Shared Inflammatory Genetic Susceptibility Underlying Spontaneous Preterm Birth and Periodontitis: A Case–Control Study

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Abstract
Background: Preterm birth (PTB) remains the leading cause of neonatal morbidity and mortality worldwide, with approximately two-thirds of cases occurring spontaneously (SPTB), but the etiology is still poorly understood. Chronic inflammatory diseases, such as periodontitis (PD), have been considered SPTB risk factors. However, we hypothesized that SPTB may instead represent a clinical manifestation of a broader genetic predisposition to dysregulated inflammation. Using PD as a model of chronic inflammation, we examined shared genetic susceptibility. Methods: In a case–control study (N = 126 Portuguese postpartum women), we screened 56 SNPs in 36 inflammation-related genes. Four functionally plausible variants (IL1RN rs4251961, TLR1 rs5743618, IL6 rs2069827, and IL6R rs4845617) were selected for detailed regression, adjusting for gestational age, floss usage, and an SPTBxPD interaction term. Results: IL1RN rs4251961 was recessively associated with SPTB risk, consistent with reduced IL-1RA expression linked to this variant. IL6R rs4845617 showed a modest protective effect. TLR1 rs5743618 exhibited the strongest association with the composite “inflammation” phenotype under multiple models, with CC homozygotes showing four-fold increased odds, independent of SPTB/PD co-occurrence. Conclusions: This study provides original evidence that shared genetic variants in inflammatory pathways—particularly TLR1 rs5743618—may underlie susceptibility to SPTB and PD. Our findings suggest a paradigm shift, viewing SPTB as a possible outcome of systemic inflammatory dysregulation rather than merely a consequence of comorbid inflammatory conditions. Future studies should validate this marker in larger cohorts.
Funding Information
  • Egas Moniz School of Health and Sciences (CEI/11/2018, UIDP/04378/2020, UIDB/04378/2020, LA/P/0140/2020)
  • FCT, Fundação para a Ciência e a Tecnologia, I.P. (CEI/11/2018, UIDP/04378/2020, UIDB/04378/2020, LA/P/0140/2020)
  • Associate Laboratory Institute for Health and Bioeconomy—i4HB (CEI/11/2018, UIDP/04378/2020, UIDB/04378/2020, LA/P/0140/2020)

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