IJE Advance Access originally published online on February 19, 2008
International Journal of Epidemiology 2008 37(2):299-300; doi:10.1093/ije/dyn025
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Commentary: Social class, C-reactive protein and coronary heart disease
Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK.
* Corresponding author. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. E-mail: juan.pablo-casas{at}lshtm.ac.uk
Accepted 21 January 2008
It is well known that individuals from a disadvantaged socio-economic position (SEP) are at higher risk of coronary heart disease. However as suggested more than 26 years ago by Rose and Marmot, established cardiovascular risk factors, measured in adulthood, only explain part of the association.1 This observation has lead to further research to identify other (possibly) modifiable factors that could explain the link between SEP and coronary heart disease. These could exert their effects from early life but there has been limited information on this so far.2 Gimeno et al., in this issue of IJE,3 examine C-reactive protein (CRP), a sensitive biomarker of inflammatory response, as a potential link between disadvantaged SEP and risk of coronary heart disease. Although previous findings demonstrate the existence of an association of CRP levels in adulthood with both indicators of SEP and risk of coronary heart disease,4 less is known about the period in life when the socio-economic differences in CRP concentration develop, and whether these are mainly due to the cumulative exposures to environmental factors (e.g. smoking, obesity, physical inactivity, infections) or relate to a genetic predisposition. These are the areas where the work by Gimeno et al. contributes most to current knowledge.
As shown by Gimeno et al., social inequalities in CRP levels appear to be evident only in early adulthood, perhaps suggesting that cumulative exposure to cardiovascular risk factors over early life might explain the socio-economic gradient observed in CRP levels. However, there are a few caveats to this finding that merit discussion. First, as the authors correctly point out, it is also possible that the study was underpowered to detect a similar relative difference in CRP levels by social class in earlier periods of life when absolute values of CRP are lower than in adulthood. Also, whether these findings are applicable to other populations, especially from developing countries with different social structures and often with much greater social inequalities, than those observed in this Finnish population is uncertain. Nonetheless, the current study is perhaps the first to provide such empirical evidence in developed countries.
Based on the recent proposal that genetic and/or prenatal environmental factors contribute to the association of SEP and adult mortality,5 and considering that CRP might be one of the potential mechanisms for this, it is therefore theoretically possible that the social-gradient observed in CRP is genetically determined. If that was the case, the obvious candidate gene to study is the CRP gene itself, which contains several genetic polymorphisms consistently associated with differences in CRP.6 Some of them were studied by Gimeno et al. However, the findings indicate that genotypes for different CRP polymorphisms are distributed evenly among people from different socio-economic groups, implying non-genetic factors account for the differences in CRP.
The findings by Gimeno et al. would be of even greater relevance if the causal role of CRP in the development of incident coronary heart disease was proven. Unfortunately, after more than 10 years of intense research and more than 40 prospective studies reporting an association of CRP levels with incident coronary events, there is still great uncertainty as to whether this association is cause, consequence or confounding.
A randomized controlled clinical trial of a selective intervention to reduce CRP would provide an unbiased insight into the nature of the association between long-term, low-grade elevations of CRP and the risk of later coronary events. Clinical trials in humans may become possible in due course with the recent development of a small molecule CRP inhibitor, 1,6-bis(phosphocholine)-hexane.7 An alternative and immediately applicable approach to generate randomized evidence that helps to judge the causal role of CRP on the risk of incident coronary events, minimizing the problems of confounding and bias seen in non-interventional observational analyses, is to identify a common polymorphism or haplotype in the CRP gene reliably associated with long-term differences in its circulating concentration an approach known as Mendelian randomization.8
Indeed, CRP variants that reliably index differences in CRP levels have been already identified and potential confounding demographic variables appear to be evenly distributed among genotypic groups.6,9 Provisional results of such studies to date suggest that despite very consistent associations with CRP concentration, CRP variants have not been associated with either cardiovascular risk factors, or clinical cardiovascular end-points,9 with a few exceptions.10 Nonetheless, it is now well accepted that in order to reliably exclude a causal inference of CRP on coronary heart disease risk by studying unconfounded variants of the CRP gene, several tens of thousands of coronary heart disease cases are required, making international collaboration compulsory. This has been the main drive for the establishment of a CRP Coronary Disease Genetics Collaboration (CCGC), the first prospective large-scale Mendelian randomization experiment that will provide the most comprehensive evidence to judge the causal role of CRP in incident coronary heart disease.
Until such randomized evidence on CRP is obtained, a more cautious statement is to maintain CRP in the category of ‘emerging’ but not proven risk factors for coronary heart disease. Findings such as those provided by Gimeno et al. are nonetheless important contributions to the CRP puzzle.
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I am grateful to Aroon D Hingorani for a critical reading of the manuscript.
Conflict of interest: The author is part of the joint coordinating centre (together with Professor John Danesh at Cambridge University and Dr Aroon D Hingorani at University College London) of the CRP Coronary Disease Genetics Collaboration.
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1 Rose G, Marmot M. Social class and coronary heart disease. Br Heart J (1981) 45:13–19.
2 Marmot MG, Shipley MJ, Rose G. Inequalities in death–specific explanations of a general pattern? Lancet (1984) 1:1003–6.[CrossRef][Web of Science][Medline]
3 Gimeno D, Ferrie JE, Elovainio M, et al. When do social inequalities in C-reactive protein start? A life course perspective from conception to adulthood in the Cardiovascular Risk in Young Finns Study. Int J Epidemiol (2008) 37:290–98.
4 Lawlor DA, Smith GD, Rumley A, Lowe GD, Ebrahim S. Associations of fibrinogen and C-reactive protein with prevalent and incident coronary heart disease are attenuated by adjustment for confounding factors. British Women's Heart and Health Study. Thromb Haemost (2005) 93:955–63.[Web of Science][Medline]
5 Osler M, Petersen L, Prescott E, Teasdale TW, Sørensen TI. Genetic and environmental influences on the relation between parental social class and mortality. Int J Epidemiol (2006) 35:1272–77.
6 Verzilli C, Shah T, Casas JP, et al. Bayesian meta-analysis of genetic association studies with different sets of markers. Am J Hum Genet (2008) in press.
7 Pepys MB, Hirschfield GM, Tennent GA, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature (2006) 440:1217–21.[CrossRef][Medline]
8 Hingorani A, Humphries S. Nature's randomised trials. Lancet (2005) 366:1906–8.[CrossRef][Web of Science][Medline]
9 Casas JP, Shah T, Cooper J, et al. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol (2006) 35:922–31.
10 Lange LA, Carlson CS, Hindorff LA, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA (2006) 296:2703–11.
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