Study population
We analyzed a database from the community-based Korean Genome and Epidemiology Study longitudinal prospective cohort of subjects from the Ansan (urban) and Anseong (rural) areas. The inclusion criteria included age ≥40 years, complete data measurements, and informed consent from subjects. Subjects with mental disorders, malignant tumors, or incomplete recorded information in their medical records were excluded from this study. Among 9,333 participants, a total of 3,580 subjects (1,666 males and 1,914 females) with complete data were included in this study. From 2001 to 2014, these participants have been biennially followed up. We defined the participants with newly diagnosed of MetS by the modified NCEP-ATP III criteria as MetS group, the healthy participants as Non-MetS group. The study protocol was approved by the Institutional Review Board (IRB; KBP-2017-014) of Korea Centers for Disease Control and Prevention. All participants provided written informed consent before the commencement of the study.
Clinical and laboratory assessments
Each subject completed a past medical history questionnaire and underwent anthropometric assessment. Laboratory and radiological tests were conducted on the same day. Waist circumference was measured at the midpoint between the lower costal margin and the level of the anterior superior iliac crest. The laboratory evaluations included serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, HDL cholesterol, fasting glucose, and serum insulin.
Definition of MetS
MetS was diagnosed as the presence of three or more of the following parameters according to the modified NCEP-ATP III criteria: (i) waist circumference: ≥90 cm in men and ≥80 cm in women (in accordance with the International Obesity Task Force criteria for Asian-Pacific population); (ii) triglycerides: ≥150 mg/dL; (iii) HDL-cholesterol: <40 mg/dL in men and <50 mg/dL in women; (iv) blood pressure: ≥130/85 mmHg or antihypertensive medications; and (v) fasting blood glucose: ≥110 mg/dL (fasting blood glucose ≥100 mg/dL was revised in 2005) or antidiabetic medications.
Clinical surrogate markers
The TyG index was calculated as ln [fasting triglycerides (mg/dL) × FPG (mg/dL)/2]. HOMA-IR was calculated as FPG (mmol/L) × fasting insulin (mIU/L)/22.5.
Genotyping
In this study, genotyping of the HumanCoreExome 12v1 chip (Illumina, Inc., San Diego, CA, USA) was performed and the data was analyzed. First, all genetic variants were examined for Hardy–Weinberg equilibrium. From the 77,421 SNPs in the HumanCoreExome 12v1 chip data, we excluded SNPs based on the Hardy-Weinberg equilibrium test for quality control, SNPs in sex chromosomes and the mitochondria, and monomorphic SNPs. After filtering the SNPs, 1,284 SNPs remained.
Statistical analysis
Data are presented as the mean ± standard deviation. The patient characteristics were compared using the χ2 test for categorical variables and Student’s t-test and Mann–Whitney U-Test for continuous variables. A logistic regression analysis was performed to examine the association between the development of MetS and genetic polymorphisms using the SNP & Variation Suite (Golden Helix, Bozeman, MT, USA). PolyPhen-2, SIFT, and PROVEAN software were used for predicting protein damage caused by SNPs. AUROC, sensitivity, and specificity were assessed using the “ROC curve analysis” function of MedCalc. The Youden index (YI) was calculated as: (sensitivity + specificity) - 1. AUROC was defined as excellent (AUC 0.9–1), good (AUC 0.8–0.89), fair (AUC 0.7–0.79), poor (AUC 0.6–0.69), or fail/no discriminatory capacity (AUC 0.5–0.59).