Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease

Abstract

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

Keywords: Epidemiology; Genetics of cardiovascular disease; IGF1; IGFBP3; Risk factors.

Figure 1

Feature maps of the IGF1 (A) and IGFBP3 (B) genes. Positions of the 39 SNPs at the IGF1 locus and the 26 SNPs at the IGFBP3 locus with MAF ≥0.05 in the resequenced CEPH samples are shown relative to the locus (purple) and chromosome (black bar). SNPs highlighted in orange depict tSNPs and those highlighted blue are tSNPs that were force included (see text for details). tSNPs highlighted in grey were discarded (see text). Underlying each SNP is QC information and MAF in the CEPH samples. The bottom of each figure depicts an LD plot for the locus with pair-wise LD values (D’) presented. See the key for details. The figures were generated using LocusView (T. Petryshen, A. Kirby, M. Ainscow, unpublished software, available from the Broad Institute, Cambridge, MA (http://www.broad.mit.edu/mpg/locusview/). (Refer to next page for Figure 1B).

Figure 1

Feature maps of the IGF1 (A) and IGFBP3 (B) genes. Positions of the 39 SNPs at the IGF1 locus and the 26 SNPs at the IGFBP3 locus with MAF ≥0.05 in the resequenced CEPH samples are shown relative to the locus (purple) and chromosome (black bar). SNPs highlighted in orange depict tSNPs and those highlighted blue are tSNPs that were force included (see text for details). tSNPs highlighted in grey were discarded (see text). Underlying each SNP is QC information and MAF in the CEPH samples. The bottom of each figure depicts an LD plot for the locus with pair-wise LD values (D’) presented. See the key for details. The figures were generated using LocusView (T. Petryshen, A. Kirby, M. Ainscow, unpublished software, available from the Broad Institute, Cambridge, MA (http://www.broad.mit.edu/mpg/locusview/). (Refer to next page for Figure 1B).