Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.
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ABSTRACT:
SUBMITTER: Li S
PROVIDER: S-EPMC7462857 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: Inflammatory cytokines disturbance is the main result of immune dysregulation, which is widely described in major depressive disorder (MDD). However, the potential causal relationship between these two factors has not been discovered. Therefore, the purpose of this study was to investigate the causal relationship between inflammatory cytokines and MDD risk by using the two-sample Mendelian randomization (MR) analysis. Method: Two genetic instruments obtained from publicly available gene profile data were utilized for the analysis. We obtained the genetic variation data of 41 inflammatory cytokines from genome-wide association studies (GWAS) meta-analysis of 8293 individuals of Finnish descent. The MDD data, including 135,458 MDD cases and 344,901 controls, were obtained from the Psychiatric Genomics Consortium Database. For the Mendelian randomization (MR) estimation, several methods were employed, namely, MR-Egger regression, inverse-variance weighted (IVW), weighted median, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Result: A causal relationship was identified between the genetically proxied levels of Interleukin (IL) -18, IL-1β, and Regulated upon activation normal T cell expressed and secreted (RANTES) and the risk of MDD (OR = 0.968, 95%CI = 0.938, 0.998, p = 0.036; OR = 0.875, 95%CI = 0.787, 0.971, p = 0.012; OR = 0.947, 95%CI = 0.902, 0.995, p = 0.03; respectively). However, our Mendelian randomization (MR) estimates provided no causality of MDD on inflammatory cytokines. Conclusion: Our study elucidates the connection between inflammatory cytokines and MDD by using MR analysis, thereby enhancing our comprehension of the potential mechanisms. By identifying these associations, our findings hold substantial implications for the development of more effective treatments aimed at improving patient outcomes. However, further investigation is required to fully comprehend the exact biological mechanisms involved.
| S-EPMC10436531 | biostudies-literature
Project description:BackgroundCirculating cytokines play a crucial role in the onset and progression of immune skin diseases. However, the causal relationships and the direction of causal effects require further investigation.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal relationships between 41 circulating cytokines and six immune skin diseases including alopecia areata, chloasma, hidradenitis suppurativa (HS), lichen planus (LP), seborrheic dermatitis, and urticaria, using summary statistics from genome-wide association studies. Reverse MR analyses was performed to test for the reverse causation. Pleiotropy and heterogeneity tests were conducted to assess the robustness of the findings.ResultsTwelve unique cytokines showed a suggestive causal relationship with the risk of six immune skin diseases. Among them, the causal effects between 9 unique cytokines and immune skin diseases have strong statistical power. Additionally, the concentrations of six cytokines might be influenced by LP and urticaria. After Bonferroni correction, the following associations remained significant: the causal effect of beta-nerve growth factor on HS (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.226-2.177, p = 7.97e-04), interleukin (IL)-6 on LP (OR = 0.615, 95% CI = 0.481-0.786, p = 1.04e-04), IL-4 on LP (OR = 1.099. 95% CI = 1.020-1.184, p = 1.26e-02), and IL-2 on urticaria (OR = 0.712, 95% CI = 0.531-0.955, p = 2.33e-02).ConclusionThis study provides novel perspectives on the relationship between circulating cytokines and immune skin diseases, potentially providing valuable insights into their etiology, diagnostic approaches, and treatment.
| S-EPMC10637377 | biostudies-literature
Project description:The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6 , vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10-7 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10-6 ) higher risk of overall and ER+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER-ve breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.
| S-EPMC8268064 | biostudies-literature
Project description:BackgroundInflammation plays a pivotal role in the pathogenesis of cancer. Though previous studies have reported a link between several inflammatory biomarkers and risk of certain types of cancer, there is a lack of systematic investigation. Therefore, we aimed to assess the role of circulating cytokines on the risk of cancer using a two-sample Mendelian randomization (MR) approach.MethodWe used genetic variants associated with circulating levels of cytokines from a meta-analysis of genome-wide association studies (GWASs) of 8,293 Finns as instrumental variables. Summary level data of 20 site-specific cancer were obtained from the UK BioBank including up to 456,348 participants of European ancestry. We performed two-sample MR analyses using inverse-variance weighted (IVW) method as the main method, followed by weighted-median and likelihood-based methods as sensitivity analysis. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.Results224 genetic variants associated with 27 circulating cytokines achieving genome-wide significance (P<5×10-8) were used as IVs. After Bonferroni correction, genetically predicted high levels of interleukin-18 (IL-18) were associated with a decreased risk of acute myeloid leukemia (odds ratio (OR) per 1 standard deviation (SD) increase = 0.55, 95% confidence interval (CI):0.43-0.69, P=5.39×10-7), and circulating levels of IL-17 were associated with altered stomach cancer risk (OR per 1 SD increase = 0.15, 95% CI: 0.07-0.36, P=1.25×10-5) by IVW. Results were stable across sensitivity analyses, and MR-Egger regression did not suggest the presence of directional pleiotropy. Additionally, we found suggestive evidence for 48 cytokine-cancer associations including tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and cutaneous T-cell attracting chemokine (CTACK) with the risk of several types of cancer (9.26×10-5≤P<0.05).ConclusionsBy using a genetic epidemiological approach, our study systematically evaluated the role of circulating cytokines on the risk of cancer, and provided clues for potential therapeutic targets. However, the exact underlying biological mechanism warrants further investigation.
| S-EPMC9294168 | biostudies-literature
Project description:Elevated circulating copper levels have been associated with chronic kidney disease (CKD), kidney damage, and decline in kidney function. Using a two sample Mendelian randomization approach where copper-associated genetic variants were used as instrumental variables, genetically predicted higher circulating copper levels were associated with higher CKD prevalence (odds ratio 1.17; 95% confidence interval 1.04, 1.32; p-value = 0.009). There was suggestive evidence that genetically predicted higher copper was associated with a lower estimated glomerular filtration rate and a more rapid kidney damage decline. In conclusion, we observed that elevated circulating copper levels may be a causal risk factor for CKD.
| S-EPMC8840411 | biostudies-literature
Project description:Metabolites' connection to sarcopenia through inflammation and mitochondrial dysfunction is presumed, but their impact remains unclear due to limitations in conventional observational studies caused by confounding bias and reverse causation. We conducted a Mendelian randomization (MR) analysis to elucidate the association of serum metabolites with sarcopenia and its related traits, i.e., appendicular lean mass and grip strength. Genetic instruments to proxy the serum metabolites were extracted from the most comprehensive genome-wide association study on the topic published so far. The corresponding summary statistics for the associations of genetic instruments with outcomes were calculated from the UK Biobank (n = 324,976 participants). The primary analyses were assessed by an inverse-variance weighted (IVW) method. The weighted median and MR-PRESSO methods were used as sensitive analyses. Fourteen genetically predicted serum metabolites were associated with the risk of sarcopenia (PIVW < 0.05). Two metabolites showed the overlapped association with sarcopenia and its related traits, which were isovalerylcarnitine (sarcopenia: odds ratio [OR] = 4.00, 95% confidence interval [CI] = 1.11~14.52, PIVW = 0.034; appendicular lean mass: β = -0.45 kg, 95% CI = -0.81~-0.09, PIVW = 0.015; grip strength: β = -1.51 kg, 95% CI = -2.31~-0.71, PIVW = 2.19 × 10-4) and docosapentaenoate (sarcopenia: OR = 0.16, 95% CI = 0.03~0.83, PIVW = 0.029; appendicular lean mass: β = -0.45 kg, 95% CI = 0.08~0.81, PIVW = 0.016). Twenty-seven metabolites were suggestive associated with appendicular lean mass or grip strength. This MR study provided evidence for the potential effects of metabolites on sarcopenia.
| S-EPMC10536442 | biostudies-literature
Project description:BackgroundEpidemiological studies have linked various circulating cytokines to cardiovascular disease (CVD), which however remains uncertain whether these relationships represent causality or are due to bias. To address this question, we conducted a Mendelian randomization (MR) analysis to systematically investigate the causal effects of circulating cytokine levels on CVD development.MethodsThis study leveraged the summary statistic from respective genome-wide association study (GWAS) of 47 cytokines and four types of CVD. The cis-quantitative trait locus (cis-QTL) definition, derived from a GWAS meta-analysis comprising 31,112 participants of European descent, served as instruments for cytokines. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results.ResultsThe results of inverse-variance weighted method using cis-protein QTL (cis-pQTL) instruments, showed the causal effects of four cytokines (i.e., IL-1ra, MCSF, SeSelectin, SCF) on the risk of coronary artery disease (CAD). We also identified causal relationships between two cytokines (i.e., IL-2ra, IP-10) and heart failure (HF), as well as two cytokines (i.e., MCP-3, SeSelectin) and atrial fibrillation (AF), after controlling for false discovery rate (FDR). The use of cis-expression QTL (cis-eQTL) revealed additional causal associations between IL-1a, MIF and CAD, between IL-6, MIF, and HF, as well as between FGFBasic and AF. No significant sign was survived for stroke with FDR applied. Results were largely consistent across sensitivity analyses.ConclusionThe present study provides supportive evidence that genetic predisposition to levels of certain cytokines causally affects the development of specific type of CVD. These findings have important implications for the creation of novel therapeutic strategies targeting these cytokines as a means of preventing and treating CVD.
| S-EPMC10247976 | biostudies-literature
Project description:BACKGROUND:Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS:We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases? = ?46,325, controls? = ?42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS:In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]? = ?0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32?×?10-10). The associations were similar for both premenopausal (OR?? = ??0.44, 95% CI:0.31-0.62, p? = ?9.91?×?10-8) and postmenopausal breast cancer (OR? = ?0.57, 95%?CI: 0.46-0.71, p? = ?1.88?×?10-8). This association was replicated in the data from the DRIVE consortium (OR? = ?0.72, 95%?CI: 0.60-0.84, p?? = ??1.64?×?10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p?<?0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS:BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
| S-EPMC4995025 | biostudies-literature
Project description:Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.
| S-EPMC8801789 | biostudies-literature
Project description:Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (UGT1A1) gene explained 16.9% and the remaining 114 SNPs (non-UGT1A1 SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-UGT1A1 SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, P 0.04 and OR 0.64, 95% CI 0.42-0.99, p 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, p 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.
| S-EPMC7918902 | biostudies-literature