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.

Figure 1

Flow chart to generate polygenetic risk score system influencing hyperthyroidism risk.

Figure 2

Adjusted odds ratio (ORs) and 95% confidence intervals (CIs) of the PRSs of 5- and 6-SNP models generated assessing gene-gene interactions associated with hyperthyroidism risk. The best GMDR models with 6 SNPs and 7 SNPs were calculated by the summation of the number of risk alleles of six and seven SNPs, and the calculated PRSs were divided into three categories (0–3, 4–6, and ≥7) and (0–4, 5–7, and ≥8), respectively, as the low PRS, medium PRS, and high PRS groups. The adjusted OR was analyzed by logistic regression with the covariates including age, gender, residence areas, initial menstruation age, menopause, pregnancy experience, income, education, energy intake, seaweed intake, smoking status, physical activity, WBC counts, alcohol intake, autoimmune diseases, and survey year. The reference group was the low PRS in logistic regression. Red and blue boxes indicated the adjusted ORs for five SNPs and six SNPs, respectively, and the lines through red and blue boxes indicated 95% CIs.