Dataset Information

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.

ABSTRACT: To determine whether genetically predicted circulating levels of cytokines are associated with risk of overall breast cancer (BC), estrogen receptor (ER)-positive and ER-negative BC, we conducted two-sample MR analyses using data from the most comprehensive genome-wide association studies (GWAS) on cytokines in 8293 Finnish participants and the largest BC GWAS from the Breast Cancer Association Consortium (BCAC) with totally 122,977 BC cases and 105,974 healthy controls. We systematically screened 41 cytokines (of which 24 cytokines have available instruments) and identified that genetically predicted circulating levels (1-SD increase) of MCP1 (OR: 1.08; 95% CIs: 1.03-1.12; P value: 3.55 × 10^-4), MIP1b (OR: 1.02; 95% CIs: 1.01-1.04; P value: 2.70 × 10^-3) and IL13 (OR: 1.06; 95% CIs: 1.03-1.10; P value: 3.33 × 10^-4) were significantly associated with increased risk of overall BC, as well as ER-positive BC. In addition, higher levels of MIP1b and IL13 were also significantly associated with increased risk of ER-negative BC. These findings suggest the crucial role of cytokines in BC carcinogenesis and potential of targeting specific inflammatory cytokines for BC prevention.

SUBMITTER: Li S

PROVIDER: S-EPMC7462857 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.

Li Shen S Xu Yan Y Zhang Yao Y Nie Lili L Ma Zhihua Z Ma Ling L Fang Xiaoyu X Ma Xiangyu X

NPJ precision oncology 20200901

To determine whether genetically predicted circulating levels of cytokines are associated with risk of overall breast cancer (BC), estrogen receptor (ER)-positive and ER-negative BC, we conducted two-sample MR analyses using data from the most comprehensive genome-wide association studies (GWAS) on cytokines in 8293 Finnish participants and the largest BC GWAS from the Breast Cancer Association Consortium (BCAC) with totally 122,977 BC cases and 105,974 healthy controls. We systematically screen ...[more]

PMID: 32923685

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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.

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.

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Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.

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Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.

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