Section of Pulmonary/Critical Care Medicine, Harborview Medical Center, Seattle, Washington, USA.
Am J Respir Crit Care Med. 2011 Feb 1;183(3):356-63. doi: 10.1164/rccm.201003-0351OC. Epub 2010 Sep 2.
Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury.
To determine if common genetic variation in FAS is associated with acute lung injury (ALI) susceptibility, risk of death, and FAS gene expression.
We genotyped 14 single nucleotide polymorphisms (tagSNPS) in FAS in samples from healthy white volunteers (control subjects, n = 294) and patients with ALI (cases, n = 324) from the ARDSnet Fluid and Catheter Treatment Trial (FACTT). FAS genotypes associated with ALI in the discovery study were confirmed in a nested case-control validation study of critically ill patients at risk for ALI (n = 657). We also tested for associations between selected tagSNPS and FAS mRNA levels in whole blood from healthy control subjects exposed to media alone or LPS ex vivo.
We identified associations between four tagSNPs in FAS (FAS(-11341A>T) [rs17447140], FAS(9325G>A) [rs2147420], FAS(21541C>T) [rs2234978], and FAS(24484A>T) [rs1051070]) and ALI case status. Haplotype-based analyses suggested that three of the tagSNPs (FAS(9325G>A), FAS(21541C>T), and FAS(24484A>T)) function as a unit. The association with this haplotype and ALI was validated in a nested case-control study of at-risk subjects (P = 0.05). This haplotype was also associated with increased FAS mRNA levels in response to LPS stimulation. There was no association between FAS polymorphisms and risk of death among ALI cases.
Common genetic variants in FAS are associated with ALI susceptibility. This is the first genetic evidence supporting a role for FAS in ALI.
Fas（CD95）调节细胞凋亡和炎症，被认为在肺损伤中发挥重要作用。
确定 Fas 中的常见遗传变异是否与急性肺损伤（ALI）易感性、死亡风险和 Fas 基因表达相关。
我们对来自 ARDSnet 液体和导管治疗试验（FACTT）的健康白种志愿者（对照组，n=294）和 ALI 患者（病例组，n=324）样本中的 14 个 Fas 单核苷酸多态性（tagSNPs）进行了基因分型。在一项对有 ALI 风险的危重症患者的嵌套病例对照验证研究（n=657）中，对在发现研究中与 ALI 相关的 Fas 基因型进行了确认。我们还测试了选定的 tagSNPs 与暴露于单独培养基或 LPS 体外的健康对照者全血中 Fas mRNA 水平之间的相关性。
我们在 Fas 中发现了四个 tagSNPs（FAS(-11341A>T) [rs17447140]、FAS(9325G>A) [rs2147420]、FAS(21541C>T) [rs2234978]和 FAS(24484A>T) [rs1051070]）与 ALI 病例状态之间的关联。基于单倍型的分析表明，三个 tagSNPs（FAS(9325G>A)、FAS(21541C>T)和 FAS(24484A>T)）作为一个单元起作用。在对高危人群的嵌套病例对照研究中验证了与该单倍型和 ALI 的关联（P=0.05）。该单倍型也与 LPS 刺激后 Fas mRNA 水平的增加相关。FAS 多态性与 ALI 病例的死亡风险之间没有关联。
Fas 中的常见遗传变异与 ALI 易感性相关。这是 Fas 在 ALI 中起作用的第一个遗传证据。
