RT Journal Article
SR Electronic
T1 Mendelian Randomization evaluation of causal effects of fibrinogen on incident coronary heart disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 448381
DO 10.1101/448381
A1 Cavin K. Ward-Caviness
A1 Paul S. de Vries
A1 Kerri L. Wiggins, MS
A1 Jennifer E. Huffman
A1 Jennifer E. Huffman
A1 Lisa R. Yanek
A1 Lawrence F. Bielak
A1 Franco Giulianini
A1 Xiuqing Guo
A1 Marcus E. Kleber
A1 Tim Kacprowski
A1 Stefan Groβ
A1 Astrid Petersman
A1 George Davey Smith
A1 Fernando P. Hartwig
A1 Jack Bowden
A1 Gibran Hemani
A1 Martina Müller-Nuraysid
A1 Konstantin Strauch
A1 Wolfgang Koenig
A1 Melanie Waldenberger
A1 Thomas Meitinger
A1 Nathan Pankratz
A1 Eric Boerwinkle
A1 Weihong Tang
A1 Yi-Ping Fu
A1 Andrew D Johnson
A1 Ci Song
A1 Ci Song
A1 Moniek P.M. de Maat
A1 André G. Uitterlinden
A1 Oscar H. Franco
A1 Jennifer A. Brody
A1 Barbara McKnight
A1 Yii-Der Ida Chen
A1 Bruce M. Psaty
A1 Rasika A. Mathias
A1 Diane M. Becker
A1 Patricia A. Peyser
A1 Jennifer A. Smith
A1 Suzette J. Bielinski
A1 Paul M. Ridker
A1 Kent D. Taylor
A1 Jie Yao
A1 Russell Tracy
A1 Graciela Delgado
A1 Stella Trompet
A1 Naveed Sattar
A1 J. Wouter Jukema
A1 Lewis C. Becker
A1 Sharon L.R. Kardia
A1 Jerome I. Rotter
A1 Winfried März
A1 Marcus Dörr
A1 Daniel I. Chasman
A1 Abbas Dehghan
A1 Christopher J. O’Donnell
A1 Nicholas L. Smith
A1 Annette Peters
A1 Alanna C. Morrison
YR 2018
UL http://biorxiv.org/content/early/2018/10/19/448381.abstract
AB 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 incorporated data from 11 European-ancestry prospective cohorts 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.Author Summary Initial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.