Low-grade subclinical inflammation is interrelated with metabolic diseases, and its susceptibility interacts with genetic and environmental factors. We aimed to examine genetic variants related to a high risk for inflammation using serum C-reactive protein (CRP) concentration, interactions among the genetic variants and the genetic variant interaction with dietary and lifestyle factors in adults. The participants were divided into case and control by serum CRP concentrations: ≥ 0·5 mg/dl (case; n 2018) and < 0·5 mg/dl (control; n 47 185). Genetic variants contributing to high inflammation risk were selected using GWAS after adjusting covariates to influence inflammation, and genetic variant–genetic variant interactions were identified by generalised multifactor dimensionality reduction analysis. Polygenetic-risk scores (PRS) were constructed from the selected genetic variants, and PRS–nutrient interactions for the high inflammation risk were determined. The PRS included CRP_rs1205, OASL_rs3213545, APOE_rs429358, HNF1A_rs1169286, APOC1_rs7256200 and SLC13A3_rs424697. The PRS was positively associated with serum CRP concentration by 2·0 times after adjusting for covariates. The PRS interacted with age: older participants with High-PRS had much higher serum CRP concentrations than those with Low-PRS. Intake of carbohydrates, MUFA and vitamin D exhibited an interaction with PRS for inflammation risk (P < 0·05). In participants with high-carbohydrate/low-fat diets and low vitamin D intakes, those with High-PRS had a higher risk of serum CRP concentrations than those with Low-PRS. In conclusion, the participants with inflammation-related PRS potentially worsened inflammation status, especially in diets with high carbohydrates, low fat (especially MUFA) and low vitamin D. These results can be applied to personalised nutrition to reduce inflammation risk.