Causal Associations of Heparin-Binding Growth and Differentiation Factors With Thyroid Cancer: A Two-Sample Mendelian...

Heparin-binding growth and differentiation factors (GDFs) play roles in various cellular processes and are potential contributors to thyroid cancer. Although population-based studies have documented associations between heparin-binding GDFs and thyroid cancer, their causal relationships remain unclear.

A two-sample Mendelian randomization (MR) analysis was conducted using published genome-wide association studies (GWASs) data. The primary method for estimating causal effects was the inverse-variance weighted (IVW) approach, supplemented by multiple sensitivity analyses including weighted median, MR-Egger, and MR-PRESSO. Heterogeneity and outlier effects were systematically evaluated. Additionally, key MR findings were validated at the transcriptomic level using differential expression analysis of data from the Cancer Genome Atlas (TCGA).

The IVW method revealed significant causal relationships between midkine levels (OR = 1.2099, 95% CI: 1.013-1.445, p = 0.0355) and IGF2 (OR = 0.7496, 95% CI: 0.6056-0.9279, p = 0.0081) with thyroid cancer and between heparin-binding EGF-like growth factor and malignant thyroid neoplasms (OR = 0.8821, 95% CI: 0.7873-0.9882, p = 0.0304). Heterogeneity was identified in the association between FGF1 and malignant thyroid neoplasms (Q = 20.725, p = 0.036). Neither MR-Egger analysis nor the MR-PRESSO global test found evidence of horizontal pleiotropy in the association between heparin-binding GDFs and thyroid cancer. The robustness of these findings was supported by sensitivity analyses, and transcriptomic analysis of TCGA data further revealed that midkine (MDK was significantly upregulated in thyroid tumor tissues.

Genetically predicted midkine levels and IGF2 were associated with thyroid cancer, and heparin-binding EGF-like growth factor was associated with malignant thyroid neoplasms. Future studies are needed to validate these findings.