Abstract
Background: Fibroblast growth factor 21 (FGF-21) is an adipokine produced predominantly in the liver and is a metabolic regulator of glucose and lipid metabolism. Circulating FGF-21 levels have been shown to be independently associated with a host of cardio-metabolic traits, including: BMI and adiposity, metabolic syndrome, diabetes, cholesterol and triglycerides, and cardiovascular disease outcomes. Despite these epidemiological observations, causal relationships between FGF-21 and cardio-metabolic outcomes remain uncertain. Objectives: To identify the cross-sectional correlates of FGF-21 levels and to explore the causal relationship between FGF-21 and cardio-metabolic traits using a Mendelian randomization based approach. Methods & Results: FGF-21 levels were measured by ELISA in 9,572 participants from the Pakistan Risk of Myocardial Infarction Study (PROMIS), a multi-ethnic case-control study aimed at identifying genetic and non-genetic determinants of cardio-metabolic diseases. Log serum FGF-21 levels were weekly but significantly correlated with measures of obesity (BMI r=0.1, p < 0.0001) and serum lipids (total cholesterol r=0.08, p < 0.0001; LDL-C r=0.06, p < 0.0001; log triglycerides r=0.15, p < 0.0001); there was, however, no significant association with biochemical indicators of glycemic control. A Genome Wide Association Study (GWAS) was conducted to identify genetic determinants of FGF-21 levels; genetic variants were further assessed for specific associations with FGF21 levels in order to to identify instruments suitable for Mendelian Randomization studies. Variants that specifically increased FGF21 levels were not found to be associated with either Type-2 diabetes (80,000 cases and 230,000 controls) or coronary heart disease (63,746 cases and 130,681 controls). Conclusions: Although FGF-21 is weekly correlated with a number of cardiovascular risk factors; however its relationship to cardio-metabolic outcomes is less likely to be causal.
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