Periodontitis is a chronic bacterial infection that destroys the epithelial attachment, forming a crevice beneath the gingival margins. The bacteria form dentally attached biofilms that enter the crevice and cause systemic inflammatory diseases (comorbidities). Susceptibility to moderate or severe (established) periodontitis is associated with smoking, diabetes, inadequate oral hygiene, and a genetic factor related to innate immunity function. One key factor in innate immunity function and its significance for periodontitis is related to the essential amino acid lysine. While lysine is absent in saliva, it is present in gingival crevicular fluid (GCF), an inflammatory exudate from the gingival crevice that permeates dental biofilms. After 16 periodontally healthy adults refrained from oral hygiene for 1 week, nine exhibited strong and seven exhibited weak GCF exudation, despite similar biofilm lysine concentrations. Strong responders, who effectively moved biofilm bacteria back into saliva, possess the adenine (A) single nucleotide polymorphism (SNP) at site −511 of the interleukin-1β (IL1B) gene instead of guanine (G). Weak responders possess thymidine (T) SNP at site +3877 of IL1B instead of cytidine (C), leading to bacterial retention in gingival crevices where lysine promotes periodontopathic biofilm development. If both IL1B + 3877(T) and IL1B-511(A) are present, an SNP in IL6, IL10, or CD14 determines the GCF response. These genetic profiles identify 40% of the US population as susceptible to periodontitis and comorbidities, causing bacterially driven systemic inflammation.