Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
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ABSTRACT:
SUBMITTER: Yarmolinsky J
PROVIDER: S-EPMC10844944 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
Publications
Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
Yarmolinsky James J Robinson Jamie W JW Mariosa Daniela D Karhunen Ville V Huang Jian J Dimou Niki N Murphy Neil N Burrows Kimberley K Bouras Emmanouil E Smith-Byrne Karl K Lewis Sarah J SJ Galesloot Tessel E TE Kiemeney Lambertus A LA Vermeulen Sita S Martin Paul P Albanes Demetrius D Hou Lifang L Newcomb Polly A PA White Emily E Wolk Alicja A Wu Anna H AH Le Marchand Loïc L Phipps Amanda I AI Buchanan Daniel D DD Zhao Sizheng Steven SS Gill Dipender D Chanock Stephen J SJ Purdue Mark P MP Davey Smith George G Brennan Paul P Herzig Karl-Heinz KH Järvelin Marjo-Riitta MR Amos Chris I CI Hung Rayjean J RJ Dehghan Abbas A Johansson Mattias M Gunter Marc J MJ Tsilidis Kostas K KK Martin Richard M RM
EBioMedicine 20240201
<h4>Background</h4>Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.<h4>Methods</h4>We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used ...[more]
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Project description:BackgroundTumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.MethodsWe meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes.ResultsWe found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk.ConclusionOur comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.
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Project description: Not available
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Project description:Previous research has suggested that circulating inflammatory proteins are associated with benign prostatic disease (BPD). This Mendelian randomization (MR) study was conducted to further investigate the causal relationship between 91 inflammatory proteins and BPD. Genome-wide association study (GWAS) summarized data of benign prostatic hyperplasia (BPH) and prostatitis were obtained from the FinnGen Biobank. The latest study offered the GWAS data on 91 proteins related to inflammation. We performed a bidirectional MR to investigate the causal association between inflammatory proteins and BPD. The outcomes of the IVW method indicated that decreased levels of circulating interleukin-17 C (IL-17 C) (OR = 0.92, 95%CI = 0.85-0.99, p-value = 0.0344) were suggestively associated with a higher risk of BPH and elevated levels of interleukin-10 receptor subunit alpha (IL-10RA) (OR = 1.24, 95%CI = 1.05-1.47, p-value = 0.0132) and urokinase-type plasminogen activator (uPA) (OR = 1.13, 95%CI = 1.00-1.28, p-value = 0.0421) were suggestively related to a higher risk of prostatitis. Furthermore, reverse MR revealed that BPH may promote the expression of circulating factors, including natural killer cell receptor 2B4 (CD244) (OR = 1.07, 95%CI = 1.01-1.13, p-value = 0.0192), T-cell surface glycoprotein CD6 isoform (CD6) (OR = 1.07, 95%CI = 1.01-1.13, p-value = 0.0192), and leukemia inhibitory factor receptor (LIF-R) (OR = 1.07, 95%CI = 1.01-1.15, p-value = 0.0163). Moreover, the results of sensitivity analyses indicate that heterogeneity and horizontal pleiotropy are unlikely to distort the findings. The results of this study indicate a potential association between circulating inflammatory proteins and BPD, which may become new diagnostic indicators or drug targets for clinical application in the prevention and treatment of BPD. However, further investigation is required.
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Project description:BackgroundThere is still limited research on the association between immune cells and the risk of prostate cancer. Further investigations are warranted to comprehend the intricate associations at play.MethodsWe used a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between immune cell phenotypes and prostate cancer. The summary data for immune cell phenotypes was derived from a study cohort, including 3,757 individuals from Sardinia with data on 731 immune cell phenotypes. The summary data for prostate cancer were obtained from the UK Biobank database. Sensitivity analyses were conducted, and the combination of MR-Egger and MR-Presso was used to assess horizontal pleiotropy. Cochran's Q test was employed to evaluate heterogeneity, and the results were subjected to FDR correction.ResultsOur study identified two immune cell phenotypes significantly associated with the risk of prostate cancer, namely CD25 on naive-mature B cells (OR = 0.998, 95% CI, 0.997-0.999, P = 2.33E-05, FDR = 0.017) and HLA DR on CD14- CD16- cells (OR = 1.001, 95% CI, 1.000-1.002, P = 8.01E-05, FDR = 0.03). When adjusting FDR to 0.2, we additionally found six immune cell phenotypes influencing the incidence of prostate cancer. These include FSC-A on B cells (OR = 1.002, 95% CI, 1.001-1.002, P = 7.77E-04, FDR = 0.133), HLA DR on plasmacytoid dendritic cells (OR = 1.001, 95% CI, 1.000-1.001, P = 0.001, FDR = 0.133), CD14+ CD16- monocyte % monocytes (OR = 1.002, 95% CI, 1.001-1.003, P = 0.001, FDR = 0.133), and HVEM on effector memory CD4+ T cells (OR = 1.001, 95% CI, 1.000-1.002, P = 0.002, FDR = 0.169), which are positively correlated with the risk of prostate cancer. Conversely, CD25 on IgD+ B cells (OR = 0.998, 95% CI, 0.997-0.999, P = 0.002, FDR = 0.169) and Monocytic Myeloid-Derived Suppressor Cells AC (OR = 0.999, 95% CI, 0.999-1.000, P = 0.002, FDR = 0.17) are negatively correlated with the risk of prostate cancer.ConclusionThis study has revealed causal relationships between immune cell phenotypes and prostate cancer, supplying novel insights that might aid in identifying potential therapeutic targets of prostate cancer.
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Project description:BackgroundCytokines are powerful immune response factors that operate at inflammation sites and are also found in the blood. Nevertheless, research on encephalitis and these circulating inflammatory proteins is quite limited.MethodsThis study investigated the potential causal effects of 91 circulating inflammatory proteins on three different types of encephalitis using a two-sample Mendelian randomisation analysis. The data source for encephalitis was the latest Finngen_R12 dataset, released in 2024. The study investigated causal effects mainly using Steiger, MR-Egger, weighted median and inverse variance weighting (IVW) methods. In addition, sensitivity analyses were performed, including heterogeneity assessment, horizontal pleiotropy and leave-one-out techniques.ResultsIn this study, 91 circulating inflammatory proteins were subjected to MR analysis of causality with each of the three types of encephalitis. The results suggest that the inflammatory factors with a potential causal relationship with viral encephalitis are artemin, C-C motif chemokine 28, C-X-C motif chemokine 1, interleukin-10 and neurotrophin-3. Inflammatory factors potentially causally associated with acute disseminated encephalomyelitis are monocyte chemoattractant protein 2, interleukin-10 receptor subunit beta and matrix metalloproteinase-1. Inflammatory factors potentially causally associated with autoimmune encephalitis are C-C motif chemokine 28 levels and Macrophage inflammatory protein 1a levels.ConclusionThis study identifies potential causal effects of certain circulating inflammatory factors on susceptibility to three types of encephalitis. Although the exact mechanisms by which inflammatory proteins contribute to the pathogenesis of different encephalitis subtypes remain unclear, our findings provide new perspectives on these potential causal relationships.
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Project description:BackgroundA number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).Methods and findingsData from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.ConclusionsWe observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.
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Project description:ObjectiveObservational studies suggest a link between hernia and inflammatory cytokines, but randomized trials are limited by ethical and cost constraints. In this study, we used bidirectional Mendelian randomization (MR) to investigate the causal relationship between inflammatory cytokines and five types of hernia, aiming to inform preventive and therapeutic strategies.MethodsWe selected 41 inflammatory factors and five types of hernia as instrumental variables, using data from the IEU Open GWAS database including individuals of European descent. The primary analysis used the inverse variance weighted method with false discovery rate (FDR) adjustment. Additional MR methods and sensitivity analyses ensured robustness. Reverse MR was used to assess potential reverse causality.ResultsAfter FDR adjustment, stem cell growth factor beta (SCGFb) was causally associated with diaphragmatic hernia (odds ratio = 0.884, 95% confidence interval: 0.819-0.955). Reverse MR indicated that diaphragmatic hernia may increase interferon gamma-induced protein 10 (IP10) and monokine induced by interferon-gamma (MIG), and ventral hernia may elevate macrophage inflammatory protein-1b (MIP1b). Sensitivity analyses confirmed robustness.ConclusionSCGFb may protect against diaphragmatic hernia, and IP10, MIG, and MIP1b are involved in hernia development, suggesting the therapeutic potential of targeting these cytokines. Further studies are needed.
| S-EPMC11831628 | biostudies-literature
Project description:Background & aimsLifestyle and dietary risk factors for diverticulitis also have been associated with chronic inflammation. We performed a prospective study of associations among the inflammatory potential of diets, circulating markers of inflammation, and the incidence of diverticulitis.MethodsWe followed 46,418 men, initially free of diverticulitis, from 1986 through 2014 in the Health Professionals Follow-Up Study. We collected data on empiric dietary inflammatory pattern scores, which indicate the inflammatory potential of diets, and determined their association with the risk of incident diverticulitis using Cox proportional hazards regression. We used blood samples provided by 18,225 participants from 1993 through 1995 to conduct a nested case-control study; we used conditional logistic regression to evaluate prediagnostic plasma levels of markers of inflammation, including C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor-receptor superfamily member 1B, in 310 diverticulitis cases and 310 matched diverticulitis-free individuals (controls).ResultsWe documented 1110 cases of incident diverticulitis over 992,589 person-years of follow-up. Compared with participants in the lowest quintile of empiric dietary inflammatory pattern scores, men in the highest quintile had a multivariable-adjusted hazard ratio for diverticulitis of 1.31 (95% CI, 1.07-1.60; Ptrend = .01). The association did not differ significantly by strata of body mass index or vigorous activity (P for interaction > .05 for each). In the nested case-control study, plasma levels of CRP and IL6 were associated with risk of diverticulitis. When we compared extreme quintiles, the multivariable-adjusted relative risk for diverticulitis was 1.85 for CRP (95% CI, 1.04-3.30) and 2.04 for IL6 (95% CI, 1.09-3.84).ConclusionsIn a large prospective cohort of men, we found that the inflammatory potential of diet and prediagnostic plasma levels of markers of inflammation were associated with incident diverticulitis.
| S-EPMC7310666 | biostudies-literature
Project description:IntroductionA growing body of research has shown a strong connection between circulating inflammatory proteins and Peripheral artery disease (PAD). However, the causal relationship between circulating inflammatory proteins and PAD is still not fully understood. To investigate this association, we conducted a bidirectional Mendelian randomization study.Materials and methodsOur study utilized genetic variation data obtained from genome-wide association studies (GWAS) datasets. Specifically, the GWAS dataset related to PAD (identifier: finn-b-I9_PAD) included 7,098 cases and 206,541 controls. Additionally, we extracted data on 91 inflammatory proteins from another GWAS dataset (identifiers: GCST90274758-GCST90274848), involving 14,824 participants. To assess the causal relationship between circulating inflammatory proteins and PAD development, we employed methodologies such as inverse variance weighting (IVW), MR Egger regression, and the weighted median approach. Furthermore, sensitivity analyses were conducted to ensure the reliability and robustness of our findings.ResultsTwo inflammatory proteins were found to be significantly associated with PAD risk: Natural killer cell receptor 2B4 levels (OR, 1.219; 95% CI,1.019~1.457; P=0.03), Fractalkine levels (OR, 0.755; 95% CI=0.591~0.965; P=0.025). PAD had statistically significant effects on 12 inflammatory proteins: C-C motif chemokine 19 levels (OR, 0.714; 95% CI, 0.585 to 0.872; P=0.001), T-cell surface glycoprotein CD5 levels (OR, 0.818; 95% CI, 0.713 to 0.938; P=0.004), CUB domain-containing protein 1 levels (OR, 0.889; 95% CI, 0.809 to 0.977; P=0.015), Fibroblast growth factor 23 levels (OR, 1.129; 95% CI, 1.009 to 1.264; P=0.034), Interferon gamma levels (OR, 1.124; 95% CI, (1.011 to 1.250); P=0.031),Interleukin-15 receptor subunit alpha levels (OR, 1.183; 95% CI,(1.005 to 1.392); P=0.044), Interleukin-17C levels (OR,1.186; 95% CI, (1.048 to 1.342); P=0.007), Interleukin-1-alpha levels (OR, 1.349; 95% CI, (1.032 to 1.765); P=0.029), Interleukin-5 levels (OR, 1.119; 95% CI,(1.003 to 1.248); P=0.043), Latency-associated peptide transforming growth factor beta 1 levels (OR,1.123; 95% CI, (1.020 to 1.236); P=0.018), Matrix metalloproteinase-10 levels (OR, 1.119; 95% CI,(1.015 to 1.233); P=0.024), Signaling lymphocytic activation molecule levels (OR, 0.823; 95% CI, (0.693 to 0.978); P=0.027).ConclusionOur research expands on genetic studies exploring the strong association between circulating inflammatory proteins and PAD. This discovery has the potential to inform and shape future clinical and basic research endeavors in this area.
| S-EPMC11361930 | biostudies-literature
Project description:BackgroundIntracranial aneurysm (IA) accounts for a substantial source of non-traumatic subarachnoid hemorrhage, with inflammation postulated as a potential factor in its pathogenesis. The present study aims at evaluating the association between circulating inflammatory cytokines and risk of IA under a bidirectional two-sample Mendelian randomization (MR) design.MethodsFor primary analysis, summary statistics of inflammatory regulators was obtained from a genome-wide association study (GWAS) comprising 8293 Finnish participants. Summary data of IA were extracted from a GWAS which comprised 7495 cases and 71,934 controls in European descent. For targeted analysis, summary statistics were extracted from two proteomic studies, which recruit 3301 and 5368 European participants, respectively. Summary data of IA were acquired from FinnGen study with 5342 cases and 342,673 controls. We employed inverse variance weighted (IVW) method as main approach, with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods. Reverse MR analyses were conducted to minimize bias from reverse causality.ResultsNo causation of cytokines with IA subtypes was identified in both primary and targeted analysis after Bonferroni correction. In primary analysis, vascular endothelial growth factor (VEGF) and fibroblast growth factor basic (bFGF) levels were suggestively associated with aneurysmal subarachnoid hemorrhage (aSAH) [VEGF → aSAH: OR = 1.15, 95%CI 1.04-1.26, P = 0.005; bFGF → aSAH: OR = 0.62, 95% CI 0.42-0.92, P = 0.02]. Statistical significance failed to replicate in targeted analysis. Instead, suggestive protective effects for aSAH were identified in FGF-9 (FGF-9 → aSAH: OR = 0.74, 95% CI 0.62-0.89, P = 0.001) and FGF-16 (FGF-16 → aSAH: OR = 0.84, 95% CI 0.72-0.97, P = 0.017). Furthermore, reverse analyses identified suggestive effect of unruptured IA on RANTES, MIF, GRO-alpha, FGF-16, and FGF-19. Result remained robust after applying sensitivity tests.ConclusionsNo causality of inflammatory biomarkers on the risk of IA subtypes was identified. Future large-scale studies are in need to evaluate the temporal dynamics of cytokines in conjunction with IA.
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