Clinical and genetic correlates of growth differentiation factor 15 in the community

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Association of mean levels of circulating GDF-15 and clinical and genetic determinants. Error bars in each panel represent standard errors. A. Circulating mean levels of GDF-15 by Framingham risk score quartiles. B. Circulating GDF-15 levels by rs888663 genotype. GDF-15 levels were estimated (back-transformed from log-transformed data) and estimated allele frequency within FHS, error bars represent standard errors.

Figure 1

Association of mean levels of circulating GDF-15 and clinical and genetic determinants. Error bars in each panel represent standard errors. A. Circulating mean levels of GDF-15 by Framingham risk score quartiles. B. Circulating GDF-15 levels by rs888663 genotype. GDF-15 levels were estimated (back-transformed from log-transformed data) and estimated allele frequency within FHS, error bars represent standard errors.

Figure 2

Regional association plot of meta-analysis loci associated with circulating GDF-15 levels.