Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

Cavin K. Ward-Caviness, Paul S. De Vries, Kerri L. Wiggins, Jennifer E. Huffman, Lisa Yanek, Lawrence F. Bielak, Franco Giulianini, Xiuqing Guo, Marcus E. Kleber, Tim Kacprowski, Stefan Groß, Astrid Petersman, George Davey Smith, Fernando P. Hartwig, Jack Bowden, Gibran Hemani, Martina Müller-Nuraysid, Konstantin Strauch, Wolfgang Koenig, Melanie WaldenbergerThomas Meitinger, Nathan Pankratz, Eric Boerwinkle, Weihong Tang, Yi Ping Fu, Andrew D. Johnson, Ci Song, Moniek P.M. De Maat, André G. Uitterlinden, Oscar H. Franco, Jennifer A. Brody, Barbara McKnight, Yii Der Ida Chen, Bruce M. Psaty, Rasika Mathias, Diane M Becker, Patricia A. Peyser, Jennifer A. Smith, Suzette J. Bielinski, Paul M. Ridker, Kent D. Taylor, Jie Yao, Russell Tracy, Graciela Delgado, Stella Trompet, Naveed Sattar, J. Wouter Jukema, Lewis Becker, Sharon L.R. Kardia, Jerome I. Rotter, Winfried März, Marcus Dörr, Daniel I. Chasman, Abbas Dehghan, Christopher J. O’Donnell, Nicholas L. Smith, Annette Peters, Alanna C. Morrison

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere0216222
JournalPloS one
Volume14
Issue number5
DOIs
StatePublished - May 1 2019

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fibrinogen
Random Allocation
Fibrinogen
Coronary Disease
Mendelian Randomization Analysis
pleiotropy
confidence interval
Alleles
Confidence Intervals
Genome-Wide Association Study
alleles
Genes
odds ratio
Hazards
Odds Ratio
coronary disease
incidence
sampling
Incidence
Hemostatics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ward-Caviness, C. K., De Vries, P. S., Wiggins, K. L., Huffman, J. E., Yanek, L., Bielak, L. F., ... Morrison, A. C. (2019). Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. PloS one, 14(5), [e0216222]. https://doi.org/10.1371/journal.pone.0216222

Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. / Ward-Caviness, Cavin K.; De Vries, Paul S.; Wiggins, Kerri L.; Huffman, Jennifer E.; Yanek, Lisa; Bielak, Lawrence F.; Giulianini, Franco; Guo, Xiuqing; Kleber, Marcus E.; Kacprowski, Tim; Groß, Stefan; Petersman, Astrid; Smith, George Davey; Hartwig, Fernando P.; Bowden, Jack; Hemani, Gibran; Müller-Nuraysid, Martina; Strauch, Konstantin; Koenig, Wolfgang; Waldenberger, Melanie; Meitinger, Thomas; Pankratz, Nathan; Boerwinkle, Eric; Tang, Weihong; Fu, Yi Ping; Johnson, Andrew D.; Song, Ci; De Maat, Moniek P.M.; Uitterlinden, André G.; Franco, Oscar H.; Brody, Jennifer A.; McKnight, Barbara; Chen, Yii Der Ida; Psaty, Bruce M.; Mathias, Rasika; Becker, Diane M; Peyser, Patricia A.; Smith, Jennifer A.; Bielinski, Suzette J.; Ridker, Paul M.; Taylor, Kent D.; Yao, Jie; Tracy, Russell; Delgado, Graciela; Trompet, Stella; Sattar, Naveed; Jukema, J. Wouter; Becker, Lewis; Kardia, Sharon L.R.; Rotter, Jerome I.; März, Winfried; Dörr, Marcus; Chasman, Daniel I.; Dehghan, Abbas; O’Donnell, Christopher J.; Smith, Nicholas L.; Peters, Annette; Morrison, Alanna C.

In: PloS one, Vol. 14, No. 5, e0216222, 01.05.2019.

Research output: Contribution to journalArticle

Ward-Caviness, CK, De Vries, PS, Wiggins, KL, Huffman, JE, Yanek, L, Bielak, LF, Giulianini, F, Guo, X, Kleber, ME, Kacprowski, T, Groß, S, Petersman, A, Smith, GD, Hartwig, FP, Bowden, J, Hemani, G, Müller-Nuraysid, M, Strauch, K, Koenig, W, Waldenberger, M, Meitinger, T, Pankratz, N, Boerwinkle, E, Tang, W, Fu, YP, Johnson, AD, Song, C, De Maat, MPM, Uitterlinden, AG, Franco, OH, Brody, JA, McKnight, B, Chen, YDI, Psaty, BM, Mathias, R, Becker, DM, Peyser, PA, Smith, JA, Bielinski, SJ, Ridker, PM, Taylor, KD, Yao, J, Tracy, R, Delgado, G, Trompet, S, Sattar, N, Jukema, JW, Becker, L, Kardia, SLR, Rotter, JI, März, W, Dörr, M, Chasman, DI, Dehghan, A, O’Donnell, CJ, Smith, NL, Peters, A & Morrison, AC 2019, 'Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease', PloS one, vol. 14, no. 5, e0216222. https://doi.org/10.1371/journal.pone.0216222
Ward-Caviness, Cavin K. ; De Vries, Paul S. ; Wiggins, Kerri L. ; Huffman, Jennifer E. ; Yanek, Lisa ; Bielak, Lawrence F. ; Giulianini, Franco ; Guo, Xiuqing ; Kleber, Marcus E. ; Kacprowski, Tim ; Groß, Stefan ; Petersman, Astrid ; Smith, George Davey ; Hartwig, Fernando P. ; Bowden, Jack ; Hemani, Gibran ; Müller-Nuraysid, Martina ; Strauch, Konstantin ; Koenig, Wolfgang ; Waldenberger, Melanie ; Meitinger, Thomas ; Pankratz, Nathan ; Boerwinkle, Eric ; Tang, Weihong ; Fu, Yi Ping ; Johnson, Andrew D. ; Song, Ci ; De Maat, Moniek P.M. ; Uitterlinden, André G. ; Franco, Oscar H. ; Brody, Jennifer A. ; McKnight, Barbara ; Chen, Yii Der Ida ; Psaty, Bruce M. ; Mathias, Rasika ; Becker, Diane M ; Peyser, Patricia A. ; Smith, Jennifer A. ; Bielinski, Suzette J. ; Ridker, Paul M. ; Taylor, Kent D. ; Yao, Jie ; Tracy, Russell ; Delgado, Graciela ; Trompet, Stella ; Sattar, Naveed ; Jukema, J. Wouter ; Becker, Lewis ; Kardia, Sharon L.R. ; Rotter, Jerome I. ; März, Winfried ; Dörr, Marcus ; Chasman, Daniel I. ; Dehghan, Abbas ; O’Donnell, Christopher J. ; Smith, Nicholas L. ; Peters, Annette ; Morrison, Alanna C. / Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. In: PloS one. 2019 ; Vol. 14, No. 5.
@article{71fddcb697e84fd980d902c033ed25c1,
title = "Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease",
abstract = "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.",
author = "Ward-Caviness, {Cavin K.} and {De Vries}, {Paul S.} and Wiggins, {Kerri L.} and Huffman, {Jennifer E.} and Lisa Yanek and Bielak, {Lawrence F.} and Franco Giulianini and Xiuqing Guo and Kleber, {Marcus E.} and Tim Kacprowski and Stefan Gro{\ss} and Astrid Petersman and Smith, {George Davey} and Hartwig, {Fernando P.} and Jack Bowden and Gibran Hemani and Martina M{\"u}ller-Nuraysid and Konstantin Strauch and Wolfgang Koenig and Melanie Waldenberger and Thomas Meitinger and Nathan Pankratz and Eric Boerwinkle and Weihong Tang and Fu, {Yi Ping} and Johnson, {Andrew D.} and Ci Song and {De Maat}, {Moniek P.M.} and Uitterlinden, {Andr{\'e} G.} and Franco, {Oscar H.} and Brody, {Jennifer A.} and Barbara McKnight and Chen, {Yii Der Ida} and Psaty, {Bruce M.} and Rasika Mathias and Becker, {Diane M} and Peyser, {Patricia A.} and Smith, {Jennifer A.} and Bielinski, {Suzette J.} and Ridker, {Paul M.} and Taylor, {Kent D.} and Jie Yao and Russell Tracy and Graciela Delgado and Stella Trompet and Naveed Sattar and Jukema, {J. Wouter} and Lewis Becker and Kardia, {Sharon L.R.} and Rotter, {Jerome I.} and Winfried M{\"a}rz and Marcus D{\"o}rr and Chasman, {Daniel I.} and Abbas Dehghan and O’Donnell, {Christopher J.} and Smith, {Nicholas L.} and Annette Peters and Morrison, {Alanna C.}",
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language = "English (US)",
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TY - JOUR

T1 - Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

AU - Ward-Caviness, Cavin K.

AU - De Vries, Paul S.

AU - Wiggins, Kerri L.

AU - Huffman, Jennifer E.

AU - Yanek, Lisa

AU - Bielak, Lawrence F.

AU - Giulianini, Franco

AU - Guo, Xiuqing

AU - Kleber, Marcus E.

AU - Kacprowski, Tim

AU - Groß, Stefan

AU - Petersman, Astrid

AU - Smith, George Davey

AU - Hartwig, Fernando P.

AU - Bowden, Jack

AU - Hemani, Gibran

AU - Müller-Nuraysid, Martina

AU - Strauch, Konstantin

AU - Koenig, Wolfgang

AU - Waldenberger, Melanie

AU - Meitinger, Thomas

AU - Pankratz, Nathan

AU - Boerwinkle, Eric

AU - Tang, Weihong

AU - Fu, Yi Ping

AU - Johnson, Andrew D.

AU - Song, Ci

AU - De Maat, Moniek P.M.

AU - Uitterlinden, André G.

AU - Franco, Oscar H.

AU - Brody, Jennifer A.

AU - McKnight, Barbara

AU - Chen, Yii Der Ida

AU - Psaty, Bruce M.

AU - Mathias, Rasika

AU - Becker, Diane M

AU - Peyser, Patricia A.

AU - Smith, Jennifer A.

AU - Bielinski, Suzette J.

AU - Ridker, Paul M.

AU - Taylor, Kent D.

AU - Yao, Jie

AU - Tracy, Russell

AU - Delgado, Graciela

AU - Trompet, Stella

AU - Sattar, Naveed

AU - Jukema, J. Wouter

AU - Becker, Lewis

AU - Kardia, Sharon L.R.

AU - Rotter, Jerome I.

AU - März, Winfried

AU - Dörr, Marcus

AU - Chasman, Daniel I.

AU - Dehghan, Abbas

AU - O’Donnell, Christopher J.

AU - Smith, Nicholas L.

AU - Peters, Annette

AU - Morrison, Alanna C.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

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 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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