Bilirubin, albumin, and uric acid are established endogenous antioxidant biomarkers, whereas the antioxidant role of creatinine has not yet been fully clarified. As a byproduct of creatine metabolism, creatinine may reflect underlying metabolic activity and redox balance, particularly under conditions of oxidative stress such as cigarette smoking. This study aimed to evaluate the associations between serum creatinine and other antioxidant biomarkers and lung cancer risk, stratified by smoking status. We analyzed 83,371 cancer-free men from the Korean Cancer Prevention Study II (KCPS II) cohort. During a mean follow-up of 13.5 years, 533 incident lung cancer cases were identified. Serum creatinine, total bilirubin, albumin, and uric acid were measured. Smoking status classified participants as never-, former, and ever-smokers, with ever-smokers including both current and former smokers. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), stratified by smoking status. Biomarkers were also analyzed by quartiles and linear trends. A single standard deviation increase in serum creatinine was significantly and inversely associated with lung cancer risk among former smokers (HR: 0.774, 95% CI: 0.620 to 0.967) and ever-smokers (HR: 0.823, 95% CI: 0.716 to 0.945). Total bilirubin also showed significant inverse associations in former smokers (HR: 0.826, 95% CI: 0.705 to 0.967) and ever-smokers (HR: 0.785, 95% CI: 0.708 to 0.870). Albumin was inversely associated only with ever-smokers (HR: 0.878, 95% CI: 0.807 to 0.955), while uric acid showed inverse associations with both former smokers (HR: 0.832, 95% CI: 0.699 to 0.989) and ever-smokers (HR: 0.847, 95% CI: 0.760 to 0.944). None of the biomarkers showed significant associations among never-smokers. Serum creatinine and other endogenous antioxidant biomarkers were inversely associated with lung cancer risk, particularly in individuals with a history of smoking exposure.

Background: Bilirubin is a potent endogenous antioxidant that plays a key role in regulating oxidative stress and inflammation, both closely linked to lung carcinogenesis. This study reinterprets the ALBI (Albumin–Bilirubin) and PALBI (Platelet–Albumin–Bilirubin) indices as composite markers of antioxidant and inflammatory status and evaluates their associations with lung cancer risk by sex, including stratified analyses by major lifestyle factors such as smoking and alcohol use. Methods: This study utilized data from the Korean Cancer Prevention Study-II (KCPS-II) cohort, which included 133,630 participants. During a mean follow-up of 13.5 years, 721 incident lung cancer cases were identified. Serum bilirubin and the ALBI and PALBI indices were analyzed by sex, and quartile-based and trend analyses were conducted. Stratified analyses by smoking and alcohol status (never, former, current, ever) and intensity were performed to assess potential effect modification. Cox proportional hazards regression models were used to estimate HRs and 95% CIs. Results: A 1SD increase in total bilirubin and ALBI was inversely associated with lung cancer risk in men (HR: 0.83, 95% CI: 0.75–0.91; HR: 0.86, 95% CI: 0.79–0.94, respectively), whereas PALBI showed a positive association (HR: 1.17, 95% CI: 1.07–1.28). In contrast, in women, total bilirubin and ALBI showed positive associations (HR: 1.19, 95% CI: 1.00–1.40; HR: 1.19, 95% CI: 1.02–1.40, respectively), while PALBI was inversely associated (HR: 0.82, 95% CI: 0.69–0.97). These associations were significant among men who were smokers (former, current, ever) and men who drank alcohol (current, ever), whereas in women, significance was observed only among never drinkers. Stronger interactions were observed in men who were heavy smokers and low-to-moderate drinkers. Conclusions: Bilirubin and the ALBI and PALBI indices exhibit sex-specific and contrasting associations with lung cancer risk, highlighting the need to consider sex-based physiological differences in cancer risk assessment.

Previous research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated. Two-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (KCPS-II; n=159,844) and the Korean Genome and Epidemiology Study (KoGES; n=72,299). Data on ischemic stroke were obtained from BioBank Japan (BBJ; n=201,800). Colocalization analysis was performed, focusing on the UGT1A1, SLCO1B1, and SLCO1B3 genes, which are the primary loci associated with serum bilirubin levels. Crude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke. Our study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.

Background: This study evaluated the association between bilirubin subtypes (total, indirect, and direct bilirubin) and thyroid cancer risk, with a particular focus on stratified analyses using the ALBI (Albumin-Bilirubin) and PALBI (Platelet-Albumin-Bilirubin) indices by sex, smoking and drinking status, and age under 50 years. Methods: Data were obtained from 133,596 participants in the Korean Cancer Prevention Study-II (KCPS-II) cohort. During a mean follow-up period of 13.55 years, 2314 cases of thyroid cancer (ICD-10: C73) were identified. Serum bilirubin levels and ALBI and PALBI indices were analyzed using Cox proportional hazards regression models stratified by age, sex, smoking, and alcohol consumption status to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In women, indirect bilirubin showed the strongest inverse association with thyroid cancer risk. ALBI and PALBI indices based on indirect bilirubin also demonstrated significant associations. A 1 standard deviation (SD) increase in indirect bilirubin was associated with a decreased risk of thyroid cancer (HR: 0.92, 95% CI: 0.84–0.99), and the ALBI index similarly showed an inverse association (HR: 0.92, 95% CI: 0.87–0.99). In contrast, the PALBI index was positively associated with thyroid cancer risk (HR: 1.11, 95% CI: 1.03–1.20). Among women who had never smoked, significant associations were observed for indirect bilirubin (HR: 0.91, 95% CI: 0.83–1.00), ALBI (HR: 0.93, 95% CI: 0.86–1.00), and PALBI (HR: 1.14, 95% CI: 1.05–1.23). In analyses stratified by alcohol consumption, the PALBI index was associated with increased thyroid cancer risk in non-drinkers, former drinkers, and ever drinkers, with respective risk increases of 15%, 18%, and 9%. Conclusions: In women, indirect bilirubin was significantly and inversely associated with thyroid cancer risk, and the ALBI and PALBI indices incorporating indirect bilirubin showed consistent results. These findings suggest that indirect bilirubin may play a critical role in the metabolic pathways underlying thyroid cancer in women.

High LDL-cholesterol (LDL-C) is a well-known risk factor for coronary artery disease (CAD). PCSK9, HMGCR, NPC1L1, ACLY, and LDLR gene have been reported as lipid lowering drug genes related to LDL-C lowering. However relevant Asian studies were rare. We examined the causality between LDL-c drug target genes and CAD using Korean and Japanese data using the two sample Mendelian Randomization (MR) method. We conducted two-sample MR analysis of LDL-c lowering drug target genes (7 Single-nucleotide polymorphisms (SNP) in PCSK9, 6 SNPs in HMGCR, 5 SNPs in NPC1L1, 9 SNPs in ACLY, 3 SNPs in LDLR) and CAD. We used summary statistics data from the Korean Genome Epidemiology Study (KOGES) for LDL-C data, and Biobank of Japan (BBJ) for CAD data. For every 10 mg/dl decrease in LDL-C determined by four significant SNPs in the PCSK9 gene, the risk of CAD decreased by approximately 20% (OR = 0.80, 95% CI: 0.75–0.86). The risk of CAD decreased by 10% for every 10 mg/dl decrease in LDL-C due to the six significant SNPs in the HMGCR gene (OR = 0.90, 95% CI: 0.86–0.94). Due to the two significant SNPs in the gene LDLR, the risk of CAD decreased by approximately 26% for every 10 mg/dl decrease in LDL-C (OR = 0.74, 95% CI: 0.66–0.82). The combined effect on CAD showed the largest effect size for the PCSK9 gene and LDLR gene, and the reduced CAD risk induced by these two genes together was OR = 0.78 (95%CI, 0.74–0.83). Finally, the combined effect of all three genes (PCSK9, HMGCR, and LDLR) was OR = 0.85 (95%CI, 0.79–0.91). LDL-C reduction estimated by SNPs in LDL-C lowering drug target genes significantly reduced the risk of CAD. We found the potential of using of proxy research design for clinical trials using LDL-C lowering drugs.