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Investigating the causal associations between metabolic biomarkers and the risk of kidney cancer.

ABSTRACT: Metabolic reprogramming plays an important role in kidney cancer. We aim to investigate the causal effect of 249 metabolic biomarkers on kidney cancer from population-based data. This study extracts data from previous genome wide association studies with large sample size. The primary endpoint is random-effect inverse variance weighted (IVW). After completing 249 times of two-sample Mendelian randomization analysis, those significant metabolites are included for further sensitivity analysis. According to a strict Bonferrion-corrected level (P < 2e-04), we only find two metabolites that are causally associated with renal cancer. They are lactate (OR:3.25, 95% CI: 1.84-5.76, P = 5.08e-05) and phospholipids to total lipids ratio in large LDL (low density lipoprotein) (OR: 0.63, 95% CI: 0.50-0.80, P = 1.39e-04). The results are stable through all the sensitivity analysis. The results emphasize the central role of lactate in kidney tumorigenesis and provide novel insights into possible mechanism how phospholipids could affect kidney tumorigenesis.

SUBMITTER: Lin L

PROVIDER: S-EPMC10984917 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Investigating the causal associations between metabolic biomarkers and the risk of kidney cancer.

Lin Lede L Tang Yaxiong Y Ning Kang K Li Xiang X Hu Xu X

Communications biology 20240401 1

Metabolic reprogramming plays an important role in kidney cancer. We aim to investigate the causal effect of 249 metabolic biomarkers on kidney cancer from population-based data. This study extracts data from previous genome wide association studies with large sample size. The primary endpoint is random-effect inverse variance weighted (IVW). After completing 249 times of two-sample Mendelian randomization analysis, those significant metabolites are included for further sensitivity analysis. Acc ...[more]

PMID: 38561482

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Project description:ObjectivesNephrolithiasis, with a prevalence of 9% and increasing worldwide, has a recurrence rate close to 50%. Urinary stones significantly impact quality of life and impose substantial economic burdens on patients and healthcare systems. Systemic inflammation is postulated as a risk factor for urinary stones. Previous studies have identified associations between inflammatory markers and kidney stones, but these often rely on patient recall, introducing potential recall bias. This study investigates whether inflammatory markers vary according to the presence of nephrolithiasis using health check-up data from a large cohort in South Korea.Materials and methodsData were collected from participants in health checkups at a university hospital in Seoul between 2010 and 2020. The study included 18,243 males and 12,919 females who underwent blood tests, KUB (Kidneys, Ureters, and Bladder) radiography, and ultrasound examinations. Only stones larger than 5 mm were counted, enrolling 328 males and 99 females with kidney stones. Exclusion criteria included pyuria, congenital renal deformities, renal cancer, kidney transplant, and diuretic use. Inflammatory markers assessed included the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammatory index (SII). The primary outcome was the presence of nephrolithiasis, detected using combined ultrasonography and KUB radiography. Logistic regression analyses determined the association between inflammatory markers and nephrolithiasis, adjusting for confounders such as age, BMI, blood pressure, triglycerides, LDL, HDL, creatinine, BUN, uric acid, fasting glucose, calcium, and medical history.ResultsIn females, an LMR ≤ 5.02 (OR: 2.30, 95% CI: 1.47-3.61, p < 0.001), NLR > 1.94 (OR: 1.97, 95% CI: 1.24-3.12, p = 0.004), and SII > 484.05 (OR: 2.12, 95% CI: 1.38-3.24, p < 0.001) were significantly associated with kidney stones after adjusting for confounders. In males, an LMR ≤ 7.79 (OR: 1.82, 95% CI: 1.33-2.49, p < 0.001) and NLR > 1.32 (OR: 1.55, 95% CI: 1.12-2.15, p = 0.009) were significantly associated with kidney stones, but SII > 560.11 was not (OR: 1.21, 95% CI: 0.87-1.68, p = 0.255), after adjusting. The significant relationships between these inflammatory markers and kidney stones were maintained only in participants aged ≥ 50 years. Specifically, in females aged ≥ 50 years, LMR ≤ 5.02 (OR: 2.38, 95% CI: 1.52-3.74, p < 0.001), NLR > 1.94 (OR: 2.05, 95% CI: 1.30-3.24, p = 0.002), and SII > 484.05 (OR: 2.18, 95% CI: 1.43-3.32, p < 0.001) were significant predictors of nephrolithiasis. In males aged ≥ 50 years, LMR ≤ 7.79 (OR: 1.90, 95% CI: 1.38-2.62, p < 0.001) and NLR > 1.32 (OR: 1.62, 95% CI: 1.17-2.25, p = 0.004) were significant predictors.ConclusionElevated inflammatory markers are significantly associated with the presence of kidney stones, particularly in individuals aged 50 years or older. These findings suggest that systemic inflammation plays a crucial role in the pathogenesis of nephrolithiasis, especially in the older population. The results imply that inflammation contributes to the increasing prevalence of urinary stones with age, highlighting the importance of managing systemic inflammation in preventing nephrolithiasis. Future research would be needed to explore causal relationships and investigate whether anti-inflammatory interventions can reduce the risk of kidney stones.

Project description:Previous observational studies have suggested that the effect of diet-derived circulating micronutrient concentrations on lung cancer (LC) risk is controversial. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between circulating micronutrient concentrations and the overall risk of LC and three LC subtypes (namely lung adenocarcinoma (LA), squamous cell lung cancer (SqCLC), and small cell lung cancer (SCLC)). The instrumental variables (IVs) of 11 micronutrients (beta-carotene, calcium, copper, folate, lycopene, magnesium, phosphorus, retinol, selenium, zinc, and vitamin B6) were screened from the published genome-wide association studies (GWAS). Summary statistics related to LC and its subtypes came from the largest meta-analysis, including 29,266 cases and 56,450 controls. Inverse-variance weighted (IVW) method is used as the main MR analysis, and the sensitivity analysis is carried out to ensure the MR assumptions. This MR study found suggestive evidence that genetically predicted 6 circulating micronutrient concentrations was correlated with the risk of overall LC (odds ratio (OR): 1.394, 95% confidence interval (CI): 1.041-1.868, p = 0.026, phosphorus), LA (OR: 0.794, 95% CI: 0.634-0.995, p = 0.045, beta-carotene; OR: 0.687, 95%CI: 0.494-0.957, p = 0.026, calcium), SqCLC (OR: 0.354, 95% CI: 0.145-0.865, p = 0.023, retinol), and SCLC (OR: 1.267, 95% CI: 1.040-1.543, p = 0.019, copper; OR: 0.801, 95% CI: 0.679-0.944, p = 0.008, zinc). We found no evidence that other micronutrients are associated with the risk of overall LC or its subtypes. Our study suggested that the increase in circulating beta-carotene, calcium, retinol, and zinc concentration may reduce the risk of LC; the increase in circulating copper and phosphorus concentration may be related to the increased risk of LC. In the future, larger replication samples of LC genetic data and larger micronutrient-related GWAS will be needed to verify our findings.

Project description:ObjectiveTo examine whether sleep traits have a causal effect on risk of breast cancer.DesignMendelian randomisation study.SettingUK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.Participants156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis.ExposuresSelf reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.Main outcome measureBreast cancer diagnosis.ResultsIn multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.ConclusionsFindings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.

Project description:BackgroundMetabolic biomarkers are reported to be associated with the risk of lung cancer (LC). However, the observed associations from epidemiological studies are either inconsistent or inconclusive.MethodsThe genetic summary data of high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), triglyceride (TG), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) and those of the LC and its histological subtypes were retrieved from previous GWASs. We performed two-sample Mendelian randomization (MR) and multivariable MR analyses to examine the associations between genetically predicted metabolic biomarkers and LC in East Asians and Europeans.ResultsIn East Asians, the inverse-variance weighted (IVW) method suggests that LDL (odds ratio [OR] = 0.799, 95% CI 0.712-0.897), TC (OR = 0.713, 95% CI 0.638-0.797), and TG (OR = 0.702, 95% CI 0.613-0.804) were significantly associated with LC after correction for multiple testing. For the remaining three biomarkers, we did not detect significant association with LC by any MR method. Multivariable MR (MVMR) analysis yielded an OR of 0.958 (95% CI 0.748-1.172) for HDL, 0.839 (95% CI 0.738-0.931) for LDL, 0.942 (95% CI 0.742-1.133) for TC, 1.161 (95% CI 1.070-1.252) for TG, 1.079 (95% CI 0.851-1.219) for FPG, and 1.101 (95% CI 0.922-1.191) for HbA1c. In Europeans, the univariate MR analyses did not detect significant association between exposures and outcomes. However, in MVMR analysis integrating circulating lipids and lifestyle risk factors (smoking, alcohol drinking, and body mass index), we found that TG was positively associated with LC in Europeans (OR = 1.660, 95% CI 1.060-2.260). Subgroup and sensitivity analysis yielded similar results to the main analyses.ConclusionsOur study provides genetic evidence that circulating levels of LDL was negatively associated with LC in East Asians, whereas TG was positively associated with LC in both populations.

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Investigating the causal associations between metabolic biomarkers and the risk of kidney cancer.

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Investigating the causal associations between metabolic biomarkers and the risk of kidney cancer.

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