Host genetic variants may affect oral biofilms, playing a role in the periodontitis–systemic disease axis. This is the first study to assess the associations between host genetic variants and subgingival microbiota in patients with metabolic syndrome (MetS); 103 patients with MetS underwent medical and periodontal examinations and had blood and subgingival plaque samples taken. DNA was extracted and processed, assessing a panel of selected single nucleotide polymorphisms (SNPs) first (hypothesis testing) and then expanding to a discovery phase. The subgingival plaque microbiome from these patients was profiled. Analysis of associations between host genetic and microbial factors was performed and stratified for periodontal diagnosis. Specific SNPs within RUNX2, CAMTA1 and VDR genes were associated with diversity metrics with no genome-wide associations detected for periodontitis severity or Mets components at p < 10−7. Severe periodontitis was associated with pathogenic genera and species. Some SNPs correlated with specific bacterial genera as well as with microbial taxa, notably VDR (rs12717991) with Streptococcus mutans and RUNX2 (rs3749863) with Porphyromonas gingivalis. In conclusion, variation in host genotypes may play a role in the dysregulated immune responses characterizing periodontitis and thus the oral microbiome, suggesting that systemic health-associated host traits further interact with oral health and the microbiome.