First, we validated genetic variants previously associated with IGF levels in the literature to confirm reported associations of the SNPs (especially SNPs selected from candidate gene studies), and to assess the potential for pleiotropic effects of the genetic variants on more than one IGF protein. We used an MR approach in an attempt to assess the causal role of the IGF axis in prostate cancer. Additionally, the instrument is expected to influence the outcome only via the exposure ( i.e., absence of horizontal pleiotropy 13) and to be independent from confounders of the relationship between exposure and outcome. To determine causality, MR relies on an association between genetic variant (also known as instrument) and exposure so that the greater the correlation between the two, and thus the more variation in the exposure phenotype explained by the genotype, the more reliable the causal inference. Genetic variation may also be a better measure of exposure over a lifetime than a single serum measurement, as those with genotypes causing high (or low) IGF levels will have been, in effect, randomly allocated to high (or low) IGF levels from birth. Since alleles randomly assort at gamete formation and segregate randomly at conception to generate genotypes, associations between genotypes and outcome are not generally confounded by behavioural or environmental factors and cannot be explained by reverse causation. Mendelian randomization (MR) 12 seeks to establish causality by using genetic variants as proxies for the exposure of interest. Alternative explanations for the observed association of IGF‐axis peptides with prostate cancer include: reverse causality, because tumours may promote an endocrine response 7 confounding by dietary, 8 nutritional 9 and lifestyle 10 factors measurement error, 11 as single serum measurements may inadequately reflect long‐term exposure or detection bias, 11 occurring, for example, if IGF‐I causes symptomatic benign prostatic hyperplasia (BPH) that results in the serendipitous finding of latent cancer on diagnostic biopsy. Such diverse evidence indicates that causation remains to be established. 1 Meta‐analyses of epidemiological studies generally observe positive associations of circulating IGF‐I with prostate cancer, 2, 3, 4 but substantial differences exist between studies. 1 The nutritionally regulated IGFs, and their modulating binding proteins (IGFBPs) play a key role in somatic growth, and activate carcinogenic intracellular signalling networks. Prostate cancer is the most common male cancer in industrialised countries, yet there are no established, potentially modifiable risk factors for prevention. Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.Ībbreviations BPH benign prostatic hyperplasia CV coefficient of variation GWAS genome‐wide association study IBD identity by descent ICC intra‐class correlation IGF insulin‐like growth factor IGFBP insulin‐like growth factor‐binding proteins IV instrumental variable LD Linkage disequilibrium MR Mendelian randomization PSA prostate specific antigen QC quality control RIA radioimmunoassay SD standard deviation SNP single nucleotide polymorphism UKHLS UK Household Longitudinal Study. Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05 95% CI: 1.00, 1.10). Rs11977526 was associated with high ( vs. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. advanced stage, and mortality, in 22,936 controls and 22,992 cases. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. In ∼700 men without prostate cancer and two replication cohorts ( N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study and 48 in reported candidate genes). Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer.
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