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Survival related to plasma C-reactive-protein in nonagenarians is modified by apolipoprotein E genotype.

To the Editor:

In the present study, we combined 2 thoroughly studied markers of inflammation and lipid metabolism--sensitive C-reactive protein (hsCRP) and apolipoprotein E genotype (apoE)--to predict mortality in the elderly (1, 2). Plasma hsCRP concentration (1) and apoE genotype (2) are both important predictors of coronary artery disease (CAD) and stroke (1, 2). The risk of myocardial infarction in people with hsCRP concentrations in the highest third of the population range is twice that of those with hsCRP in the lowest third (1). ApoE genotype is a key regulator of lipoprotein metabolisms (2, 3), and the [epsilon]4-allele has been associated with increased plasma LDL cholesterol concentration and CAD (2, 3). These 2 factors are biologically linked; low hsCRP concentrations have been measured in apoE [epsilon]4-allele carriers, indicating that variation in plasma hsCRP concentration is partially determined by the common apoE ([epsilon]2, [epsilon]3 and [epsilon]4) gene polymorphism (3, 4).

ApoE [epsilon]4 allele carrier status has been shown to modify the predictive value of hsCRP for CAD (3). Therefore we hypothesized that apoE [epsilon]4 status may also modify the clinical value of plasma hsCRP in predicting total mortality among nonagenarians.

The present study included 291 nonagenarian volunteers who were participants in the population-based Vitality 90+ study, which included all nonagenarians born in 1909-1910 and living in the city of Tampere and its surroundings in southern Finland in 2000. At the beginning of the study, we determined apoE gene polymorphisms and hsCRP concentrations in 285 persons (67 men, 218 women) (4). Four years later, in April 2004, we extracted mortality data from the Finnish Register of Causes of Death.

As hypothesized, multinomial regression analysis revealed a statistically significant interaction between apoE [epsilon]4-allele group and hsCRP group (low/high) (P = 0.040) in relation to 4-year survival status. Therefore, we analyzed the apoE [epsilon]4-allele carriers and noncarriers separately.

Cox regression analysis showed that in noncarriers of the apoE [epsilon]4-allele, after adjustment for sex and baseline LDL cholesterol concentration, high plasma hsCRP concentrations ([greater than or equal to]3.3 mg/L, upper third) were associated with increased mortality [odds ratio (OR) 1.95, 95% confidence interval (CI) 1.39-2.73, P <0.0001] but lower plasma hsCRP concentrations (<3.3 mg/L) were not. In [epsilon]4-allele carriers no similar relationship between plasma hsCRP groups and mortality was found (OR 0.78, 95% CI 0.32-1.90, P = 0.589). The statistical power to detect the observed differences at the a level of 0.05 was >0.95 for noncarriers and <0.5 for apoE [epsilon]4-carriers. The number of deaths according to apoE genotype and hsCRP groups is shown in Table 1. In all study participants, the mean (SD) plasma hsCRP concentrations of those who did not survive were higher than for those who did survive [6.62 (15.64) vs 3.39 (8.38) mg/L, P = 0.04]. ApoE allele or genotype distributions did not differ between survivors (n = 114) and nonsurvivors (n = 171).

Our findings suggest that the relationship between plasma hsCRP concentration and mortality in Finnish nonagenarians is dependent on apoE [epsilon]4-allele carrier status.

In Finland in 2004 the main causes of death in persons older than 90 years were cardiovascular system diseases (51%) and mental/behavioral disturbances and neurological diseases (21%). Several of these diseases involve vascular pathology, in which CRP has been localized within atheromatous plaques, where it precedes and mediates monocyte recruitment (5). Moreover, in vitro studies have shown that CRP can bind to LDL, which in turn can enhance foam cell formation, stimulate tissue factor production in macrophages, and start coagulation (5). Therefore the relatively lower hsCRP concentration of apoE [epsilon]4-allele carriers (4) may lead to slower recruitment of monocytes to atheroma, decreased binding of CRP to LDL (5), and slower foam cell and atheroma formation. In the case of low plasma LDL concentrations ([epsilon]4-noncarriers) (4), high hsCRP concentration might be the rate-limiting step in the CRP-LDL complex and foam-cell formation in the arterial wall. This hypothesis is in line with findings indicating that per sons with low LDL cholesterol and high plasma hsCRP can develop CAD (1).

One limitation of the study was that data were available on all-cause mortality, but not cardiovascular mortality. The small number of participants who were [epsilon]4-allele carriers leads to low statistical power, making it difficult to rule out an effect of hsCRP in that group, and the data cannot be generalized to other age groups.

Nevertheless, our study results indicate that the prognostic value of hsCRP in predicting total mortality of Finnish nonagenarians is dependent on the apoE polymorphism.

This work was supported by grants from the Emil Aaltonen Foundation (T.L.) and Tampere University Hospital Medical Fund.

DOI: 10.1373/clinchem.2006.075002


(1.) Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:363-9.

(2.) Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622-30.

(3.) Marz W, Scharnagl H, Hoffmann MM, Boehm B0, Winkelmann BR. The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study). Eur Heart J 2004;25:210919.

(4.) Rontu R, Ojala P, Hervonen A, Goebler S, Karhunen PJ, Nikkih M, et al. Apolipoprotein E genotypes relates to plasma C-reactive protein, lipid levels and longevity in nonagenarians. Clin Endocrinol (Oxf) 2006;64:265-70.

(5.) Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001;103:1194-7.

Terho Lehtimaki, [1] * Antti Hervonen, [2] Riikka Rontu, [1] Pekka Karhunen, [3] Marja Jylha, [2] Mikko Hurme [4]

[1] Laboratory of Atherosclerosis Genetics Tampere University Hospital Centre for Laboratory Medicine Department of Clinical Chemistry University of Tampere Medical School

[2] Laboratory of Gerontology Tampere School of Public Health University of Tampere

[3] Department of Forensic Medicine University of Tampere Medical School and Tampere University Hospital Centre for Laboratory Medicine

[4] Department of Microbiology and Immunology University of Tampere Medical School and Tampere University Hospital Centre for Laboratory Medicine Tampere, Finland

* Address correspondence to this author at: Tampere University Hospital, Centre for Laboratory Medicine, Department of Clinical Chemistry, Finn-Meth 2, 3rd floor, P.O. Box 2000, 33521 Tampere, Finland. Fax 358-3-311-74168; e-mail
Table 1. The number of deaths according to apoE genotype and hsCRP
concentration during 4-year follow up.


ApoE [member of] ApoE genotype <3.3

No (a) [member of]2/[member of]2 0 (0)
 [member of]3/[member of]2 9 (21)
 [member of]3/[member of]3 66 (126)
 All 75 (147)

Yes (b) [member of]4/[member of]4 1 (1)
 [member of]4/[member of]3 26 (39)
 [member of]4/[member of]2 2 (3)
 All 30 (43)

 hsCRP-concentration, mg/L

ApoE [member of] [greater than Total
4-carriers or equal to]3.3

No (a) 1 (1) 1 (1)
 10 (16) 19 (37)
 50 (67) 116 (193)
 61 (84) 231 (136)

Yes (b) 0 (0) 1 (1)
 5 (8) 31 (47)
 1 (3) 3 (6)
 6 (11) 36 (54)

The numbers in parentheses indicate the total number of study
Statistics: (a) [x.sup.2]-test, difference between high and low
hsCRP groups in the occurrence of deaths in apoE [member of]
4-noncarriers; P = 0.001; (b) in apoE [member of]4 carriers,
P = 0.489.
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Article Details
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Title Annotation:Letters
Author:Lehtimaki, Terho; Hervonen, Antti; Rontu, Riikka; Karhunen, Pekka; Jylha, Marja; Hurme, Mikko
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Feb 1, 2007
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