Mendelian randomization study on the association of circulating ketone bodies with lung cancer and respiratory diseases

Abstract

The liver produces various ketone bodies (KBs) including 3-Hydroxybutyrate (3-OHB), acetoacetate (AcAc), and acetone, with 3-OHB being the major component. Previous studies have shown that KBs protect against respiratory diseases; however, there is no evidence of a genetic link. To avoid biases existing in traditional observational studies, a two-sample Mendelian randomization (MR) analysis was carried out to investigate genetic causation and novel therapeutic uses for KBs. This study used databases from genome-wide association studies (GWAS) and single nucleotide polymorphisms as instrumental variables for KBs from a recently published metabonomics study (n = 121,584) and respiratory diseases [lung cancer, n = 85,716; asthma, n = 127,669; chronic bronchitis, n = 450,422; chronic obstructive pulmonary disease (COPD), n = 468,475; FEV₁/FVC < 0.7, n = 353,315] from their publicly available GWAS, respectively. Strong sets of instrumental variables (P < 5 × 10^{- 8}) were selected, with inverse-variance weighted as the primary MR method. Sensitivity analyses included Cochran's Q test, MR Egger, MR-PRESSO, leave-one-out test, and funnel plots. The Steiger test and reversed MR were used to exclude reverse causality. Additionally, independent replication MR studies were conducted using databases from another large public GWAS and similar methods as described above. After MR analyses and sensitivity filtering, we discovered a protective effect of 3-OHB on lung cancer (odds ratio [OR] = 0.771; 95% confidence interval [CI] = 0.648-0.916; P_FDR=0.006), small cell carcinoma (OR = 0.485, 95% CI = 0.301-0.781, P_FDR=0.006), asthma (OR = 0.585, 95% CI = 0.395-0.867, P_FDR=0.010), chronic bronchitis (OR = 0.753, 95% CI = 0.570-0.994, P_FDR=0.045), COPD (OR = 0.690, 95% CI = 0.535-0.890, P_FDR=0.008) and lung function (OR = 0.970, 95%CI = 0.950-0.990, P_FDR =0.008). In summary, our findings suggest that 3-OHB acts as a protective factor against lung cancer and respiratory diseases. However, heterogeneity implies that other mechanisms may also be involved in COPD improvement by 3-OHB.

Keywords: 3-Hydroxybutyrate; Asthma; COPD; Lung cancer; Mendelian randomization.

Fig. 1

The overall framework of this research. Notes: Assumption 1: Genetic variants are strongly related to the exposure (e.g., 3-OHB); Assumption 2: IVs should be independent of potential confounders; Assumption 3: IVs can only influence the risk of outcomes (e.g., a respiratory outcome such as lung cancer, asthma) through this exposure, and not via an alternate pathway. MR, Mendelian randomization; LDSC, linkage disequilibrium score regression; SNPs, single nucleotide polymorphisms; GWAS, genome-wide association study.

Fig. 2

Forest plot illustrates the causal associations between 3-OHB (ebi-a-GCST90092811) and the risk of lung cancer and three subtypes in the MR analysis. OR odds ratio, CI confidence interval, 3-OHB 3-hydroxybutyrate.

Fig. 3

Forest plot depicts the causal associations between 3-OHB (met-d-bOHbutyrate) and the risk of lung cancer and three subtypes in the MR analysis. OR odds ratio, CI confidence interval, 3-OHB 3-hydroxybutyrate.

Fig. 4

Forest plot illustrating the causal associations between 3-OHB and the risk of respiratory diseases in the MR analysis. The boxes in the forest plot reflect effect sizes, while the whiskers are 95% confidence intervals. OR odds ratio, CI confidence interval, IVW inverse variance weighted. FEV₁ forced expiratory volume in 1 s, FVC forced vital capacity, GWAS genome-wide association study, IVW inverse-variance weighted, MR Mendelian randomization, 3-OHB 3-hydroxybutyrate.

Fig. 5

Meta-analysis of the causal association between 3-OHB and respiratory diseases. OR odds ratio, CI confidence interval, 3-OHB 3-hydroxybutyrate.