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Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease
Cavin K Ward-Caviness1, Paul S de Vries2,3, Kerri L Wiggins4
1Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Insights
Mendelian randomization (MR) analyses suggest a small causal effect of fibrinogen on coronary heart disease (CHD), but not myocardial infarction (MI). Advanced multi-variant MR methods, accounting for pleiotropy, indicate a weaker association than previously observed.
Area of Science:
- Genetics and Epidemiology
- Cardiovascular Disease Research
- Biomarker Analysis
Background:
- Fibrinogen is a key hemostatic factor and a recognized risk factor for cardiovascular diseases (CVDs).
- Previous Mendelian randomization (MR) studies investigating the causal link between fibrinogen and coronary heart disease (CHD) or myocardial infarction (MI) were limited by single-variant approaches and did not leverage recent genome-wide association studies (GWAS) or advanced MR methodologies.
Purpose of the Study:
- To evaluate the causal effect of fibrinogen on CHD and MI using modern, pleiotropy-robust MR methodologies.
- To compare findings from multi-variant MR approaches with traditional single-variant analyses.
Main Methods:
- Utilized an allele score approach with 38 fibrinogen-associated variants from recent GWAS, meta-analyzed across 11 European-ancestry prospective cohorts.
- Employed two-sample MR methods using data from a prevalent CHD and MI GWAS, incorporating pleiotropy-robust models.
- Assessed causal effects using hazard ratios (HR) for incidence data and odds ratios (OR) for prevalent data, with 95% confidence intervals (CI).
Main Results:
- Single-variant MR analyses did not reveal a significant causal effect of fibrinogen on CHD or MI.
- Multi-variant MR using an allele score approach indicated a causal effect (HR = 1.62, CI = 1.12–2.36) for a 1 g/L increase in fibrinogen on incident CHD.
- Two-sample MR analyses accounting for pleiotropy yielded reduced causal estimates for CHD (OR = 1.18, CI = 0.98–1.42 and OR = 1.09, CI = 0.89–1.33 in the most precise models). Evidence for a causal effect on MI was very weak.
Conclusions:
- Multi-variant MR approaches that account for pleiotropy suggest a small, but not definitively null, causal effect of fibrinogen on CHD.
- These findings indicate that even with large sample sizes and advanced MR techniques, the causal effect of fibrinogen on CHD may be substantially smaller than suggested by traditional epidemiological studies.
- Current MR analyses cannot exclude the null hypothesis for the causal effect of fibrinogen on CHD, highlighting the need for cautious interpretation of its role in cardiovascular disease.
Background:
Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.
Methods And Findings:
We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.
Conclusions:
A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
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