A Letter to the Editor: Using C-reactive protein to suggest an alternative explanation of the findings of Simanek et al.

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Dear Editor,

The study by Simanek et al. reported that seropositivity for Cytomegalovirus (CMV) was associated with increased all-cause and CVD-related mortality after adjustment for a range of potential confounders [1]. The authors also report that the association between CMV and mortality was considerable stronger among those with a high level of C-reactive protein (CRP).

One interpretation – which seems to be advocated by the authors – is that CMV has a causal effect on mortality, possibly mediated by CRP. An alternative explanation that does not receive much attention in the paper is reverse causality: That CMV serostatus, CMV antibody levels among the infected, and CRP are markers of risk, not causal agents. While this may sound as a very speculative explanation, there are examples. A highly illustrative example of reverse causation happens to be that of CRP.

For many years, it has been known that low grade inflammation as measured by CRP was strongly predictive of a number of adverse health outcomes. Many of these earlier studies (including some cited by Simanek et al.) were very careful in describing CPR as a strong predictor, which does not necessarily make it a causal factor [2,3]. In recent year, it has been proved beyond a reasonable doubt that CRP has no causal effect on CVD and a number of other health outcomes. These recent studies have used the genetically informed design of mendelian randomization to show that CRP is a marker of morbidity, not a cause of morbidity [4–11]. These studies have not been confined to specialty journals that would have made them difficult for Simanek et al. to identify, but have been published in the most prominent journals in Medicine, including the New England Journal of Medicine, Lancet, the Journal of the American Medical Association, and the British Medical Journal.

In spite of this evidence, CPR is still studied by many (including Simanek et al.) as a potential causal agent. Given that the scientific community got the association between CRP and mortality wrong, could the same be the case for the much less studied risk factor of CMV? I think the answer must be yes. Susceptibility to CMV is known to vary considerably. However, surprisingly little is known about the causes of this susceptibility [12]. In our view, confounding from common causes of susceptibility, immune reaction once infected, and mortality may possibly explain the findings for CMV and CMV antibody titer reported here and elsewhere.

Given that CPR is a marker of risk, why does the association between CMV and the outcomes change upon stratification? Suppose that the causal relationship is such that CMV and CPR are caused by (an unobserved) mortality risk, and that CMV affects CRP levels. Given this causal structure stratification on CRP will open an otherwise closed pathway between CMV and mortality risk. Even if CMV was not affected by mortality risk, an association would be induced by stratification on CPR. There is no saying if the relationships pertaining to CMV assumed to exist under this scenario are true, but I would suggest Simanek et al. and other interested in CMV to consider such alternative explanations.

Reference List

1. Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE (2011) Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS One 6: e16103. 10.1371/journal.pone.0016103 [doi].
2. Ridker PM (2003) Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation 108: e81-e85. 10.1161/01.CIR.0000093381.57779.67 [doi];108/12/e81 [pii].
3. Tice JA, Browner W, Tracy RP, Cummings SR (2003) The relation of C-reactive protein levels to total and cardiovascular mortality in older U.S. women. Am J Med 114: 199-205. S0002934302014973 [pii].
4. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG (2008) Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 359: 1897-1908. 359/18/1897 [pii];10.1056/NEJMoa0707402 [doi].
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6. Dahl M, Vestbo J, Zacho J, Lange P, Tybjaerg-Hansen A, Nordestgaard BG (2011) C reactive protein and chronic obstructive pulmonary disease: a Mendelian randomisation approach. Thorax 66: 197-204. thx.2009.131193 [pii];10.1136/thx.2009.131193 [doi].
7. Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, Erdmann J, Braund P, Engert JC, Bennett D, Coin L, Ashby D, Tzoulaki I, Brown IJ, Mt-Isa S, McCarthy MI, Peltonen L, Freimer NB, Farrall M, Ruokonen A, Hamsten A, Lim N, Froguel P, Waterworth DM, Vollenweider P, Waeber G, Jarvelin MR, Mooser V, Scott J, Hall AS, Schunkert H, Anand SS, Collins R, Samani NJ, Watkins H, Kooner JS (2009) Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302: 37-48. 302/1/37 [pii];10.1001/jama.2009.954 [doi].
8. Marott SC, Nordestgaard BG, Zacho J, Friberg J, Jensen GB, Tybjaerg-Hansen A, Benn M (2010) Does elevated C-reactive protein increase atrial fibrillation risk? A Mendelian randomization of 47,000 individuals from the general population. J Am Coll Cardiol 56: 789-795. S0735-1097(10)02305-3 [pii];10.1016/j.jacc.2010.02.066 [doi].
9. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day IN, Palmer LJ, Hattersley AT, Ebrahim S, Lowe GD, Rumley A, Davey SG (2005) C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 366: 1954-1959. S0140-6736(05)67786-0 [pii];10.1016/S0140-6736(05)67786-0 [doi].
10. Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjaerg-Hansen A, Smith GD (2011) C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int J Obes (Lond) 35: 300-308. ijo2010137 [pii];10.1038/ijo.2010.137 [doi].
11. Wensley F, Gao P, Burgess S, Kaptoge S, Di AE, Shah T, Engert JC, Clarke R, Davey-Smith G, Nordestgaard BG, Saleheen D, Samani NJ, Sandhu M, Anand S, Pepys MB, Smeeth L, Whittaker J, Casas JP, Thompson SG, Hingorani AD, Danesh J (2011) Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 342: d548.
12. Mortensen LH, Maier AB, Slagbom PE, Pawelec G, Derhovanessian E, Petersen I, Jahn G, Westendorp RG, Christensen K (2011) Early-life environment influencing susceptibility to cytomegalovirus infection: evidence from the Leiden Longevity Study and the Longitudinal Study of Aging Danish Twins. Epidemiol Infect 1-7. S0950268811001397 [pii];10.1017/S0950268811001397 [doi].
StatusUdgivet - 2011

ID: 34335515