Mendelian randomization analysis of lipidomic profiles and thyroid cancer risk in European populations

Thyroid cancer (TC) remains a prevalent malignancy with a rising incidence worldwide, yet the causal relationship between the plasma lipidome and TC is still poorly understood. This study aims to explore this relationship using two-sample Mendelian randomization (MR) analysis. We analyzed genetic variants associated with 179 lipid species from a genome-wide association study (GWAS) of the plasma lipidome, as well as data on TC and its subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), from the FinnGen consortium. The primary analysis was conducted using the inverse variance weighted (IVW) method, with additional validation through other MR approaches. Sensitivity analyses were also performed to assess the robustness of the results. Our MR analysis revealed significant causal associations between the plasma lipidome and the risks of TC, PTC, and FTC. For TC, sphingomyelin (d36:1) was associated with a reduced risk (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.97, p = 0.0146), while triacylglycerol (56:8) (OR = 1.18, 95% CI = 1.02-1.37, p = 0.0233), triacylglycerol (50:1) (OR = 1.24, 95% CI = 1.03-1.49, p = 0.0244) and phosphatidylethanolamine (O-18:2_20:4) (OR = 1.31, 95% CI = 1.09-1.57, p = 0.0033) were associated with an increased risk. For PTC, sterol ester (27:1/20:3) was potentially protective (OR = 0.84, 95% CI = 0.73-0.97, p = 0.0137), while phosphatidylcholine (16:0_22:6) (OR = 1.29, 95% CI = 1.05-1.59, p = 0.0175) and phosphatidylethanolamine (O-18:2_20:4) (OR = 1.45, 95% CI = 1.17-1.78, p = 0.0005) were linked to a higher risk. For FTC, phosphatidylcholine (18:2_18:2) (OR = 1.67, 95% CI = 1.04-2.70, p = 0.0351), sterol ester (27:1/18:0) (OR = 1.69, 95% CI = 1.05-2.74, p = 0.0320), triacylglycerol (54:3) (OR = 1.71, 95% CI = 1.08-2.73, p = 0.0233), phosphatidylcholine (18:0_0:0) (OR = 1.80, 95% CI = 1.01-3.21, p = 0.0450), triacylglycerol (48:3) (OR = 1.96, 95% CI = 1.13-3.40, p = 0.0159), triacylglycerol (50:4) (OR = 2.12, 95% CI = 1.30-3.45, p = 0.0024), triacylglycerol (58:8) (OR = 2.17, 95% CI = 1.24-3.80, p = 0.0065), triacylglycerol (51:3) (OR = 2.19, 95% CI = 1.31-3.64, p = 0.0027), and triacylglycerol (49:1) (OR = 2.28, 95% CI = 1.16-4.49, p = 0.0167) were linked to an increased risk, with no protective lipid identified. This study underscores the distinct effects of lipid molecular structures on TC subtypes, offering insights into potential therapeutic strategies.