Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.
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SUBMITTER: Li S
PROVIDER: S-EPMC7462857 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: The association between inflammatory cytokines and osteoarthritis (OA) has been reported in several observational studies, but the causal relationship between these two remains unknown. Hence, we performed this two-sample Mendelian randomization (MR) to confirm the causal relationship between circulating levels of inflammatory factors and osteoarthritis risk. Method: We used genetic variants associated with cytokine circulation levels from a meta-analysis of genome-wide association studies (GWASs) in 8,293 Finns as instrumental variables and obtained OA data from the United Kingdom Biobank, including a total of 345,169 subjects of European ancestry (66,031 diagnosed OA cases and 279,138 controls). Inverse variance weighting (IVW), MR-Egger, Wald Ratio, weighted median, and MR multiplicity residual sums with outliers (MR-PRESSO) were used. Result: We found a causal relationship between circulating levels of macrophage inflammatory protein-1beta (MIP-1β) and risk of OA (OR = 0.998, 95% CI = 0.996–0.999p = 9.61 × 10−5); tumour necrosis factor beta (TNF-β) was also causally associated with risk of OA (OR = 0.996,95%CI = 0.994–0.999, p = 0.002); finally we found a suggestive association between C-C motif chemokine ligand 5(CCL5, also called Rantes) and OA risk (OR = 1.013, 95%CI = 1.002–1.024,p = 0.016). Conclusion: Our findings offer promising leads for the development of new therapeutic targets in the treatment of osteoarthritis. By identifying the role of inflammatory cytokines in this debilitating condition through a genetic epidemiological approach, our study contributes to a better understanding of the underlying disease mechanisms. These insights may ultimately pave the way for more effective treatments that improve patient outcomes.
| S-EPMC10043178 | biostudies-literature
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:To investigate the causal relationship between circulating serum homocysteine (Hcy) levels and osteoporosis (OP). Using public datasets gathered from independently published genome-wide association studies (GWAS), Mendelian randomization (MR) analysis was done to investigate the causal influence of Hcy on OP. SNPs were selected from a meta-analysis of GWAS on Hcy concentrations in 44,147 individuals of European ancestry. Meanwhile, SNPs of individuals of European descent for OP were extracted from the Genetic Factors of Osteoporosis Consortium (GEFOS) UK Biobank. The odds ratio (OR) of inverse variance weighted (IVW) approaches was established as the primary outcome. Moreover, weighted median (WM) and MR-Egger regressions were included in the sensitivity analysis. There were no causal effects of Hcy on forearm bone mineral density and lumbar bone mineral density according to IVW, MR-Egger, and WM analyses (all p > 0.05). In the IVW, we discovered the causality between genetically predicted Hcy and heel bone mineral density (H-BMD) with an OR of 0.96 [95% confidence interval (CI) = 0.927-0.990, p = 0.011]. In the additional sensitivity analysis, WM regression (OR = 0.97, 95% CI = 0.995-1.076, p = 0.084) and MR-Egger regression (OR = 0.98, 95% CI = 0.918-1.049, p = 0.609) yielded values that were comparable in direction but less precise. The MR-Egger intercept, funnel plot, and IVW all indicate the absence of any discernible directional pleiotropy. The leave-one-out analysis revealed that a single SNP did not influence the results of the MR analysis. In conclusion, our MR investigation revealed evidence of a causal relationship between circulating serum Hcy levels and H-BMD, but not OP in the European population. However, larger sample sizes are needed in the future to get more reliable conclusions.
| S-EPMC10239750 | 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:Background Current studies have reported conflicting associations between circulating micronutrient levels and kidney stone disease (KSD). We aimed to elucidate the causal relationship between circulating micronutrient levels and KSD by a two-sample Mendelian randomization (MR) analysis. Methods Total of 36 single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) significantly associated with eight micronutrients (vitamin B12, folic acid, magnesium, iron, phosphorus, copper, zinc, and selenium) were used as instrumental variables. The GWAS summary data associated with KSD (8,060 cases and 301,094 controls) were obtained from the FinnGen consortium. Inverse variance weighted was the main MR analysis method. MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), weighted median and MR-Egger were used to assess pleiotropy and heterogeneity. Results Genetically predicted circulating vitamin B12 and zinc levels were causally associated with the risk of KSD (vitamin B12: OR: 1.17, 95% CI: 1.04–1.32, p = 0.008; zinc: OR: 1.15, 95% CI: 1.03–1.28, p = 0.015). We found no evidence that other circulating micronutrients were associated with risk of KSD. p-value for Cochrane Q test, MR Egger intercept test, and MR-PRESSO were >0.05, indicating no significant heterogeneity or horizontal pleiotropy in this MR analysis. Conclusion Increasing circulating zinc levels may increase the risk of KSD. More studies are needed to provide evidence on whether genetically predicted circulating vitamin B12 and zinc levels are a risk factor for KSD.
| S-EPMC10476526 | 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