Atherosclerosis refers to a spontaneous vascular embolism disease, highly correlated with the levels of plasma cholesterol and low-density lipoprotein cholesterol (LDL-C). It acts as the main cause of coronary heart disease, cerebral infarction, peripheral vascular disease and other diseases. Over the past few years, numerous studies  reported that apo E gene polymorphism is associated with atherosclerotic disease, Bennet et al. suggested a linear relationship between apolipoprotein genotype and LDL-C level and coronary heart disease risk. Apolipoprotein E is recognized as a polymorphic protein, critically regulating the stable state of human cholesterol by regulating the intake of chylomicrons, significantly low density lipoproteins, medium density lipoproteins and several high density lipoproteins [21, 22]. The apo E gene has 3 alleles, i.e., ε2, ε3 and ε4, constituting a total of 6 different genotypes, including 3 homozygous types (ε2ε2, ε3ε3 and ε4ε4) and 3 heterozygous types (ε2ε4, ε3ε4 and ε2ε3). A compared with the ε3ε3 genotype, the most common genotype, the risk of coronary heart disease carrying the ε4 allele is higher, while the ε2 allele exhibits the neutral risk . Over the past few years, the inflammatory response is considered a vital factor in the development of atherosclerosis, stimulating the formation of atherosclerosis, reducing the stability of damaged atherosclerotic plaques, and forming occlusive thrombi. Alan R. Tall et al. considered that hypercholesterolemia leads to the accumulation of cholesterol in macrophages, thereby promoting inflammation.
CRP, a marker of inflammation, has been shown in multiple prospective studies to have a risk prediction effect on atherosclerotic diseases (e.g., myocardial infarction, stroke, peripheral arterial disease). Treatment with statins therapy can effectively down-regulate LDL-C and CRP levels, thereby reducing cardiovascular events and mortality . It is an independent predictor of future cardiovascular events, though the causal relationship between serum CRP levels and atherosclerotic disease remains unclear. Apo E as a lipid transport protein has been suggested to be related to immune regulation and inflammation of the disease as well [27–29]. A question is raised that whether, there are any connections between them.
In comparison with other genotypes, apo E ε4 allele carriers have relatively high levels of TC, triglycerides, and LDL , and the risk of CHD in apo E E4 isoform is also higher than others . Interestingly, in the present meta-analysis, we found that the apo E ε4 allele, as a high-risk genotype of atherosclerotic disease, has lower CRP levels than other carriers. Among the three isoforms of apo E, the CRP level of E4 is lower than that of the other two as well. As a high-risk factor for atherosclerotic disease, CRP is not positively correlated with apo E E4 genotype as expected. It is generally known that cholesterol is synthesized via the mevalonate pathway , and statins have been suggested to down-regulate CRP expression in liver cells by inhibiting the mevalonate pathway . Chasman et al.  reported that the trend for plasma levels of apo E protein with apo E allele was more similar to that for CRP. Carriers of the apo E ε4 allele are capable of absorbing cholesterol more efficiently than those of other genotypes , so their cholesterol biosynthesis is hindered. Accordingly, this study speculates that in carriers of the apo E ε4 allele, CRP levels are lowered by inhibiting mevalonate pathway, suggesting that the mechanism of apo E genotype and CRP on atherosclerotic disease are different and independent. In other words, apo E gene polymorphism shows that association with plasma CRP levels, whereas no causal relationship is identified. Since apo E and CRP are both produced by the liver, the expression of the mentioned proteins may be derived from the regulation of similar factors, whereas there is currently no evidence to prove this.
Though CRP is an independent risk factor for atherosclerosis, numerous studies [36, 37] have doubted the predictive effect of CRP on atherosclerosis. There is no causal relationship between them, and it is not conclusively evidenced that lowering CRP levels can prevent atherosclerosis. CRP is of low negative predictive value and cannot be employed to exclude diseases for its sensitivity difference. Though CRP is still recommended as a routine test for patients with atherosclerosis , its effect in guiding treatment remains controversial. Moreover, this study considers that the predicting effect of the apo E E4 genotype on the risk of atherosclerosis may be masked by low CRP levels, and adopting CRP as a biomarker to assess the risk of atherosclerosis may underestimate the risk of carriers of ε4 alleles.