Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart 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.
Competing Interests: BMP reports serving on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. WK reports personal fees from AstraZeneca Novartis, Pfizer, The Medicines Company, GlaxoSmithKline, DalCor, Sanofi, Berlin-Chemie, Kowa, and Amgen. WK also reports grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex. All reports from WK are outside the submitted work. WM reports grants and personal fees from Siemens Diagnostics, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Danone Research, Sanofi/Genzyme, Pfizer, BASF, and Numares. WM reports personal fees from Hoffmann LaRoche, MSD, Sanofi, and Alexion. WM is employed by Synlab Holding Deutschland GmbH and all reports by WM are outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.