Associations of Polygenetic Variants at the 11q23 Locus and Their Interactions with Macronutrient Intake for the Risk of 3GO, a Combination of Hypertension, Hyperglycemia, and Dyslipidemia

3GO is a condition in which hypertension, hyperglycemia, and dyslipidemia co-occur, and these conditions are related to each other and genetic and environmental factors. We hypothesized that common genetic variants and their interactions with lifestyles influenced 3GO risk. We aimed to explore common genetic variants to affect 3GO risk and their haplotype interaction with lifestyles in a city hospital-based cohort in 58,701 Koreans > 40 years. 3GO was defined as SBP ≥ 140 mmHg and DBP ≥ 90 mmHg for hypertension, fasting blood glucose ≥ 126 mg/dL for hyperglycemia, and LDL ≥ 160 mg/dL or HDL ≤ 40 mg/dL, or triglyceride ≥ 200 mg/dL for dyslipidemia. Haplotypes were generated by genetic variants selected from genome-wide association study ((GWAS) an observational study of the genetic variation of the whole genome in different individuals, used to see if any variation is related to traits) after adjusting for age, sex, area of residence, and body mass index (BMI). Nutrient intakes were assessed using food frequency questionnaires. Interactions between haplotype and lifestyles and 3GO risk were investigated. Parameters related to metabolic syndrome were significantly different in the 0GO, 1–2GO, and 3GO groups, that is, groups of individuals with none, one to two, or all three of the components of 3GO. At the 11q23 locus, KCNQ1_rs2237892, ZPR1_rs2075291, APOA5_rs662799, APOA1_rs5072, and SIK3_rs151139277, influenced 3GO risk, and the minor alleles of their haplotype had a 3GO risk 3.23 times higher than the major alleles. For subjects with a high energy intake, the 3GO risk of the minor alleles was significantly higher than that of the major alleles (OR = 3.230, 95% confidence interval (CI) = 2.062~5.061, p < 0.001). BMI, HbA1c, SBP, and serum concentrations of glucose, HDL, and triglyceride were significantly higher for the minor allele than the major alleles (p < 0.001). The haplotype interacted with the intakes of protein (p = 0.033), digestible carbohydrate (p = 0.012), fat (p = 0.008), and undigestible carbohydrates (p = 0.015) to increase 3GO risk. An interaction was also observed between smoking and the haplotype (p = 0.007). The minor allele effects on 3GO incidence were higher in the high digestible carbohydrate intake and smoking groups. By contrast, the minor allele impacts on 3GO frequencies were much higher in the low intake of undigestible carbohydrates, protein, and fat. In conclusion, people who carry a minor allele of the 11q23 locus haplotype should avoid smoking and replace digestible carbohydrate intake with consuming high-quality protein, healthy fat, and undigestible carbohydrates.