Article Text

PDF

Fibrinogen, social position, and risk of heart disease
  1. J Macleod1,
  2. G Davey Smith2
  1. 1Division of Primary Care, Public and Occupational Health and The Medical School Birmingham, UK
  2. 2Department of Social Medicine, University of Bristol, Bristol, UK
  1. Correspondence to:
 Dr J Macleod
 Division of Primary Care, Public and Occupational Health and The Medical School Birmingham, B15 2TT, UK; j.a.macleodbham.ac.uk

Statistics from Altmetric.com

The report by Jousilahti and colleagues adds to growing evidence of a consistent association between serum inflammatory markers—particularly fibrinogen—and social position.1–3 These authors interpret their data as suggesting that the fibrinogen-social position link is not merely a reflection of the social patterning of prevalent disease, smoking, and obesity (all of which are associated with increased serum fibrinogen and lower social position) as a strong trend of increasing fibrinogen with decreasing social status survived statistical adjustment for these covariates. Fibrinogen, they conclude, is therefore a promising candidate for the “missing link” between social position and cardiovascular health.

The authors’ reasoning implicitly accepts that fibrinogen is a cause of coronary heart disease (CHD). However, this runs contrary to recently published evidence using the principle of “Mendelian randomisation” (the situation where a particular genetic polymorphism influences exposure level of a putative disease risk factor, and should in turn be related to increased risk of disease if the risk factor is indeed a cause).45 In fact we discussed this evidence in a recent commentary on psychosocial explanations of health inequalities.6 Plasma fibrinogen concentrations are related to a polymorphism in the β-fibrinogen gene, with presence of the “T” allele being associated with higher levels. Among controls of a recent large case-control study, fibrinogen increased by 0.12 g/l per T allele present. Comparing cases with controls, a 0.12 g/l higher fibrinogen was associated with a relative risk of CHD of 1.20 (95% CI 1.13 to 1.26). If increased fibrinogen actually caused heart disease then a similar per allele relative risk of CHD should be seen. In fact the per-allele relative risk of CHD was 1.03 (0.96 to 1.10). People whose genotype would have subjected them to long term raised plasma fibrinogen experienced no substantial increased risk of heart disease, suggesting that observed associations between fibrinogen and CHD risk are not causal. This finding is in keeping with evidence from randomised controlled trials that suggests that drugs lowering fibrinogen do not decrease the risk of CHD.7

Fibrinogen probably predicts cardiovascular events because of reverse causation (atherosclerosis is an inflammatory condition and raises circulating fibrinogen concentrations) and because of confounding—smoking, abstaining from alcohol, not exercising and being poor are all associated with raised fibrinogen and themselves increase the risk—or are markers for factors that increase the risk—of cardiovascular disease.

The data presented by Jousilahti and colleagues illustrate how easy it is to misattribute causality to associations in social epidemiology. Many factors are socially patterned and thus appear as possible candidates for a causal role in the processes that generate any disease outcome that is also socially patterned.68 Demonstrating apparent statistical independence of associations between such exposures and outcomes does little to infer their causal basis as it is often likely to reflect issues of residual confounding and measurement imprecision of correlated covariates.9 Strategies such as randomised control trials and Mendelian randomisation can help untangle these issues. Where feasible, they should be more widely adopted in epidemiology.

References

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.