ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio
ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio
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DOI：
10.1164/rccm.201005-0701oc
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发表时间：
2011-05-15
影响因子：
24.7
通讯作者：
Christie, Jason D.
中科院分区：
文献类型：
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作者：
Meyer, Nuala J.;Li, Mingyao;Christie, Jason D.
理由：急性肺损伤（ALI）是一种复杂的遗传特征，但其遗传风险因素仍不完全清楚。此前尚未有针对 All 进行大规模基因分型的报道。目标：使用大规模候选基因方法识别重大创伤后的 ALI 风险变异。方法：我们进行了两阶段遗传关联研究。我们使用以心肺疾病为中心的 50K 单核苷酸多态性 (SNP) 阵列在非裔美国人队列 (n = 222) 中得出了研究结果。比较患有 ALI 和未患有 ALI 的受试者之间的基因型和单倍型分布，并根据临床因素进行调整。在多中心欧洲美国创伤相关所有病例对照人群（n = 600 ALI；n = 2,266 基于人群的对照受试者）中测试了表现最佳的 SNP（P < 10(-4)）以进行复制。对 ALI 相关基因组区域进行测序，进行计算机功能预测分析，并通过 ELISA 和免疫印迹对血浆进行测定。测量和主要结果：在调整 I 期协变量后，5 个 SNP 证明与 ALI 显着相关。ANGPT2 中的两个 SNP（rs1868554 和 rs2442598）在 II 期重复了它们与 ALI 的显着相关性。 rs1868554 对多重比较校正具有稳健性：优势比 1.22 (1.06-1.40)，P = 0.0047。重新测序鉴定出与 rs1868554 连锁不平衡的预测新剪接位点，免疫印迹显示与 rs1868554T 相关的变体血管生成素-2 (ANG2) 同工型的比例更高（0.81 vs. 0.48；P = 0.038）。结论：ANGPT2 区域与 ALI 和血浆变异相关。 血管生成素-2同工型。变异亚型的表征及其遗传调控可能会产生有关 ALI 发病机制和易感性的重要见解。
Rationale: Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for All.Objectives: To identify ALI risk variants after major trauma using a large-scale candidate gene approach.Methods: We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated All case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot.Measurements and Main Results: Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038).Conclusions: An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.