Couceiro Joana, Família Carlos, Brito José, Mendes José João, Baptista Pedro V, Fernandes Alexandra R, Quintas Alexandre
UCIBIO-Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal.
Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2829-516 Caparica, Portugal.
J Clin Med. 2025 Sep 2;14(17):6195. doi: 10.3390/jcm14176195.
: 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. : In a case-control study (N = 126 Portuguese postpartum women), we screened 56 SNPs in 36 inflammation-related genes. Four functionally plausible variants ( rs4251961, rs5743618, rs2069827, and rs4845617) were selected for detailed regression, adjusting for gestational age, floss usage, and an SPTBxPD interaction term. : rs4251961 was recessively associated with SPTB risk, consistent with reduced IL-1RA expression linked to this variant. rs4845617 showed a modest protective effect. 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. : This study provides original evidence that shared genetic variants in inflammatory pathways-particularly 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.
早产（PTB）仍然是全球新生儿发病和死亡的主要原因，约三分之二的病例为自发性早产（SPTB），但其病因仍知之甚少。慢性炎症性疾病，如牙周炎（PD），被认为是SPTB的危险因素。然而，我们推测SPTB可能反而代表了更广泛的炎症调节异常的遗传易感性的一种临床表现。我们以PD作为慢性炎症的模型，研究了共同的遗传易感性。
在一项病例对照研究（N = 126名葡萄牙产后妇女）中，我们筛选了36个炎症相关基因中的56个单核苷酸多态性（SNP）。选择了四个功能上合理的变体（rs4251961、rs5743618、rs2069827和rs4845617）进行详细的回归分析，并对胎龄、使用牙线情况以及SPTB与PD的相互作用项进行了校正。
rs4251961与SPTB风险呈隐性关联，这与该变体导致白细胞介素-1受体拮抗剂（IL-1RA）表达降低一致。rs4845617显示出适度的保护作用。在多种模型下，rs5743618与复合“炎症”表型的关联最强，CC纯合子的患病几率增加了四倍，且独立于SPTB/PD的共现情况。
本研究提供了原始证据，表明炎症途径中的共同遗传变体——尤其是rs5743618——可能是SPTB和PD易感性的基础。我们的研究结果表明了一种范式转变，即将SPTB视为全身炎症调节异常的可能结果，而不仅仅是合并炎症性疾病的后果。未来的研究应在更大的队列中验证这一标志物。
