Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Am J Respir Crit Care Med. 2013 May 1;187(9):950-9. doi: 10.1164/rccm.201208-1501OC.
Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete.
To identify genetic risk variants for ARDS using large scale genotyping.
A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 × 10(-4) for replication in stage II, a trauma case-control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS-associated genotype and plasma protein levels.
A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 × 10(-5)). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN.
The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.
急性呼吸窘迫综合征（ARDS）表现为一种复杂的遗传特征，但对遗传易感性因素的了解仍不完整。
使用大规模基因分型来确定 ARDS 的遗传风险变异。
对三个进行 ARDS 表型分析的危重病患者群体进行了多阶段遗传关联研究。第一阶段，一项创伤队列研究（n=224），使用 50K 基因中心单核苷酸多态性（SNP）阵列进行基因分型。我们在第二阶段，一项创伤病例对照研究（n=778）中，对与 ARDS 相关的 P < 5×10(-4)的 SNP 进行了复制检验。在第二阶段复制其关联的 SNP（P < 0.005），在 ICU 中混合受试者的第三阶段嵌套病例对照研究中进行了测试（n=2063）。逻辑回归用于调整潜在的临床混杂因素。我们进行 ELISA 检测以检验 ARDS 相关基因型与血浆蛋白水平之间的关联。
共有 12 个 SNP 符合与 ARDS 相关的关联的第一阶段阈值。编码白细胞介素 1 受体拮抗剂（IL1RA）的 IL1RN 基因中的 rs315952 在第二阶段（P < 0.004）和第三阶段（P < 0.02）中与 ARDS 风险降低相关，并且对临床调整具有稳健性（合并比值比=0.81；P=4.2×10(-5)）。在一组危重病患者中，IL1RA 水平与 rs315952C 相关。rs315952 的作用独立于 IL1RN 中的串联重复变异。
在三个具有异质性 ARDS 危险因素的人群中，IL1RN SNP rs315952C 与 ARDS 风险降低相关，并且与增加的血浆 IL1RA 反应相关。IL1RA 可能会降低 ARDS 风险。
