Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury
Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury
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DOI：
10.1165/rcmb.2005-0404oc
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发表时间：
2006-04-01
影响因子：
6.4
通讯作者：
Garcia, JGN
中科院分区：
文献类型：
--
作者：
Gao, L;Grant, A;Garcia, JGN
急性肺损伤（ALI）的遗传基础知之甚少。肌球蛋白轻链激酶（MYLK）基因编码非肌肉肌球蛋白轻链激酶亚型，一种参与炎症反应（细胞凋亡、血管通透性、白细胞渗出）的多功能蛋白。为了研究MYLK作为脓毒症相关ALI的新候选基因，我们对MYLK的外显子、外显子-内含子边界和2 kb的5' UTR进行了测序，发现了51个单核苷酸多态性（SNP）。在288例单纯脓毒症的欧洲裔美国受试者（EA）、脓毒症相关ALI受试者或健康对照受试者的病例对照样本以及158例脓毒症和ALI的非洲裔美国受试者（AA）样本人群中评价了28个MYLK SNP与脓毒症相关ALI的潜在关联。在EAs中观察到四个MYLK SNP与脓毒症表型之间的显著单位点关联（P < 0.001），另外一个SNP与ALI表型相关（P = 0.03）。在AA与脓毒症（P = 0.002）和ALI（P = 0.01）中观察到单个SNP（与EA中鉴定的SNP相同）的显著相关性。在EAs中的三种脓毒症风险赋予单倍型被定义为平滑肌MYLK亚型起始密码子下游，该区域含有推定的调控元件（P < 0.001）。相比之下，多个单倍型分析显示，在欧洲人和非洲裔美国人中，MYLK基因的5'端有一个ALI特异性的风险单倍型，而在非洲裔美国人中只有一个额外的3'端区域单倍型。这些数据强烈暗示MYLK基因变异增加了脓毒症和脓毒症相关ALI的风险。
The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon-intron boundaries, and 2 kb of 5' UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P < 0.001), with an additional SNP associated with the ALI phenotype (P = 0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P = 0.002) and with ALI (P = 0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P < 0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5' of the MYLK gene in both European and African Americans and an additional 3' region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI.