a substantial body of evidence indicates , that low - grade 
 inflammation in the vascular endothelium promotes atherogenesis 
 [ 1 , 2 ] .
this is indirectly evidenced by the fact that several 
 inflammatory markers are linked to an increased risk of 
 atherosclerosis .
high - sensitive crp ( hscrp ) has been reported to 
 associate with an increased risk of myocardial infarction , stroke , 
 sudden death from cardiac causes , and peripheral arterial disease 
 .
in addition , hscrp has been shown to predict the first 
 cardiovascular event better than low - density lipoprotein 
 cholesterol ( ldl - c ) .
recruitment of inflammatory cells 
 from the circulation and their transendothelial migration is one 
 of the earliest phases of atherogenesis .
vascular 
 endothelium expresses cellular adhesion molecules ( cams ) in 
 response to several inflammatory stimuli .
the evidence 
 for the role of cams in the pathogenesis of atherosclerosis has 
 emerged from experimental studies which have demonstrated the 
 focal expression of adhesion molecules in atherosclerotic plaques [ 46 ] . 
 
selectins and their ligands are involved in the first steps in 
 leukocyte adhesion at sites of endothelial injury as they mediate 
 the rolling and tethering of leukocytes in the 
 vascular wall [ 1 , 2 ] .
intercellular adhesion 
 molecule-1 ( icam-1 ) and vascular cell adhesion molecule-1 
 ( vcam-1 ) induce firm adhesion of inflammatory cells to the 
 vascular surface .
overall , both soluble icam-1 ( sicam-1 ) 
 and soluble vcam-1 ( svcam-1 ) have been linked to increase risk of 
 atherosclerosis [ 79 ] .
apoe is transported in lipoproteins , and it 
 regulates the hepatic uptake of remnant lipoproteins and 
 facilitates cholesterol efflux from foam cells . in 
 addition , apoe has a central role in inflammation and in mediating 
 the central nervous system response to injury [ 1113 ] . 

there are three common apoe isoforms , designated e2 , e3 , and e4 , 
 which are encoded for by distinct alleles on human chromosome 19 . 

apoe isoforms are distributed in six different phenotypes e2/2 , 
 e2/3 , e3/3 , e4/2 , e4/3 , and e4/4 .
the presence of e4 
 isoform is associated with coronary heart disease   and 
 with the early onset of alzheimer 's disease .
so far , there are sparse data on apoe polymorphism in relation to 
 the parameters of inflammation .
mnttri et al 
 showed that dyslipidemic men with e4/4 , e4/3 , and e4/2 phenotypes 
 exhibit lower crp values than men carrying other apoe phenotypes . 
 in a recent report by mrz 
 et al , carriers of apoe2 allele and apoe3/3 
 homozygotes had significantly higher crp than individuals with the 
 genotypes apoe3/4 and apoe4/4 . in dyslipidemic men and women , 

c - reactive protein has been reported to be lower in subjects with one or two copies of e4 allele than in 
 those with zero e4 allele .
paradoxically , 
 e4 allele has been associated with an 
 enhanced inflammatory reaction after cardiopulmonary bypass 
 . in line ,
transgenic mice expressing the 
 e4 allele had greater systemic and brain 
 elevations of proinflammatory cytokines than 
 e3 carriers .
we hypothesize that the apoe phenotype , as a critical component in 
 inflammatory processes , may influence the levels of inflammation 
 markers .
hdl has been demonstrated to exhibit antiinflammatory 
 properties by inhibiting cytokine induced expression of adhesion 
 molecules [ 2123 ] .
in contrast , acute inflammation process 
 may decrease hdl concentration and thus compromise its 
 antiatherogenic function [ 24 , 25 ] .
therefore we 
 studied the effects of apoe phenotype on the levels of crp 
 and scams on a sample of   finnish low - hdl families and in 
 normolipidemic subjects .
the study subjects were recruited according to the study protocol 
 as reported previously . to identify the low - hdl 
 families , first degree relatives of the probands were examined . 

the family members were coded as affected if their hdl - c levels 
 were below the 10th percentile cut - off levels . if at least two 
 affected subjects were identified in the family , all available 
 second - degree relatives and spouses were contacted and included in 
 the study .
the blood samples for the lipid and lipoprotein 
 analysis were taken at the same visit as the inflammation 
 parameters and therefore the lipid and lipoprotein values in this 
 study represent the values of that visit , and not those of the 
 screening visit .
altogether 211 low - hdl family members and 157 
 normolipidemic subjects had measures of their apoe phenotype , 
 hscrp , and svcam-1 concentrations .
the normolipidemic group comprised healthy 
 volunteers and normolipidemic spouses from the low - hdl families . 

they were required to have no signs of chd or diabetes , and no 
 lipid lowering medication .
the smoking status of the patients was 
 categorized into current smokers and nonsmokers ( including 
 exsmokers ) .
hypertension was defined as self - reported use of 
 antihypertensive drugs , systolic blood pressure  140 mmhg , or diastolic blood pressure  90 mmhg .
estrogen use was defined as any means of estrogen administration 
 ( oral contraceptives , or oral or transdermal postmenopausal 
 hormone replacement therapy ) .
serum levels of 
 sicam-1 , svcam-1 , and se - selectin were measured by using 
 commercially available monoclonal antibody - based elisas ( r & d 
 systems , minneapolis , mn , usa ) .
serum highly sensitive crp ( hscrp ) 
 was determined by a commercial kit from medix biochemica , 
 kauniainen , finland .
statistical comparisons of clinical and 
 biochemical parameters were performed with spss 11.0 for windows 
 ( spss inc . , chigaco , il , usa ) .
the frequency distribution between the groups was compared with 
 the chi - square test .
the correlation coefficients between the 
 biochemical and clinical characteristics were examined by 
 pearson 's correlation for continuous variables .
multiple 
 regression analysis was performed to determine the relative 
 contribution of different variables to hscrp and svcam-1 values . 
 in the low - hdl group ,
because the subjects in the present cohort were 
 not independent , we used the family number ( which indicates 
 belonging to a certain family ) as a random variable . 

family - number - adjusted residuals of log crp and log vcam were used 
 in the multiple regression model for low - hdl family members .
since 
 control subjects were not related , the family - number adjustment 
 was performed only in the low - hdl group .
the effects of apoe phenotype was studied by dividing subjects 
 into two subgroups ( apoe groups ) : into the e3 group , which 
 included e3/2 and e3/3 phenotypes , and into the e4 group which 
 included e4/2 , e4/3 , and e4/4 phenotypes .
table 2 shows that serum hscrp values were 
 significantly lower in the e4 than in the e3 subgroup both in the 
 low - hdl group ( p < .01 ) and in the normolipidemic group ( p < .05 ) 
 after adjustment for age , bmi , serum apoa - i , apoa - ii , apob , hdl - c , 
 ldl - c , triglycerides , smoking status , hypertension , and gender in 
 normolipidemic subjects , and after additional adjustment for 
 family number in the low - hdl group .
the concentration of serum 
 svcam-1 was significantly lower in the e4 group than in the e3 
 group in low - hdl subjects ( p < .01 ) but the significance 
 disappeared after adjustment for family number ( table 2 ) .
multiple regression analysis revealed that 
 apoe phenotype was a significant predictor of serum hscrp values both in 
 low - hdl and normolipidemic subjects ( p = .023 and p = .011 , resp ) 
 ( table 3 ) .
estrogen used was also a strong 
 predictor of serum hscrp concentration in low - hdl subjects 
 ( p = .026 ) as well as in normolpidemic subjects ( p = .036 ) 
 ( table 3 )
the major finding of the present study is that subjects presenting 
 the apoe4 allele have decreased levels of 
 serum hscrp .
this is an interesting observation , since apoe plays 
 a central role in inflammation and atherosclerosis .
apoe knockout 
 mice are especially prone to atherosclerosis   and to die 
 from lipopolysaccharide ( lps)-induced sepsis .
apoe 
 participates in cholesterol efflux , and has been observed to be 
 recycled from triglyceride - rich lipoproteins into hdl - particles 
  [ 10 , 26 ] . in mice ,
exogenous apoe injection has been 
 demonstrated to decrease the lps - induced production of 
 proinflammatory cytokines , probable by decreasing the release of 
 cytokines from macrophages , which was accompanied by reduced 
 mortality .
in addition , human crp 
 transgene expression has been shown to cause accelerated 
 atherosclerosis in apolipoprotein e - deficient mice . 

thus , according to these studies , the role of apoe in inflammation 
 and atherosclerosis may be protective . despite the importance of apoe in the inflammatory process
, only 
 few studies have linked apoe polymorphisms to inflammatory 
 parameters . in the central nervous system
, apoe4 has been reported 
 to be less effective than apoe3 or apoe2 at suppressing the 
 activation of microglia in cell culture models of brain 
 inflammation .
transgenic mice expressing the apoe4 
 allele have significantly greater systemic and brain elevations of 
 proinflammatory cytokines tnf - alpha and il-6 as compared with 
 their apoe3 counterparts . in the present study ,
the 
 hscrp concentration was significantly lower in subjects exhibiting 
 apoe4 allele than in those exhibiting other alleles . 

likewise , mnttri and associates demonstrated , in a 
 population of 179 dyslipidemic finnish men , that subjects with 
 apoe4/3 phenotype had lower mean crp concentration than those 
 with apoe3/3 phenotype .
in japanese americans , crp 
 values have been reported to be significantly higher in 
 apoe2 carriers than in apoe3 or 
 apoe4 carriers , and similar between apoe3 and 
 apoe4 carriers . in line with the japanese 
 data , german patients with or without coronary heart disease also 
 showed higher crp values in apoe2 carriers than in 
 apoe3/4 heterozygotes or in apoe4/4 homozygotes . 
 however , crp was also significantly higher in apoe3/3 homozygotes 
 than in apoe3/4 heterozygotes or in apoe4/4 homozygotes 
 .
similarly , in the cardiovascular health study 
 , crp values were lower in apoe4 
 positive than in apoe4 negative 
 individuals independently of the amount of used alcohol .
thus , the 
 present data extend these previous observations to a cohort of 
 low - hdl family members as well as to normolipidemic subjects .
the mechanisms behind low serum crp values in 
 apoe4 carriers in this study , and in 
 previous works [ 1618 , 31 ] are unclear .
since apoe 
 phenotype remained as a predictor of hscrp in multiple regression 
 model , the difference between apoe4 and apoe3 groups can not be 
 explained by confounding factors , such as estrogen use .
one 
 explanation , originally suggested by mrz and associates 
 , could be that the metabolism of crp is related to 
 mevalonate pathway . in carriers of apoe4
, 
 the mevalonate pathway may be down - regulated resulting in 
 decreased crp .
the observed low serum crp values in apoe4 
 carriers in the present study , and reportedly low crp values in 
 apoe4 carriers in previous works 
 [ 1618 , 31 ] , are perplexing findings since 
 apoe4 allele is associated to an increased 
 risk of atherosclerosis . however , in the present study , 
 the low - hdl family members within the e4 group had an atherogenic 
 lipid profile : they had higher concentrations of apob , a trend for 
 higher serum triglycerides , and lower concentration of hdl - c as 
 compared with the e3 group .
thus , the changes in lipoproteins 
 rather than changes in inflammatory parameters may explain the 
 atherogenity of apoe4 allele .
we conclude that apoe phenotype has a strong influence on 
 c - reactive protein .
apoe may be a double - faced protein having 
 different actions in lipid metabolism and inflammation .
the clinical characteristics and lipid values of the study subjects . data are expressed as means  sems . * p < .05 , p < .06 after adjustment for smoking .
the concentrations of hscrp , svcam-1 , sicam-1 , and se - selectin in low - hdl subjects and normolipidemic subjects 
 divided by apoe subgroups .
data are expressed as means  sems . * * p < .01 ; * p < .05 for the comparison with the e3 group after adjustment for age , gender , bmi , hypertension , smoking status , and lipoprotein variables ; and family number in 
 the low - hdl group . multiple regression analysis of predictors of crp values in low - hdl and normolipidemic subjects .
0.202 ( p < .001 ) for low - hdl 
 subjects and 0.326 ( p < .001 ) for normolipidemic subjects when all 
 variables are included .
the dependent variable in low - hdl family 
 members is the family number adjusted residual of log crp , and in 
 normolipidemic subjects , the dependent variable is log crp . 

 the study was aimed to compare inflammatory parameters between 
 carriers of apoe4 isoforms ( apoe4/3 , apoe4/2 , and apoe4/4 
 phenotypes ) and those of carrying apoe3 isoform without apoe4 
 isoform ( apoe3/3 phenotypes and apoe2/3 phenotypes ) . 
 the 
 concentrations of serum hscrp , svcam-1 , sicam-1 , and se - selectin 
 were measured in 211 subjects from finnish low - hdl families and in 
 157 normolipidemic subjects . 
 the subjects with apoe4 isoform had 
 lower concentrations of serum hscrp both in low - hdl family members 
 ( p < 0.05 ) and in normolipidemic subjects ( p < 0.01 ) . 
 the differences in serum crp values remained significant after 
 adjustment for age , bmi , smoking status , hypertension , gender , 
 lipoprotein variables , and family number . 
 we conclude that apoe 
 phenotype has a strong influence on serum crp values . 
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
Figures and Tables