Abstract
BackgroundAutoimmune thyroid disease (AITD) comprises diseases including Hashimoto's thyroiditis and Graves' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD.MethodsPolymorphisms in the IL6-174 G/C (rs1800795), TNFA-308 G/A (rs1800629), IL1B-511 C/T (rs16944), and IFNGR1-56 T/C (rs2234711) genes were assessed in a case-control study comprising 420 Hashimoto's thyroiditis patients, 111 Graves' disease patients and 735 unrelated controls from Portugal. Genetic variants were discriminated by real-time PCR using TaqMan SNP genotyping assays.ResultsA significant association was found between the allele A in TNFA-308 G/A and Hashimoto's thyroiditis, both in the dominant (OR = 1.82, CI = 1.37–2.43, p-value = 4.4×10−5) and log-additive (OR = 1.64, CI = 1.28–2.10, p-value = 8.2×10−5) models. The allele C in IL6-174 G/C is also associated with Hashimoto's thyroiditis, however, only retained significance after multiple testing correction in the log-additive model (OR = 1.28, CI = 1.06–1.54, p-value = 8.9×10−3). The group with Graves' disease also registered a higher frequency of the allele A in TNFA-308 G/A compared with controls both in the dominant (OR = 1.85, CI = 1.19–2.87, p-value = 7.0×10−3) and log-additive (OR = 1.69, CI = 1.17–2.44, p-value = 6.6×10−3) models. The risk for Hashimoto's thyroiditis and Graves' disease increases with the number of risk alleles (OR for two risk alleles is, respectively, 2.27 and 2.59).ConclusionsThis study reports significant associations of genetic variants in TNFA and IL6 with the risk for AITD, highlighting the relevance of polymorphisms in inflammation-related genes in the etiopathogenesis of AITD.
Highlights
Autoimmune diseases, which affect 5 to 7% of the population and are frequently responsible for severe disability, represent a major cause of chronic illness and an important issue in general healthcare [1]
The diagnosis of Graves’ disease (GD) was established on the basis of clinical findings, decreased serum thyroid stimulating hormone (TSH) (,0.35 IU/mL), elevated serum free thyroxine (FT4) (.1.48 ng/dL) and/or free triidothyronine (FT3) (.3.71 pg/mL), positive serum antibodies to TSHreceptor (TRAb) (.1.8 IU/L), and typical ultrasound signs
The frequencies of all single nucleotide polymorphisms (SNPs) did not deviate significantly from those expected under Hardy-Weinberg equilibrium (p-value for IL1B-511, TNFA-308, IL6-174 and IFNGR156 is, respectively, 0.059, 0.122, 0.491 and 0.347)
Summary
Autoimmune diseases, which affect 5 to 7% of the population and are frequently responsible for severe disability, represent a major cause of chronic illness and an important issue in general healthcare [1]. Autoimmune thyroid diseases (AITD), including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), are the most common organ specific autoimmune disorders [2]. HT is a T cell-mediated organ-specific autoimmune disease characterized by lymphocytic infiltration that leads to thyroid cells loss, clinically expressed by hypothyroidism [4]. GD patients exhibit hyperthyroidism, which is due to excessive secretion of the thyroid hormone induced by specific autoantibodies to the thyrotropin receptor (TSHR) produced by TSHR-reactive B cells [5]. Autoimmune thyroid disease (AITD) comprises diseases including Hashimoto’s thyroiditis and Graves’ disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. Cytokines are key regulators of the immune and inflammatory responses; genetic variants at cytokine-encoding genes are potential risk factors for AITD
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