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A genetic instrument for Mendelian randomization of fibrinogen

  • Genetic Epidemiology
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Abstract

Mendelian randomization studies on fibrinogen commonly use a single genetic variant as an instrument, but this may explain only a small proportion of the total phenotypic variance. We examined the contribution of multiple common single nucleotide polymorphisms (SNPs) and haplotypes in the entire fibrinogen gene cluster to plasma fibrinogen levels in two prospective cohorts, for use as instruments in future Mendelian randomization studies. Genotypes for 20 SNPs were determined in 2,778 middle-age (49–64 years) men from the Second-Northwick-Park-Heart Study (NPHS-II). These were replicated in 3,705 men from the Whitehall-II study (WH-II). Plasma fibrinogen levels were determined six times in NPHS-II and three times in WH-II. The minor alleles of four SNPs from the FGB gene, two from the FGA gene, and one from the FGG gene were associated with higher plasma fibrinogen levels. SNP rs1800790 (−455G > A) commonly used in Mendelian randomization studies was associated with R2 = 1.22% of the covariate adjusted residual variance in fibrinogen level. A variable selection procedure identified one additional SNP: rs2070011 (FGA) altogether explaining R2 = 1.45% of the residual variance in fibrinogen level. Using these SNPs no evidence for causality between the fibrinogen levels and coronary heart diseases was found in instrumental variables analysis. In the replication cohort, WH-II, the effects of the two SNPs on fibrinogen levels were consistent with the NPHS-II results. There is statistical evidence for several functional sites in the fibrinogen gene cluster that determine an individual’s plasma fibrinogen levels. Thus, a combination of several SNPs will provide a stronger instrument for fibrinogen Mendelian randomization studies.

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Acknowledgments

We acknowledge the contribution of the late Professor George Miller (1939–2006) who was the PI on the NPHS-II study. The British Heart Foundation support FD and SEH (PG2005/014). The NPHS-II study was supported by the Medical Research Council, the US National Institutes of Health (NHLBI 33014) and Du Pont Pharma. We also thank all the medical staff and patients who contributed to the NPHS-II study and the Office for National Statistics (NHS) Central Registry for provision of mortality data. This work on WHII was supported by the British Heart Foundation (BHF) PG/07/133/24260, RG/08/008, Dr Kumari’s and Prof. Kivimaki’s time on this manuscript was partially supported by the National Heart Lung and Blood Institute (NHLBI: HL36310. The WHII study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart, Lung, and Blood Institute (HL036310) and National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health.

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Authors and Affiliations

  1. Centre for Cardiovascular Genetics, BHF Laboratories, The Rayne Building, Department of Medicine, Royal Free and University College Medical School, 5 University St, London, WC1E 6JF, UK

    Gie Ken-Dror, Steve E. Humphries & Fotios Drenos

  2. Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London, WC1E 6BT, UK

    Meena Kumari & Mika Kivimaki

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  1. Gie Ken-Dror
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Correspondence to Steve E. Humphries.

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Ken-Dror, G., Humphries, S.E., Kumari, M. et al. A genetic instrument for Mendelian randomization of fibrinogen. Eur J Epidemiol 27, 267–279 (2012). https://doi.org/10.1007/s10654-012-9666-x

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