Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma
Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma
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DOI：
10.1016/j.jaci.2007.03.019
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发表时间：
2007-05-01
影响因子：
14.2
通讯作者：
Barnes, Kathleen C.
中科院分区：
文献类型：
--
作者：
Gao, Li;Grant, Audrey V.;Barnes, Kathleen C.
背景：肌球蛋白轻链激酶 (MYLK) 是一种多功能蛋白，参与调节气道高反应性和其他与哮喘相关的活动。目的：确定 MYLK 基因变异在非洲加勒比和非裔美国人人群哮喘中的作用。方法：我们在 2 个独立的、以家庭为基础的非洲裔人群中进行了 MYLK 基因单核苷酸多态性 (SNP) 与哮喘易感性和总血清 IgE 浓度之间的关联测试。此前，我们在 MYLK 中发现了导致脓毒症和急性肺损伤风险的变异/单倍型；我们将哮喘人群的发现与非裔美国人败血症和急性肺损伤组的发现进行了比较。结果：在非洲加勒比家庭中观察到 MYLK SNP 与哮喘和总血清 IgE 浓度之间的显着关联：平滑肌形式的启动子 SNP (rs936170) 给出最强的关联 (P = .009)。在美国 (P = .005) 和加勒比家庭 (P = .004) 中，包含与非肌肉和平滑肌形式的肌动蛋白结合活性相对应的 rs936170 的单倍型与哮喘（例如，风险降低）呈负相关，并且与赋予严重脓毒症风险的相同单倍型（P = .002）。对 PBMC 和 rs936170 的 RNA 表达研究表明，患有该变异的哮喘患者中 MYLK 表达显着降低 (P = .025)。结论：MYLK 多态性可能作为涉及支气管平滑肌收缩和炎症的临床不同疾病的常见遗传因素。临床意义：MYLK 的遗传变异与非洲血统人群中的哮喘和败血症显着相关。
Background: Myosin light chain kinase (MYLK) is a multifunctional protein involved in regulation of airway hyperreactivity and other activities relevant to asthma.Objective: To determine the role of MYLK gene variants in asthma among African Caribbean and African American populations.Methods: We performed association tests between single nucleotide polymorphisms (SNPs) in the MYLK gene and asthma susceptibility and total serum IgE concentrations in 2 independent, family-based populations of African descent. Previously we identified variants/haplotypes in MYLK that confer risk for sepsis and acute lung injury; we compared findings from our asthma populations to findings in the African American sepsis and acute lung injury groups.Results: Significant associations between MYLK SNPs and asthma and total serum IgE concentrations were observed in the African Caribbean families: a promoter SNP (rs936170) in the smooth muscle form gave the strongest association (P = .009). A haplotype including rs936170 corresponding to the actin-binding activity of the nonmuscle and smooth muscle forms was negatively associated with asthma (eg, decreased risk) in both the American (P = .005) and Caribbean families (P = .004), and was the same haplotype that conferred risk for severe sepsis (P = .002). RNA expression studies on PBMCs and rs936170 suggested a significant decrease in MYLK expression among patients with asthma with this variant (P = .025).Conclusion: MYLK polymorphisms may function as a common genetic factor in clinically distinct diseases involving bronchial smooth muscle contraction and inflammation.Clinical implications: Genetic variants in MYLK are significantly associated with both asthma and sepsis in populations of African ancestry.