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

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.