Association of Polygenetic Risk Scores Related to Immunity and Inflammation with Hyperthyroidism Risk and Interactions between the Polygenetic Scores and Dietary Factors in a Large Cohort

Abstract

Graves’s disease and thyroiditis induce hyperthyroidism, the causes of which remain unclear, although they are involved with genetic and environmental factors. We aimed to evaluate polygenetic variants for hyperthyroidism risk and their interaction with metabolic parameters and nutritional intakes in an urban hospital-based cohort. A genome-wide association study (GWAS) of participants with (cases; n = 842) and without (controls, n = 38,799) hyperthyroidism was used to identify and select genetic variants. In clinical and lifestyle interaction with PRS, 312 participants cured of hyperthyroidism were excluded. Single nucleotide polymorphisms (SNPs) associated with gene-gene interactions were selected by hyperthyroidism generalized multifactor dimensionality reduction. Polygenic risk scores (PRSs) were generated by summing the numbers of selected SNP risk alleles. The best gene-gene interaction model included tumor-necrosis factor (TNF)_rs1800610, mucin 22 (MUC22)_rs1304322089, tribbles pseudokinase 2 (TRIB2)_rs1881145, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)_rs231775, lipoma-preferred partner (LPP)_rs6780858, and human leukocyte antigen (HLA)-J_ rs767861647. The PRS of the best model was positively associated with hyperthyroidism risk by 1.939-fold (1.317–2.854) after adjusting for covariates. PRSs interacted with age, metabolic syndrome, and dietary inflammatory index (DII), while hyperthyroidism risk interacted with energy, calcium, seaweed, milk, and coffee intake ( P < 0.05 ). The PRS impact on hyperthyroidism risk was observed in younger (<55 years) participants and adults without metabolic syndrome. PRSs were positively associated with hyperthyroidism risk in participants with low dietary intakes of energy (OR = 2.74), calcium (OR = 2.84), seaweed (OR = 3.43), milk (OR = 2.91), coffee (OR = 2.44), and DII (OR = 3.45). In conclusion, adults with high PRS involved in inflammation and immunity had a high hyperthyroidism risk exacerbated under low intakes of energy, calcium, seaweed, milk, or coffee. These results can be applied to personalized nutrition in a clinical setting.

Interactions between Polygenetic Variants and Lifestyle Factors in Hypothyroidism: A Hospital-Based Cohort Study

“…According to the location of mutation sites on the TSHR gene, hypothyroidism or hyperthyroidism may be induced. However, no TSHR mutation has been found for hyperthyroidism in the city hospital-based cohort of KoGES [50]. In Chinese patients with congenital hypothyroidism, seven genetic variants of TSHR, such as mutations in Ile216, Ala275, Asn372, and Ser567 with loss-of-function, and genetic variants of DUOX2 are also found [54,55].…”

“…Autoimmune activation can induce both hypothyroidism and hyperthyroidism, which result from different mechanisms within the autoimmune process [50]. Over time, the autoimmune attack leads to destroying thyroid tissue, reducing the gland's ability to produce thyroid hormones (T3 and T4) and inducing hypothyroidism [51].…”

Identification of potential immunotherapeutic targets and prognostic biomarkers in Graves' disease using weighted gene co-expression network analysis

“…Although there is no direct evidence that PRSS1 plays a role in the immunology of GDe, studies suggest that dysregulated proteases and protease inhibitors are associated with autoimmunity and inflammation in GD [ 66 ]. Proteases, including serine proteases like PRSS1, play important roles in various physiological processes, such as inflammation and tissue remodeling [ 67 , 68 ]. In GD, autoantibodies that bind to and stimulate the TSHR on thyroid cells are produced, leading to increased production of thyroid hormones and hyperthyroidism [ 69 , 70 ].…”

Diet Quality and Dietary Inflammatory Index in Dutch Inflammatory Bowel Disease and Irritable Bowel Syndrome Patients

“…This resulted in a (weighed) positive (pro-inflammatory) or a negative (anti-inflammatory) value for each component. The sum finally indicates the overall diet score, which has been validated in healthy individuals, elderly and those at risk of type 2 diabetes and cardiovascular disease [13,29,30], and used in various patient groups [31][32][33][34].…”