Clinical and Genetic Correlates of Growth Differentiation Factor 15 in the Community

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 58; no. 11; pp. 1582 - 1591
• Main Authors: HO, Jennifer E, MAHAJAN, Anubha, LIND, Lars, INGELSSON, Erik, VASAN, Ramachandran S, JANUZZI, James, WOLLERT, Kai C, MORRIS, Andrew P, WANG, Thomas J, CHEN, Ming-Huei, LARSON, Martin G, MCCABE, Elizabeth L, GHORBANI, Anahita, SUSAN CHENG, JOHNSON, Andrew D, LINDGREN, Cecilia M, KEMPF, Tibor
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for Clinical Chemistry 01.11.2012; Oxford University Press
• Subjects: Acute coronary syndromes; Age; Aged; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Biomarkers; Blood; Cardiac arrhythmia; Cardiovascular disease; Cardiovascular Diseases - blood; Cardiovascular Diseases - genetics; Cardiovascular Diseases - physiopathology; Cholesterol, HDL - blood; Cohort Studies; Family medical history; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Growth Differentiation Factor 15 - blood; Growth Differentiation Factor 15 - genetics; Heart failure; Humans; Hypertension; Immunoassay; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Molecular biophysics; Mortality; Multivariate Analysis; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Software; Growth differentiation factor 15; Clinical biology; Macrophage inhibitory cytokine 1; Genetics; Biochemistry; Molecular biology; Community
• ISSN: 0009-9147; 1530-8561; 1530-8561
• DOI: 10.1373/clinchem.2012.190322

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.