Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
Department of Pediatrics, Duke University, Durham, NC.
J Pediatr. 2015 Mar;166(3):531-7.e13. doi: 10.1016/j.jpeds.2014.09.052. Epub 2014 Nov 6.
To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors.
A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models.
Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD.
Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.
鉴定与支气管肺发育不良（BPD）相关的单核苷酸多态性（SNP）和通路，因为 36 周龄时的氧需求风险强烈受遗传因素影响。
使用极低出生体重儿的 DNA 库，对 120 万个已基因分型的 SNP 进行全基因组扫描，并对另外 700 万个推断的 SNP 进行全基因组关联和基因集分析，以研究 BPD 或死亡、严重 BPD 或死亡以及幸存者中的严重 BPD。通过 BPD 肺组织和小鼠模型中的基因表达，验证特定靶点。
在分析的 751 名婴儿中，有 428 名发生 BPD 或死亡。尽管腺苷脱氨酶、CD44 和其他基因中的多个 SNP 仅略低于 P < 10(-6)，但没有 SNP 达到全基因组显著性（P < 10(-8)）。在大约 8000 条通路中，有 75 条通路在 FDR < 0.1 和 P <.001 时与 BPD/死亡显著相关，95 条通路与严重 BPD/死亡显著相关，90 条通路与幸存者中的严重 BPD 显著相关。FDR 最低的通路是 miR-219 靶标（P = 1.41E-08，FDR 9.5E-05），用于 BPD/死亡，以及磷氧裂解酶活性（包括腺苷酸和鸟苷酸环化酶），用于严重 BPD/死亡（P = 5.68E-08，FDR 0.00019）和幸存者中的严重 BPD（P = 3.91E-08，FDR 0.00013）。基因表达分析证实 miR-219 和 CD44 在 BPD 中显著增加。
通路分析证实了肺发育和修复的已知通路（CD44、磷氧裂解酶活性）的参与，并表明与 BPD 遗传易感性相关的新分子和通路（腺苷脱氨酶、miR-219 的靶标）。
