two biologically plausible novel loci associated with PTH levels, providing us with further insights into the genetics of this complex trait.
The knowledge about dietary habits and their influence in the development of autoimmune thyroid disease is insufficient. The aim of this study was to analyse the association of dietary factors and ...plasma thyroid peroxidase antibodies (TPO-Ab) and/or thyroglobulin antibodies (Tg-Ab). The study enrolled 1887 participants originating from the South Croatia. Participants with elevated plasma TPO-Ab and/or Tg-Ab were defined as cases (
= 462) and those with TPO-Ab and/or Tg-Ab within referent values were defined as controls (
= 1425). Dietary intake was evaluated according to a food frequency questionnaire containing 58 food items. Principal component analysis was used to group food items into dietary groups. We used logistic regression analysis to examine dietary groups associated with positive plasma TPO-Ab and/or Tg-Ab. The results indicate that the dietary group with frequent consumption of animal fats and butter is associated with positive plasma TPO-Ab and/or Tg-Ab (
= 0.01). The dietary group with frequent consumption of vegetables as well as the dietary group with high consumption of dried fruit, nuts, and muesli are associated with negative findings of TPO-Ab and/or Tg-Ab (
= 0.048 and
= 0.02, respectively). We showed that the anti-inflammatory dietary groups are associated with the negative findings of plasma TPO-Ab and/or Tg-Ab.
Thyroid antibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are key markers of Hashimoto's thyroiditis (HT), the most common autoimmune thyroid disorder. Genetic determinants of ...thyroid antibodies are still poorly known, especially as they were not studied in patients with thyroid diseases. We performed the first genome-wide association analysis of thyroid antibodies in 430 HT patients that may be considered as population extremes for thyroid antibodies distribution. We detected two suggestively associated genetic variants with TgAb, rs6972286 close to ANKRD7 and LSM8 (P = 2.34 × 10
) and rs756763 inside CA10 (P = 6.05 × 10
), and one with TPOAb, rs12507813 positioned between TRIM61 and TRIM60 (P = 4.95 × 10
). Bivariate analysis resulted with three suggestively associated genetic variants that predispose to both antibodies: rs13190616 inside RP11-138J23.1 (P = 2.01 × 10
), rs561030786 close to DUBR (P = 7.33 × 10
) and rs12713034 inside FSHR (P = 7.66 × 10
). All identified genomic regions have a substantial literature record of involvement with female-related traits, immune-mediated diseases and personality traits that are all characterized by increased thyroid antibody levels. Our findings demonstrate the existence of genetic overlap between thyroid autoimmunity in HT and different non-thyroid diseases characterized by the presence of thyroid antibodies. We also suggest that genetic variants that regulate antibody levels may differ between HT patients and individuals with normal thyroid function.
PDF
