Risk of remnant cholesterol and chronic obstructive pulmonary disease: a mendelian randomization study

Abstract

Background: Remnant cholesterol (RC) represents the cholesterol of triglyceride (TG)-rich lipoproteins and is the portion of cholesterol other than both high-density (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Higher RC levels have been associated with heightened inflammation. Chronic obstructive pulmonary disease (COPD) has been attributed mostly to cigarette smoking or environmental pollution. Disorders of lipid metabolism contribute to inflammation, but no studies have shown an association between RC and COPD. We aimed to investigate the association between RC levels and the pathogenesis of COPD.

Methods: Pooled statistics for the associations between RC and COPD were obtained from published data of individuals of European ancestry, primarily sourced from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Studies (OpenGWAS) project (including 115,078 European populations) and the FinnGen Biobank (including 16,410 COPD cases and 283,589 controls). To evaluate the causal relationship between RC and COPD, a two-sample Mendelian randomization (MR) analysis was employed. The primary MR method was inverse variance weighting (IVW). Statistical analysis and data visualization were performed using R software.

Results: RC levels were positively associated with COPD risk according to MR analysis [IVW, odds ratio (OR): 1.222, 95% confidence interval (CI): 1.092-1.368; P<0.001; MR-Egger, OR: 1.279, 95% CI: 1.065-1.536; P=0.01; weighted median, OR: 1.208, 95% CI: 1.048-1.393; P=0.008]. No significant heterogeneity or horizontal pleiotropy was detected.

Conclusions: High RC levels might increase the risk of developing COPD. Whether reducing RC levels among the population contributes to a lower risk of COPD remains to be investigated.

Keywords: Mendelian randomization (MR); Remnant cholesterol (RC); chronic obstructive pulmonary disease (COPD); triglycerides (TGs).

Figure 1

Rationale of two-sample MR concerning the causal effect of RC and COPD. COPD, chronic obstructive pulmonary disease; GWAS, Genome-Wide Association Study; IVW, inverse variance weighted; MR, Mendelian randomization; RC, respiratory condition; SNP, single nucleotide polymorphism.

Figure 2

Radial plots for all MR analyses: abnormal outliers that were not detected by the RadialMR method. Black point usually represents the standard of instrumental variable, the distribution of these points provides overall data, relatively concentrated in the center area of point usually reflects most of the effects of the instrumental variables estimates close to the mean. IVW, inverse variance weighted; MR, Mendelian randomization; RadialMR, Radial Mendelian Randomization.

Figure 3

Forest plot of the results concerning the causal effect of residual cholesterol on the risk of COPD: the OR, 95% CI and P value of IVW, MR-Egger, and weighted median consistently indicated that the higher the remaining cholesterol was, the greater the risk of COPD. CI, confidence interval; COPD, chronic obstructive pulmonary disease; IVW, inverse variance weighted; MR, Mendelian randomization; OR, odds ratio; SNP, single nucleotide polymorphism.

Figure 4

Leave-one-out plots for all MR analyses indicating that no single SNP drives causal estimates. The red line segment represents the pooled causal effect value of all SNPs, the black line segment represents the recalculated causal effect value after excluding single SNP, and the black point represents the specific value of effect value after SNP exclusion. MR, Mendelian randomization; SNP, single nucleotide polymorphism.