Framingham Heart Study, Framingham, MA, USA.
Clin Chem. 2012 Nov;58(11):1582-91. doi: 10.1373/clinchem.2012.190322. Epub 2012 Sep 20.
Growth differentiation factor 15 (GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively.
Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study.
GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic factors accounted for up to 38% of the residual variability (h(2) = 0.38; P = 2.5 × 10(-11)). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 × 10(-32) for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines.
In ambulatory individuals, both cardiometabolic risk factors and genetic factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.
生长分化因子 15（GDF15）是一种在心血管细胞中产生的炎症和氧化应激条件下的应激反应细胞因子，作为一种重要的预后标志物，在有或没有现有心血管疾病（CVD）的个体中逐渐显现。因此，我们研究了循环 GDF15 浓度的临床和遗传相关性，这些相关性尚未被综合研究。
在弗莱明汉后代研究中，有 2991 名无临床明显 CVD 的参与者（平均年龄 59 岁，56%为女性），测量了他们的血浆 GDF15 浓度。在多变量分析中检查了 GDF15 的临床相关性。然后，我们对 GDF15 浓度进行了全基因组关联研究，包括弗莱明汉后代研究的参与者和皮乌斯（乌普萨拉老年人血管前瞻性研究）研究的参与者。
GDF15 与年龄、吸烟、降压治疗、糖尿病、肾功能恶化和使用非甾体抗炎药（NSAIDs）呈正相关，但与总胆固醇和高密度脂蛋白胆固醇呈负相关。临床相关性解释了循环 GDF15 浓度个体间差异的 38%，而遗传因素解释了残留变异性的高达 38%（h(2) = 0.38；P = 2.5 × 10(-11)）。我们确定了一个全基因组显著的位置。该位置位于 19p13.11 染色体上，包括 GDF15 基因，与 GDF15 浓度相关（rs888663 的最小 P = 2.74 × 10(-32)）。条件分析显示，该位置存在 2 个独立的关联信号（rs888663 和 rs1054564），这两个信号与血细胞系中顺式基因表达的改变相关。
在非住院个体中，心血管代谢危险因素和遗传因素都在决定循环 GDF15 浓度方面发挥重要作用，并且对总体变异性的贡献相似。
