Srinivasan Lakshmi, Page Grier, Kirpalani Haresh, Murray Jeffrey C, Das Abhik, Higgins Rosemary D, Carlo Waldemar A, Bell Edward F, Goldberg Ronald N, Schibler Kurt, Sood Beena G, Stevenson David K, Stoll Barbara J, Van Meurs Krisa P, Johnson Karen J, Levy Joshua, McDonald Scott A, Zaterka-Baxter Kristin M, Kennedy Kathleen A, Sánchez Pablo J, Duara Shahnaz, Walsh Michele C, Shankaran Seetha, Wynn James L, Cotten C Michael
Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, Research Park, North Carolina, USA.
Arch Dis Child Fetal Neonatal Ed. 2017 Sep;102(5):F439-F445. doi: 10.1136/archdischild-2016-311545. Epub 2017 Mar 10.
To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants.
Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10. Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points.
Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values<0.001 and FDR<20%).
No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.
在一组极早产儿队列中，通过全基因组关联（GWA）分析来识别与败血症（早发型和晚发型）相关的基因变异。
本研究使用了之前从新生儿研究网络的极早产儿匿名基因组数据库生物样本库中生成的GWA数据。败血症定义为培养阳性的早发型或晚发型败血症或培养证实的脑膜炎。对基因组和全基因组扩增的DNA进行了120万个单核苷酸多态性（SNP）的基因分型；91%的SNP成功进行了基因分型。我们又推算出另外720万个SNP。通过多变量逻辑回归分析计算p值和错误发现率（FDR），并对性别、胎龄和祖先进行了校正。目标统计值为p<10。二级分析评估了SNP与病原体类型的关联。还对主要和次要终点进行了通路分析。
纳入了757名极早产儿的数据：351名患有败血症的婴儿和406名未患败血症的婴儿。没有SNP达到全基因组显著水平（5×10）；靠近FOXC2和FOXL1基因的两个SNP达到了目标显著水平。在二级分析中，ELMO1、IRAK2（革兰氏阳性败血症）、RALA、IMMP2L（革兰氏阴性败血症）和PIEZO2（真菌性败血症）的SNP达到了目标显著水平。与败血症和革兰氏阴性败血症相关的通路包括间隙连接、成纤维细胞生长因子受体、细胞分裂调节因子和白细胞介素-1相关受体激酶2（p值<0.001且FDR<20%）。
在这组极低出生体重婴儿队列中，没有SNP达到全基因组显著水平；然而，确定了潜在关联区域和值得进一步研究的通路。
