Population-based studies examining the relationship between IGF-I and IGFBP-3 with lipids have yielded conflicting results [1-3]. However, most of the studies are limited by their cross-sectional design and suffer from problems such as reverse causality and confounding. Several epidemiological studies have shown that statin use is associated with decreased levels of circulating IGF-I and IGFBP-3 [4-6]. These findings suggest that changes in the IGF pathway can be affected by metabolic changes. Further studies are needed to elucidate the direction of the causal relationship between lipids and the IGF pathway. One approach to investigate causality is Mendelian randomization (MR) which uses genetic variants as proxies for an observational exposure to assess and quantify the causal relationship between exposures of interest and outcomes or intermediate phenotypes [7]. Using summary level Genome Wide Association Studies (GWAS) results from two large-scale GWAS for IGF pathway (IGF-I and IGFBP-3) [8] and lipids traits (low density lipoprotein C (LDL-C), high density lipoprotein C (HDL-C) and triglycerides (TG)) [9], our recent MR analysis found evidence that increased LDL-C levels was associated with increased IGFBP-3 levels (unpublished results). To replicate these findings and to investigate the causal relationship between circulating LDL-C levels and members of the IGF pathway (IGF-I, IGF-II, IGFBP-2 and IGFBP-3), we are proposing to carry out a sample-based Recall by Genotype (RbG) study using a rare genetic variant in PCSK9 (rs11591147) that is associated with circulating LDL-C levels [10].

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