Dataset Information

Insulin-like growth factor-1 and site-specific cancers: A Mendelian randomization study.

ABSTRACT: Insulin-like growth factor-1 (IGF-1) is involved in several processes relevant to carcinogenesis. We used 416 single-nucleotide polymorphisms robustly associated with serum IGF-1 levels to assess the potential causal associations between this hormone and site-specific cancers through Mendelian randomization. Summary-level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large-scale consortia including individuals of European-descent. Furthermore, we estimated genetic associations with 14 site-specific cancers in European-descent individuals in UK Biobank. Supplementary analyses were conducted for six site-specific cancers using summary-level data from the BioBank Japan Project. Genetically predicted serum IGF-1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF-1 levels was 1.11 (95% confidence interval [CI] 1.01-1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09-1.36; P = 3.9 × 10-4 ) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01-1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97-1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95-1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92-1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02-1.13; P = 4.4 × 10-3 ) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF-1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF-1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF-1 levels with prostate, breast, and other cancers.

SUBMITTER: Larsson SC

PROVIDER: S-EPMC7520358 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Insulin-like growth factor-1 and site-specific cancers: A Mendelian randomization study.

Larsson Susanna C SC Carter Paul P Vithayathil Mathew M Kar Siddhartha S Mason Amy M AM Burgess Stephen S

Cancer medicine 20200727 18

Insulin-like growth factor-1 (IGF-1) is involved in several processes relevant to carcinogenesis. We used 416 single-nucleotide polymorphisms robustly associated with serum IGF-1 levels to assess the potential causal associations between this hormone and site-specific cancers through Mendelian randomization. Summary-level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large-scale consortia including individuals of European-descent. Furthermore, we ...[more]

PMID: 32717139

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Project description:BackgroundRecent studies have implicated remnant cholesterol (RC) in the etiology, progression, and prognosis of cancer. However, very few of them concentrated on the study of the precise relationship between serum RC levels and cancer risk, leaving this subject unexplored. Consequently, this study aims to investigate the association between serum RC levels and 4 site-specific cancers, employing a dual approach that combines observational and mendelian randomization (MR) analysis.MethodsBased on data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020, this study collected data from18,067 participants. To rule out confounders, this study utilized weighted multivariable logistic regression and assessed non-linear associations using restricted cubic spline (RCS) regression, followed by two-piecewise linear regression. Sensitivity analysis conducted in this study included subgroup analysis, multiple imputation, outlier removal, and propensity score matching. To strengthen causal inference, this study employed univariable and multivariable MR analysis. The robustness and reliability of the findings were estimated by the application of replication and meta-analysis.ResultsThe results of multivariable logistic regression analysis demonstrated a significant association between serum RC levels and breast cancer, showing that individuals in the higher logRC category had a higher risk of breast cancer compared to those in the lower category (Q3 vs. Q1: OR = 1.71, 95% CI: 1.01-2.88, P = 0.044). Weighted RCS revealed an inverted L-shape association between RC and the risk of breast cancer (P-nonlinear = 0.0386, P-overall = 0.010). Primary MR analysis provided evidence for an increased risk of breast (IVW: OR = 1.08, 95% CI: 1.03-1.12, P = 0.000951) and colorectal cancer (IVW: OR = 1.12, 95% CI: 1.00-1.24, P = 0.0476) associated with RC. However, the results of replication and meta-analysis did not support a significant causal association of RC with the risk of breast cancer (OR = 1.04, 95% CI: 0.95-1.13), lung cancer (OR = 0.95, 95% CI: 0.88-1.03), colorectal cancer (OR = 1.05, 95% CI: 0.92-1.19), and prostate cancer (OR = 1.01, 95% CI: 0.95-1.08).ConclusionAlthough a non-linear relationship was observed in the cross-sectional study between remnant cholesterol levels and breast cancer risk, MR analyses failed to provide any causal evidence.

Project description:BackgroundInsulin-like growth factor 1 (IGF-1) plays a vital role in the attainment and maintenance of bone mass throughout life and is closely related to the stature of children. 25-Hydroxyvitamin D (25-OHD) is an intermediate of vitamin D (Vit D) metabolism and a key indicator of Vit D nutritional status. Multiple studies have revealed that IGF-1 levels undergo a non-significant increase after Vit D supplementation. Here, we analyzed the causal and reverse causal relationships between 25-OHD and IGF-1 levels using Mendelian randomization (MR).MethodsTwo-sample MR was used to estimate an unconfounded bidirectional causal relationship between the level of IGF-1 and those of Vit D and 25-OHD. Single nucleotide polymorphisms (SNPs) were filtered from genome-wide association studies (GWAS) after a comprehensive search of the Integrative Epidemiology Unit GWAS database. Several MR methods were employed, including inverse-variance weighted (IVW) method, and a sensitivity analysis was undertaken to detect whether pleiotropy or heterogeneity biased the MR results.ResultsGenetically predicted IGF-1 was found to have a causal association with Vit D and serum 25-OHD levels, where Vit D and serum 25-OHD levels increased with increasing IGF-1 concentrations (Vit D: IVW β:0.021, 95% CI: 0.005-0.036, p = 7.74 × 10-3; 25-OHD: IVW β: 0.041, 95% CI: 0.026-0.057, p = 2.50 × 10-7). A reverse causal effect was also found, indicating Vit D and serum 25-OHD have a positive causal relationship with IGF-1 (Vit D: IVW β:0.182, 95% CI: 0.061-0.305, p = 3.25 × 10-3; 25-OHD: IVW β: 0.057, 95% CI = 0.017-0.096, p = 4.73 × 10-3). The sensitivity analysis showed that horizontal pleiotropy was unlikely to bias the causality in this study (MR-Egger: Vit D intercept p = 5.1 × 10-5, 25-OHD intercept p = 6.4 × 10-4 in forward analysis; Vit D intercept p = 6.6 × 10-4, 25-OHD intercept p = 1.9 × 10-3 in reverse analysis), and a leave-one-out analysis did not identify evidence of bias in the results.ConclusionThe results of the MR analysis provide evidence that IGF-1 has positive causal and reverse causal relationships with Vit D and serum 25-OHD, respectively, in European populations. Our findings also provide guidance for the prevention and treatment of short stature and other related diseases.

Dataset Information

Insulin-like growth factor-1 and site-specific cancers: A Mendelian randomization study.

Publications

Insulin-like growth factor-1 and site-specific cancers: A Mendelian randomization study.

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