The Role of C-Reactive Protein and Fibrinogen in the Development of Intracerebral Hemorrhage: A Mendelian Randomization Study in European Population

Background: The causal association of C-reactive protein (CRP) and fibrinogen on intracerebral hemorrhage (ICH) remains uncertain. We investigated the causal associations of CRP and fibrinogen with ICH using two-sample Mendelian randomization.Method: We used single-nucleotide polymorphisms associated with CRP and fibrinogen as instrumental variables. The summary data on ICH were obtained from the International Stroke Genetics Consortium (1,545 cases and 1,481 controls). Two-sample Mendelian randomization estimates were performed to assess with inverse-variance weighted and sensitive analyses methods including the weighted median, the penalized weighted median, pleiotropy residual sum and outlier (MR-PRESSO) approaches. MR-Egger regression was used to explore the pleiotropy.Results: The MR analyses indicated that genetically predicted CRP concentration was not associated with ICH, with an odds ratio (OR) of 1.263 (95% CI = 0.935–1.704, p = 0.127). Besides, genetically predicted fibrinogen concentration was not associated with an increased risk of ICH, with an OR of 0.879 (95% CI = 0.060–18.281; p = 0.933). No evidence of pleiotropic bias was detected by MR-Egger. The findings were overall robust in sensitivity analyses.Conclusions: Our findings did not support that CRP and fibrinogen are causally associated with the risk of ICH.

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Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization

Frontiers in Oncology ◽

10.3389/fonc.2020.630994 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Su Yon Jung ◽

Jeanette C. Papp ◽

Eric M. Sobel ◽

Matteo Pellegrini ◽

Herbert Yu ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Mendelian Randomization ◽

Postmenopausal Breast Cancer ◽

Nucleotide Polymorphisms ◽

Reverse Causality ◽

C Reactive Protein ◽

Reactive Protein ◽

Increased Risk

BackgroundImmune-related etiologic pathways that influence breast cancer risk are incompletely understood and may be confounded by lifestyles or reverse causality. Using a Mendelian randomization (MR) approach, we investigated the potential causal relationship between genetically elevated C-reactive protein (CRP) concentrations and primary invasive breast cancer risk in postmenopausal women.MethodsWe used individual-level data obtained from 10,179 women, including 537 who developed breast cancer, from the Women’s Health Initiative Database for Genotypes and Phenotypes Study, which consists of five genome-wide association (GWA) studies. We examined 61 GWA single-nucleotide polymorphisms (SNPs) previously associated with CRP. We employed weighted/penalized weighted–medians and MR gene–environment interactions that allow instruments’ invalidity to some extent and attenuate the heterogeneous estimates of outlying SNPs.ResultsIn lifestyle-stratification analyses, genetically elevated CRP decreased risk for breast cancer in exogenous estrogen-only, estrogen + progestin, and past oral contraceptive (OC) users, but only among relatively short-term users (<5 years). Estrogen-only users for ≥5 years had more profound CRP-decreased breast cancer risk in dose–response fashion, whereas past OC users for ≥5 years had CRP-increased cancer risk. Also, genetically predicted CRP was strongly associated with increased risk for hormone-receptor positive or human epidermal growth factor receptor-2 negative breast cancer.ConclusionsOur findings may provide novel evidence on the immune-related molecular pathways linking to breast cancer risk and suggest potential clinical use of CRP to predict the specific cancer subtypes. Our findings suggest potential interventions targeting CRP–inflammatory markers to reduce breast cancer risk.

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Abstract 25: Six-year Change in C-reactive Protein Levels and Risk of Incident Diabetes, Cardiovascular Events and Mortality

Circulation ◽

10.1161/circ.129.suppl_1.25 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Christina M Parrinello ◽

Pamela L Lutsey ◽

Christie M Ballantyne ◽

Aaron R Folsom ◽

James S Pankow ◽

...

Keyword(s):

Cardiovascular Disease ◽

Proportional Hazards ◽

Cohort Analysis ◽

Cox Proportional Hazards ◽

Sensitivity Analyses ◽

C Reactive Protein ◽

Baseline Measure ◽

Reactive Protein ◽

Inflammatory Status ◽

Increased Risk

Background: High levels of C-reactive protein (CRP) are associated with cardiovascular disease, diabetes and mortality. It is unclear whether changes in CRP or persistently high CRP are associated with these outcomes beyond the baseline measure. Methods: We conducted a prospective cohort analysis of 10,229 participants from the ARIC Study with two measurements of CRP six years apart (at visits 2 and 4, 1990-92 and 1996-98, respectively). CRP was categorized into two groups using a standard cut-point for defining high levels (≥3 vs. <3 mg/L). Six-year change in CRP was categorized as: persistently not high (<3 mg/L), decreasing (≥3 to <3 mg/L), increasing (<3 to ≥3 mg/L), and persistently high (≥3 mg/L). Cox proportional hazards models were used to assess the association between visit 2 CRP, visit 4 CRP and six-year change in CRP and each of the following outcomes from visit 4 through 2010: diabetes, coronary heart disease, ischemic stroke, heart failure and all-cause mortality. Models were adjusted for traditional risk factors at visit 2. Sensitivity analyses additionally adjusted for visit 4 covariates. Results: Persons with CRP ≥3 mg/L at visit 2 or 4 had higher risk of each outcome compared to those with CRP <3 mg/L ( Table ). We observed higher risk of all outcomes in persons with persistently high CRP, and of all outcomes except stroke in persons with increasing CRP, compared to those with CRP <3 mg/L at both visits ( Table ). Persons whose CRP decreased from high to <3 mg/L did not have significantly increased risk of cardiovascular outcomes or diabetes compared to those with CRP persistently <3 mg/L. Results were similar after adjusting for visit 4 covariates. Conclusions: Persons with sustained high levels of CRP or whose CRP increased to high levels had higher risk of diabetes, cardiovascular disease, and death, while those whose levels decreased from high to moderate or low were at lower risk. Multiple measures of CRP may better characterize inflammatory status and provide more comprehensive information regarding long-term risk.

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Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

Frontiers in Nutrition ◽

10.3389/fnut.2021.780205 ◽

2021 ◽

Vol 8 ◽

Author(s):

Chunyu Li ◽

Ruwei Ou ◽

Qianqian Wei ◽

Huifang Shang

Keyword(s):

Causal Relationship ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Carnitine Level ◽

Standard Deviation Increase ◽

Inverse Variance ◽

Weighted Median ◽

Genetically Determined

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.

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Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study

Journal of Translational Medicine ◽

10.1186/s12967-021-03198-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yi Wang ◽

Hui Deng ◽

Yihuai Pan ◽

Lijian Jin ◽

Rongdang Hu ◽

...

Keyword(s):

Periodontal Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Host Susceptibility ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Inverse Variance ◽

Weighted Median ◽

First Time

Abstract Background Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. Methods Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. Results The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004–1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003–1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001–1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003–1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. Conclusions We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.

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Elucidation of a Causal Relationship Between Platelet Count and Hypertension: A Bi-Directional Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.743075 ◽

2021 ◽

Vol 8 ◽

Author(s):

Po-Chun Chiu ◽

Amrita Chattopadhyay ◽

Meng-Chun Wu ◽

Tzu-Hung Hsiao ◽

Ching-Heng Lin ◽

...

Keyword(s):

Platelet Count ◽

Causal Relationship ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

Exact Nature ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

Hypertension has been reported as a major risk factor for diseases such as cardiovascular disease, and associations between platelet activation and risk for hypertension are well-established. However, the exact nature of causality between them remains unclear. In this study, a bi-directional Mendelian randomization (MR) analysis was conducted on 15,996 healthy Taiwanese individuals aged between 30 and 70 years from the Taiwan Biobank, recorded between 2008 and 2015. The inverse variance weighted (IVW) method was applied to determine the causal relationship between platelet count and hypertension with single nucleotide polymorphisms as instrumental variables (IVs). Furthermore, to check for pleiotropy and validity of the IVs, sensitivity analyses were performed using the MR-Egger, weighted median and simple median methods. This study provided evidence in support of a positive causal effect of platelet count on the risk of hypertension (odds ratio: 1.149, 95% confidence interval: 1.131–1.578, P < 0.05), using the weighted median method. A significant causal effect of platelet count on hypertension was observed using the IVW method. No pleiotropy was observed. The causal effect of hypertension on platelet count was found to be non-significant. Therefore, the findings from this study provide evidence that higher platelet count may have a significant causal effect on the elevated risk of hypertension for the general population of Taiwan.

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Serum Parathyroid Hormone and Risk of Coronary Artery Disease: Exploring Causality Using Mendelian Randomization

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-01063 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5595-5600 ◽

Cited By ~ 1

Author(s):

Håkan Melhus ◽

Karl Michaëlsson ◽

Susanna C Larsson

Keyword(s):

Myocardial Infarction ◽

Coronary Artery Disease ◽

Parathyroid Hormone ◽

Coronary Artery ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Serum Parathyroid Hormone ◽

Increased Risk ◽

Artery Disease

Abstract Context Elevated circulating parathyroid hormone concentrations have been associated with increased risk of cardiovascular disease in observational studies, but whether the association is causal is unknown. Objective We used the Mendelian randomization design to test whether genetically increased serum parathyroid hormone (S-PTH) concentrations are associated with coronary artery disease (CAD). Design, Setting, and Participants Five single-nucleotide polymorphisms robustly associated with S-PTH concentrations were used as instrumental variables to estimate the association of genetically higher S-PTH concentrations with CAD. Summary statistics data for CAD were obtained from a genetic consortium with data from 184,305 individuals (60,801 CAD cases and 123,504 noncases). Main Outcome Measure OR of CAD per genetically predicted one SD increase of S-PTH concentrations. Results Genetically higher S-PTH concentration was not associated with CAD as a whole or myocardial infarction specifically (∼70% of total cases). The ORs per genetically predicted one SD increase in S-PTH concentration were 1.01 (95% CI: 0.93 to 1.09; P = 0.88) for CAD and 1.02 (95% CI: 0.94 to 1.10; P = 0.64) for myocardial infarction. The lack of association remained in various sensitivity analyses. Conclusion Genetic predisposition to higher S-PTH concentrations does not appear to be an independent risk factor for CAD.

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Education, Smoking and CRP Genetics in Relation to C-Reactive Protein Concentrations in Black South Africans

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17186646 ◽

2020 ◽

Vol 17 (18) ◽

pp. 6646

Author(s):

Pieter Hermanus Myburgh ◽

Cornelie Nienaber-Rousseau ◽

Iolanthé Marike Kruger ◽

Gordon Wayne Towers

Keyword(s):

Formal Education ◽

Cardiovascular Health ◽

Smoking Status ◽

Economic Status ◽

Nucleotide Polymorphisms ◽

C Reactive Protein ◽

South Africans ◽

Reactive Protein ◽

Increased Risk ◽

Black South Africans

Because elevated circulating C-reactive protein (CRP) and low socio-economic status (SES), have both been implicated in cardiovascular disease development, we investigated whether SES factors associate with and interact with CRP polymorphisms in relation to the phenotype. Included in the study were 1569 black South Africans for whom CRP concentrations, 12 CRP single nucleotide polymorphisms (SNPs), cardiovascular health markers, and SES factors were known. None of the investigated SES aspects was found to associate with CRP concentrations when measured individually; however, in adjusted analyses, attaining twelve or more years of formal education resulted in a hypothetically predicted 18.9% lower CRP concentration. We also present the first evidence that active smokers with a C-allele at rs3093068 are at an increased risk of presenting with elevated CRP concentrations. Apart from education level, most SES factors on their own are not associated with the elevated CRP phenotype observed in black South Africans. However, these factors may collectively with other environmental, genetic, and behavioral aspects such as smoking, contribute to the elevated inflammation levels observed in this population. The gene-smoking status interaction in relation to inflammation observed here is of interest and if replicated could be used in at-risk individuals to serve as an additional motivation to quit.

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Mendelian randomization analysis of C-reactive protein on colorectal cancer risk

International Journal of Epidemiology ◽

10.1093/ije/dyy244 ◽

2018 ◽

Vol 48 (3) ◽

pp. 767-780 ◽

Cited By ~ 7

Author(s):

Xiaoliang Wang ◽

James Y Dai ◽

Demetrius Albanes ◽

Volker Arndt ◽

Sonja I Berndt ◽

...

Keyword(s):

Colorectal Cancer ◽

Instrumental Variables ◽

Statistical Power ◽

Mendelian Randomization ◽

Causal Effect ◽

European Ancestry ◽

Reverse Causality ◽

C Reactive Protein ◽

Reactive Protein ◽

Increased Risk

Abstract Background Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10–4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

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Relating C-reactive Protein to Psychopathology after Cardiac Surgery and Intensive Care Unit Admission: A Mendelian Randomization Study

10.1101/196790 ◽

2017 ◽

Author(s):

Lotte Kok ◽

Bochao Danae Lin ◽

Juliette Broersen ◽

Erwin Bekema ◽

Jelena Medic ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Multiple Testing ◽

Mendelian Randomization ◽

Genetic Risk Score ◽

Nucleotide Polymorphisms ◽

Post Traumatic Stress ◽

C Reactive Protein ◽

Reactive Protein ◽

Individual Snps

AbstractPatients admitted to an intensive care unit (ICU) are subjected to a high burden of stress, rendering them prone to develop stress-related psychopathology. Dysregulation of inflammation and, more specifically, upregulation of inflammatory markers such as C-reactive protein (CRP) is potentially key in development of post-ICU psychopathology.To investigate the effects of state-independent CRP on symptoms of post-traumatic stress disorder (PTSD) and depression after ICU admission, we analysed the three leading single nucleotide polymorphisms (SNPs) of loci most strongly associated with blood CRP levels (i.e. rs2794520, rs4420638, and rs1183910) in an ICU survivor cohort. Genetic association was estimated by linear and logistical regression models of individual SNPs and genetic risk score (GRS) profiling. Mendelian Randomization (MR) was used to investigate potential causal relationships.Single-SNP analyses were non-significant for both quantitative and binary trait analyses after correction for multiple testing. In addition, GRS results were non-significant and explained little variance in psychopathology. Moreover, MR analysis did not reveal any causality and MR-Egger regression showed no evidence of pleiotropic effects (p-pleiotropy >0.05). Furthermore, estimation of causality between these loci and other psychiatric disorders was similarly non-significant.In conclusion, by applying a range of statistical models we demonstrate that the strongest plasma CRP-influencing genetic loci are not associated with post-ICU PTSD and depressive symptoms. Our findings add to an expanding body of literature on the absence of associations between trait CRP and neuropsychiatric phenotypes.

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Type 2 Diabetes and Glycemic Traits Are Not Causal Factors of Osteoarthritis: A Two-Sample Mendelian Randomization Analysis

Frontiers in Genetics ◽

10.3389/fgene.2020.597876 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhiyong Cui ◽

Hui Feng ◽

Baichuan He ◽

Yong Xing ◽

Zhaorui Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Association Studies ◽

Causal Effects ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Knee Oa ◽

Increased Risk

BackgroundIt remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA).MethodsHere, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single-nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG), and 2-h postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used the MR inverse variance weighted (IVW), the MR–Egger method, the weighted median (WM), and the Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG, and 2hGlu with hip and knee OA risks. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.ResultsWe did not find statistically significant causal effects of genetically increased T2D risk, FG, and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR–Egger OR = 1.1708, 95% CI 0.9469–1.4476, p = 0.1547). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR–Egger, intercept = −0.0105, p = 0.1367). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR–Egger Q = 30.1362, I2 < 0.0001, p = 0.6104).ConclusionOur MR study did not support causal effects of a genetically increased T2D risk, FG, and 2hGlu on hip and knee OA risk.

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