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• Fibrinogen, social position and risk of heart disease
  John Macleod
  Published on: 27 April 2016

• Published on: 27 April 2016

  Fibrinogen, social position and risk of heart disease

  • John Macleod, Clinical Research Fellow
  • Other Contributors:
    • George Davey Smith

  Dear Editor

  The report by Jousilahti and colleagues in the 2003 September's issue of JECH 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 obesi...

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  Dear Editor

  The report by Jousilahti and colleagues in the 2003 September's issue of JECH 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 positively associated with increased serum fibrinogen and lower social position) since 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 utilising the principle of “Mendelian randomisation” (the situation where a particular genetic polymorphism strongly 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).[4,5] In fact we discussed this evidence in our commentary on psychosocial explanations of health inequalities in last month’s edition of the JECH (fibrinogen has been shown to be “independently” associated with some psychosocial exposures leading to claims that it may mediate relations between these exposures and health).[6] Plasma fibrinogen levels are related to a polymorphism in the beta-fibrinogen gene, with presence of the “T” allele being associated with higher levels. Amongst controls of a recent large case-control study, fibrinogen increased by 0.12g/l per T allele present. Comparing cases with controls, a 0.12g/l rise in fibrinogen was associated with a relative risk of CHD of 1.20 (95% CI 1.13-1.26). 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 (0.96-1.10). Individuals whose genotype would have subjected them to chronically elevated plasma fibrinogen experienced no 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 RCTs 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 levels) and because of confounding – smoking, abstaining from alcohol, not exercising and being poor are all associated with elevated 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 easily one can 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.[6,8] 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 Mendelian randomisation can help untangle these issues. Where feasible, they should be more widely adopted in epidemiology.

  References

  (1) Jousilahti, P Salomaa, V Rasi, V Vahtera, E, T Palosuo T. Association of markers of systemic inflammation, C reactive protein, serum amyloid A, and fibrinogen, with socioeconomic status J Epidemiol Community Health 2003;57:730-733.

  (2) Wilson TW, Kaplan GA, Kauhanen J, et al. Association between plasma fibrinogen concentration and five socioeconomic indices in the Kuopio Ischemic Heart Disease Risk Factor Study. Am J Epidemiol 1993;137:292–300.

  (3) Brunner E, Davey Smith G, Marmot M, Canner R, Beksinska M, O’Brien J. Childhood social circumstances and psychosocial and behavioural factors as determinants of plasma fibrinogen. Lancet 1996;347:1008-13.

  (4) Youngman LD, Keavney BD, Palmer A et al. Plasma fibrinogen and fibrinogen genotypes in 4685 cases of myocardial infarction and in 6002 controls: test of causality by “Mendelian randomisation”. Circulation 2000;102(suppl II):31-32.

  (5) Davey Smith G, Ebrahim S. “Mendelian randomisation”: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22

  (6) Macleod J, Davey Smith G. Psychosocial factors and public health: a suitable case for treatment? J Epidemiol Community Health 2003; 57: 565- 570.

  (7) Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ 2002;325:1139 -41

  (8) Macleod J, Davey Smith G, Heslop P et al. Are the effects of psychosocial exposures attributable to confounding? Evidence from a prospective observational study on psychological stress and mortality. J Epidemiol Community Health 2001;55:878-84.

  (9) Phillips AN, Davey Smith G. Bias in relative odds estimation owing to imprecise measurement of correlated exposures. Statistics in Medicine 1992;11:953-961.

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  Conflict of Interest:
  None declared.

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