Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.
Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.
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DOI：
10.1161/atvbaha.112.300421
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Tracy RP
中科院分区：
文献类型：
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作者：
Reiner AP;Lange EM;Jenny NS;Chaves PH;Ellis J;Li J;Walston J;Lange LA;Cushman M;Tracy RP
CD 14是一种糖基磷脂酰肌醇（GPI）锚定的膜糖蛋白，在中性粒细胞和单核细胞/巨噬细胞上表达，也以可溶性形式（sCD 14）循环。尽管CD 14在炎症中的作用得到了广泛的认可，但对sCD 14的遗传决定因素或sCD 14与血管和衰老相关表型的关系知之甚少。我们测量了心血管健康研究中超过5,000名65岁及以上的欧洲裔美国人（EA）和非洲裔美国人（AA）成人的sCD 14基线水平，这些人在基线时具有动脉粥样硬化风险因素和亚临床心血管疾病（CVD）的特征，并对临床CVD和死亡率结果进行了长达20年的随访。在基线时，sCD 14通常与传统的心脏代谢危险因素和亚临床血管疾病指标（如颈动脉壁厚度和踝臂指数）呈强正相关（独立于传统的CVD危险因素），也与体重指数呈负相关。在sCD 14的全基因组关联分析中，我们（a）证实了染色体5 q21上的CD 14基因座在EA中的重要性;（B）确定了一种与AA中sCD 14较低相关的CD 14的新的非洲血统特异性等位基因;（c）确定了一种PIGC非同义变体在EA中的推定新关联，该变体编码GPI锚生物合成第一步所需的酶。最后，我们发现，与其他急性期炎症生物标志物一样，sCD 14可预测CVD事件，并可强烈且独立地预测老年人的全因死亡率。CD 14可独立预测老年人的死亡风险。
CD14 is a glycosylphosphotidylinositol-(GPI)-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes. We measured baseline levels of sCD14 in over 5,000 European-American (EA) and African-American (AA) adults 65 years and older from the Cardiovascular Health Study, who were well-characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease (CVD), and who have been followed for clinical CVD and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional CVD risk factors), and was also inversely correlated with body mass index. In genome-wide association analyses of sCD14, we (a) confirmed the importance of the CD14 locus on chromosome 5q21 in EA; (b) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in AA; (c) identified a putative novel association in EA of a non-synonymous variant of PIGC, which encodes an enzyme required for the first step in GPI anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident CVD, and strongly and independently predicts all-cause mortality in older adults. CD14 independently predicts risk mortality in older adults.