AbstractBackgroundTo search for new prevention markers for early detection of the diseases caused by tobacco, we aimed to investigate the polymorphisms in TSLP and TSLPRs associated with cigarette smoking in the Saudi population.Materials and methodsSamples were collected from 177 smokers and 126 healthy controls. Three TSLP SNPs [rs3806933, rs2289276, and rs10043985], three TSLPR SNPs [rs36133495, rs36177645, and rs36139698], and two IL7R SNPs rs1053496 and rs12516866 were analyzed by genotyping.ResultsTwo TSLP SNPs (rs10043985 and rs3806933) and one TSLPR SNP (rs36139698) showed significant correlations with smoking behavior, but not IL7R rs12516866 and rs1053496. rs10043985 showed a clear association with long‐term smoking regardless of daily cigarette consumption. rs2289276 was associated with short‐term smoking but not with daily cigarette consumption. rs3806933 was highly associated with different smoker subgroups. Rs36139698 was highly associated with long‐term smokers who consumed ≥20 cigarettes/day, and the “T” allele was associated only with individuals who smoked ≤20 cigarettes/day. Rs36139698 corresponds to a P195L substitution and produces a TSLPR mutant with a predicted ΔΔG increase of 2.15 kcal/mol and has a more stable structure than the wild‐type variant.ConclusionsInvestigating TSLP and TSLPR polymorphisms is crucial for elucidating the mechanisms underlying tobacco‐induced diseases.