Perez-Marques Francesca, Simpson Pippa, Yan Ke, Quasney Michael W, Halligan Nadine, Merchant Daniel, Dahmer Mary K
Section of Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Section of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Crit Care. 2016 Sep 5;20(1):281. doi: 10.1186/s13054-016-1454-7.
Previous work has demonstrated a strong association between lung injury in African American children with pneumonia and a polymorphic (TG)mTn region in cystic fibrosis transmembrane conductance (CFTR) involved in the generation of a nonfunctional CFTR protein lacking exon 9. A number of splicing factors that regulate the inclusion/exclusion of exon 9 have been identified. The objective of this study was to determine whether genetic variants in these splicing factors were associated with acute respiratory distress syndrome (ARDS) in children with pneumonia.
This is a prospective cohort genetic association study of lung injury in African American and non-Hispanic Caucasian children with community-acquired pneumonia evaluated in the emergency department or admitted to the hospital. Linkage-disequilibrium-tag single nucleotide polymorphisms (LD-tag SNPs) in genes of the following splicing factors (followed by gene name) involved in exon 9 skipping PTB1 (PTBP1), SRp40 (SFRS1), SR2/ASF (SFRS5), TDP-43 (TARDBP), TIA-1 (TIA1), and U2AF(65) (U2AF2) were genotyped. SNPs in the gene of the splicing factor CELF2 (CELF2) were selected by conservation score. Multivariable analysis was used to examine association between genotypes and ARDS.
The African American cohort (n = 474) had 29 children with ARDS and the non-Hispanic Caucasian cohort (n = 304) had 32 children with ARDS. In the African American group multivariable analysis indicated that three variants in CELF2, rs7068124 (p = 0.004), rs3814634 (p = 0.032) and rs10905928 (p = 0.044), and two in TIA1, rs2592178 (p = 0.005) and rs13402990 (p = 0.018) were independently associated with ARDS. In the non-Hispanic Caucasian group, a single variant in CELF2, rs2277212 (p = 0.014), was associated with increased risk of developing ARDS.
The data indicate that SNPs in CELF2 may be associated with the risk of developing ARDS in both African American and non-Hispanic Caucasian children with pneumonia and suggest that the potential role of the splicing factor CELF2 in ARDS should be explored further.
先前的研究表明，患有肺炎的非裔美国儿童的肺损伤与囊性纤维化跨膜传导调节因子（CFTR）中的一个多态性（TG）mTn区域密切相关，该区域参与生成一种缺乏外显子9的无功能CFTR蛋白。已经鉴定出许多调节外显子9包含/排除的剪接因子。本研究的目的是确定这些剪接因子中的基因变异是否与肺炎患儿的急性呼吸窘迫综合征（ARDS）相关。
这是一项前瞻性队列基因关联研究，研究对象为在急诊科接受评估或入院的患有社区获得性肺炎的非裔美国儿童和非西班牙裔白人儿童的肺损伤情况。对参与外显子9跳跃的以下剪接因子（后接基因名称）基因中的连锁不平衡标签单核苷酸多态性（LD-tag SNPs）进行基因分型：PTB1（PTBP1）、SRp40（SFRS1）、SR²/ASF（SFRS5）、TDP-43（TARDBP）、TIA-1（TIA1）和U2AF(65)（U2AF2）。通过保守性评分选择剪接因子CELF2（CELF2）基因中的SNP。采用多变量分析来检验基因型与ARDS之间的关联。
非裔美国人群队列（n = 474）中有29名儿童发生ARDS，非西班牙裔白人群队列（n = 304）中有32名儿童发生ARDS。在非裔美国人群组中，多变量分析表明，CELF2基因中的三个变异rs7068124（p = 0.004）、rs3814634（p = 0.032）和rs10905928（p = 0.044），以及TIA1基因中的两个变异rs2592178（p = 0.005）和rs13402990（p = 0.018）与ARDS独立相关。在非西班牙裔白人群组中，CELF2基因中的一个单一变异rs2277212（p = 0.014）与发生ARDS的风险增加相关。
数据表明，CELF2基因中的SNP可能与患有肺炎的非裔美国儿童和非西班牙裔白人儿童发生ARDS的风险相关，并提示应进一步探索剪接因子CELF2在ARDS中的潜在作用。
