The Department of Population and Quantitative Health Sciences at Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Mary Ann Swetland Center for Environmental Health at Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Pediatr Res. 2023 Mar;93(4):1085-1095. doi: 10.1038/s41390-022-02114-8. Epub 2022 Jul 14.
Late-Onset Neonatal Sepsis (LOS) is a rare condition, involving widespread infection, immune disruption, organ dysfunction, and often death. Because exposure to pathogens is not completely preventable, identifying susceptibility factors is critical to characterizing the pathophysiology and developing interventions. Prior studies demonstrated both genetics and infant sex influence susceptibility. Our study was designed to identify LOS associated genetic variants.
We performed an exploratory genome wide association study (GWAS) with 224 LOS cases and 273 controls from six European countries. LOS was defined as sepsis presenting from 3 to 90 days of age; diagnosis was established by clinical criteria consensus guidelines. We tested for association with both autosomal and X-chromosome variants in the total sample and in sex-stratified analyses.
In total, 71 SNPs associated with neonatal sepsis at p < 1 × 10 in at least one analysis. Most importantly, sex-stratified analyses revealed associations with multiple SNPs (28 in males and 16 in females), but no variants from single-sex analyses associated with sepsis in the other sex. Pathway analyses showed NOTCH signaling is over-represented among genes linked to these SNPS.
Our results indicate genetic susceptibility to LOS is sexually dimorphic and corroborate that NOTCH signaling plays a role in determining risk.
Genes associate with late onset neonatal sepsis. Notch pathway genes are overrepresented in associations with sepsis. Genes associating with sepsis do not overlap between males and females. Sexual dimorphism can lead to sex specific treatment of sepsis.
晚发型新生儿败血症（LOS）是一种罕见的病症，涉及广泛的感染、免疫紊乱、器官功能障碍，且常伴有死亡。由于无法完全预防病原体的暴露，因此确定易感性因素对于描述病理生理学和开发干预措施至关重要。先前的研究表明，遗传和婴儿性别均会影响易感性。我们的研究旨在确定与 LOS 相关的遗传变异。
我们对来自六个欧洲国家的 224 例 LOS 病例和 273 例对照进行了探索性全基因组关联研究（GWAS）。LOS 的定义为 3 至 90 天发病的败血症；采用临床标准共识指南进行诊断。我们在总样本和性别分层分析中，对常染色体和 X 染色体变异进行了关联测试。
在总样本中，有 71 个 SNP 在至少一项分析中与新生儿败血症相关，达到 p<1×10。最重要的是，性别分层分析显示，多个 SNP 与男性（28 个）和女性（16 个）相关，但来自单性分析的没有变异与另一性别中的败血症相关。通路分析表明，NOTCH 信号通路在与这些 SNPs 相关的基因中过度表达。
我们的研究结果表明，LOS 的遗传易感性存在性别二态性，并且证实 NOTCH 信号通路在确定风险中起作用。
这些基因与晚发型新生儿败血症相关联。NOTCH 通路基因在与败血症的关联中过度表达。与败血症相关的基因在男性和女性之间没有重叠。性别二态性可能导致针对败血症的性别特异性治疗。
