甲状腺激素减少症是一种常见的内分泌紊乱疾病，与多种代谢异常相关。本研究旨在调查与甲状腺激素减少症风险相关的多基因变异，并研究与膳食模式相互作用对该病风险的影响。研究对象为一家庭医院的基于人口的队列研究中，56664名年龄在40岁以上的参与者。根据医生诊断，将参与者分为甲状腺激素减少症组（n = 870）和非甲状腺激素减少症组（n = 55794）。通过全基因组关联研究（GWAS），鉴定与甲状腺激素减少症相关的遗传变异。采用广义多因子尺度约简分析选择互相作用的遗传变异，并评估与生活方式参数相互作用的PRS。咖啡、酒精、肉类摄入和韩国平衡饮食与甲状腺激素减少症风险呈负相关，硒、铜和锰摄入也与甲状腺激素减少症风险呈负相关。白细胞计数、血清碱性磷酸酶和甘油三酯浓度与甲状腺激素减少症风险呈正相关，骨质疏松和甲状腺癌也与甲状腺激素减少症风险呈正相关。广义多因子尺度约简分析产生了一个包含双氧化酶1 (DUOX1)_rs1648314、甲状腺刺激素受体(TSHR)_rs75664963和主要组织相容性复合体，类II，DQα 1 (HLA-DQA1)_rs17426593的三个单核苷酸多态性（SNPs）模型。从三个SNP模型和七个SNP模型派生的PRS分别与甲状腺激素减少症风险增加2.11倍和2.32倍相关。此外，从三个SNP模型中得出的PRS与白细胞计数相互作用，甲状腺激素减少症风险在白细胞计数低于高白细胞计数（≥4×109 /L）的参与者中更为显著。植物为基础的饮食（PBD）和西式饮食（WSD）以及吸烟状况与PRS呈交互作用，影响甲状腺激素减少症风险。在高PRS的参与者中，高PBD、低WSD和吸烟者群组的甲状腺激素减少症比例高于低PBD、高WSD和非吸烟者群组。总之，与免疫和甲状腺激素分泌相关的遗传变异与甲状腺激素减少症风险相关，其PRS与PBD和WSD摄入以及吸烟状态相互作用。这些结果为更好地理解甲状腺激素减少症及其个体化医学干预的预防策略做出了贡献。

Hypothyroidism is a prevalent endocrine disorder and is associated with a variety of metabolic disturbances. This study aimed to investigate the polygenic variants associated with hypothyroidism risk and the interaction of polygenic risk scores (PRS) with dietary patterns in influencing disease risk in 56,664 participants aged >40 in a hospital-based cohort. The participants were classified as having hypothyroidism (n = 870) diagnosed by a physician and no hypothyroidism (n = 55,794). Genetic variants associated with hypothyroidism were identified using a genome-wide association study (GWAS). Genetic variants interacting with each other were selected using a generalized multifactor dimensionality reduction analysis, and the PRS generated was evaluated for interaction with lifestyle parameters. Coffee, alcohol, meat intake, and a Korean balanced diet were inversely associated with hypothyroidism risk, as were selenium, copper, and manganese intakes. White blood cell (WBC) counts and serum alkaline phosphatase and triglyceride concentrations were positively associated with hypothyroidism risk, as were osteoporosis and thyroid cancer. The GMDR analysis generated a three-single nucleotide polymorphism (SNP) model comprising dual oxidase-1 (DUOX1)_rs1648314; thyroid-stimulating hormone receptor (TSHR)_rs75664963; and major histocompatibility complex, class-II, DQ Alpha-1 (HLA-DQA1)_rs17426593. The PRS derived from the three- and seven-SNP models were associated with a 2.11- and 2.32-fold increase in hypothyroidism risk, respectively. Furthermore, the PRS from the three-SNP model showed interactions with WBC counts, wherein the positive association with hypothyroidism risk was more pronounced in participants with low WBC counts than those with high WBC counts (≥4 × 109 /L). Dietary patterns, such as the plant-based diet (PBD) and the Western-style diet (WSD), along with smoking status, exhibited interactions with the PRS, influencing hypothyroidism risk. In participants with a high PRS, those in the high-PBD, low-WSD, and smoker groups had a higher proportion of hypothyroidism than those in the low-PBD, high-WSD, and non-smoker groups. In conclusion, genetic variants related to immunity and thyroid hormone secretion were linked to hypothyroidism risk, and their PRS interacted with PBD and WSD intake and smoking status. These results contribute to a better understanding of hypothyroidism and its prevention strategies for precision medicine intervention.