Elevated White Blood Cell Counts Despite Normal C-Reactive Protein Independently Predict Metabolic Syndrome and...

Background/Objectives: Elevated white blood cell (WBC) counts and C-reactive protein (CRP) are established inflammatory markers associated with cardiometabolic disease. However, whether elevated WBC remains prognostically important without CRP elevation is unclear. This study aimed to examine whether elevated WBC despite normal CRP would predict incident metabolic syndrome (MetS) and myocardial infarction (MI), and to investigate its genetic basis and dietary modifiability. Methods: This prospective cohort study included 54,744 Korean adults with a mean follow-up of five years. Participants were classified as WBC-Only Elevated (WOE; WBC ≥ 6.2 × 10⁹/L and CRP < 1.0 mg/dL) or normal WBC and CRP (Low Risk) at baseline. Cox proportional hazards models estimated risks of incident MetS and MI. Genome-wide association studies (GWAS) identified genetic variants associated with WOE, from which weighted genetic risk scores (GRS) were constructed and replicated in the UK Biobank (n = 352,394). GRS-diet interactions were evaluated using a validated 106-item semi-quantitative food frequency questionnaire and 24 h dietary recalls. Results: WOE was independently associated with increased risks of MetS (HR = 1.82, 95% CI: 1.57-2.11) and MI (HR = 1.60, 95% CI: 1.25-2.04; both p < 0.001) compared with Low Risk. Immune-related variants at 17q21.1 and 6p21.3 were replicated in the UK Biobank. Among individuals with high genetic risk, adherence to a Korean-style balanced diet and higher overall diet quality attenuated genetic susceptibility to WOE by 16% (p = 0.042) and 30% (p = 0.031), respectively. Conclusions: Elevated WBC despite normal CRP independently predicted incident MetS and MI. These findings suggest that incorporating WBC alongside CRP in inflammatory risk assessment, together with genetic and dietary information, may support more targeted cardiometabolic risk stratification.