Annals of Clinical & Laboratory Science 39:120-133 (2009)
© 2009 Association of Clinical Scientists
Apolipoprotein E Gene Polymorphism and Gender
Genovefa Kolovou,
Dimitris Damaskos,
Katherine Anagnostopoulou and
Dennis V. Cokkinos
Cardiology Department, Onassis Cardiac Surgery Center, and Athens University Medical School, Athens, Greece
Address correspondence to Genovefa D. Kolovou, M.D., PhD., Onassis Cardiac Surgery Center, 356 Sygrou Ave, 176 74, Athens, Greece; tel 30 210 949 3520; fax 30 210 949 3336; e-mail genovefa{at}kolovou.com.
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Abstract
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Many studies have shown that the prevalence and onset of coronary heart disease (CHD) is sex-dependent. CHD prevalence is lower in women than in men at all ages. Furthermore, women’s age of CHD onset seems to be 10 yr later. This is widely attributed to the fact that men have less favorable CHD risk factors (eg, plasma lipid profile) compared to women. Mean levels of protective high density lipoprotein cholesterol are lower, while triglyceride levels are higher in men than in women. It is possible that many of the genes involved in lipid metabolism, such as Apolipoprotein (Apo) E, as well as their polymorphisms, may be expressed in a sexually dimorphic manner. The human Apo E gene is polymorphic, encoding one of 3 common epsilon (
) alleles (2, 3, 4), with the 3 allele occurring most frequently (78%) in the Caucasian population. Association studies have shown a protective effect on CHD in 2 carriers and a harmful effect in 4 carriers. However, there are conflicting results regarding such allelic effects in respect to gender. This review is focused on the gender-related influence of Apo E polymorphism in respect to plasma lipid levels and the risk of CHD. Additionally, an effort is made to determine if this relation exists and if it can be satisfactorily explained. The studies cited here demonstrate a complex, multifactorial association between these factors, in need of further corroboration in greater population samples.
Keywords: apolipoprotein E, gene polymorphism, coronary heart disease
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Introduction
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Coronary heart disease (CHD) is the leading cause of death among both men and women worldwide and has become a true pandemic that respects no border [1]. It is a disease most often prominent due to the clinical phenotypes it presents, such as angina, myocardial infarction, and sudden death. Given the severity of CHD presentations, a major research goal has been to identify asymptomatic individuals with increased risk of coronary atherosclerosis and to initiate treatment before they reach the clinical horizon.
Hypercholesterolemia is among the better studied CHD risk factors, a group that also includes gender, ethnicity, smoking, hypertension, diabetes mellitus, and diet. The prevalence of CHD in women is lower than in men at all ages [2]. Even in serious genetic entities such as familial hypercholesterolemia, the onset of cardiovascular disease is sex-dependent [3]. In general, men have less favorable heart disease risk factors compared to women. Gender appears to exert influence on the plasma lipid profile [4]. Specifically, mean levels of protective high density lipoprotein cholesterol (HDL-C) are higher, while triglyceride levels are lower in women. It has recently been proposed that many of the genes involved in lipid metabolism and their polymorphisms are expressed in a sexually dimorphic manner. One of the genes implicated as a risk factor for atherosclerosis is the Apolipoprotein (Apo) E gene.
Apo E was discovered in 1970 as a component of triglyceride-rich lipoproteins [5]. It is an amphipathic glycoprotein that mediates the distribution of lipids and cholesterol among cells and is mainly expressed in the brain and liver [6]. The human Apo E gene is polymorphic, encoding one of 3 common epsilon () alleles (2, 3, and 4), with the 3 allele occurring most frequently (78%) in the Caucasian population [6,7], producing 3 major isoforms of human Apo E (E2, E3, and E4). The association between Apo E and CHD has been addressed in epidemiological studies [8], in animal studies of Apo E knockout mice [6,9], and in Apo E3-Leiden mice [10]. Association studies have reported a protective effect in Apo E 2 carriers and a harmful effect in Apo E 4 carriers, as far as CHD is concerned [11–13]. In this paper, we survey those studies that concern the gender-related influence of Apo E polymorphism on CHD and attempt to answer if this relation exists.
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Plasma Apolipoprotein E Structure and Function
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Apo E is a 299 amino-acid protein that is synthesised and secreted primarily by hepatocytes [14]. The primary functional role of Apo E is to transport and deliver lipids mainly through the low density lipoprotein cholesterol (LDL-C) receptor pathway. A secondary proposed pathway involves the heparan sulphate proteoglycan (HSPG)/LDL-C receptor-related protein pathway [15]. Apo E acting as a ligand for these receptors [16] plays a crucial role in determining the metabolic fate of plasma lipoproteins and consequently of cholesterol [16,17], while its accumulation on the surface of lipoproteins can slow the lipolysis rate of triglycerides by lipase [18–20]. Furthermore, Apo E as a component of HDL-C influences the cholesterol influx and efflux of cells [21,22]. Plasma Apo E isoforms have two kinds of polymorphism, one genetically determined and one not. The former polymorphism is the result of three alleles [epsilon () alleles: 2, 3, and 4] at a single gene locus, that form six genotypes ranking in order of most to least common (33, 34, 23, 44, 24, 22) [23]. The 33 genotype, being the most common, is used as reference for all Apo E-related functions. The non-genetically determined polymorphism results from variable post-translational sialyation of Apo E and accounts for 10%–20% of plasma Apo E [6].
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Apo E polymorphism
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Apo E is a member of a multi-gene family, which includes Apo A-I, Apo A-II, Apo A-IV, Apo C-I, Apo C-II, and Apo C-III genes. These genes have evolved from a primordial gene through multiple partial (internal) and complete gene duplications [24]. The Apo E gene directs the synthesis of a polypeptide of 299 amino acids, which has a molecular weight of 34,145 Da [14]. The 3 allele differs from 2 by an amino acid substitution of arginine for cysteine at codon 158. The 4 differs from 3 by a substitution of arginine for cysteine at residue 112 [14,25,26].
Apo E serves as a ligand for several cell receptors and controls the removal of Apo E-(triglyceride)-rich lipoproteins by the LDL-C receptor, thereby influencing the homeostasis of cholesterol [27]. The 2 allele is associated with higher and the 4 with lower concentrations of cholesterol [27], while the various Apo E polymorphisms explain 4 to 15% of the variation in serum LDL-C [28,29]. The mechanism whereby these polymorphisms lead to different plasma LDL-C levels is not clear. It was suggested that in 2 carriers the very low density lipoprotein cholesterol (VLDL-C) particles are smaller than in 4 carriers [30], resulting in lower LDL-C levels (decreased conversion of VLDL-C to LDL-C particles). Another explanation, suggested by Weintraub et al [31], is based on the differences in the LDL-C receptor affinity among Apo E variants. In more detail, Apo E3 and E4 have the same affinity for this receptor, while E2 shows defective binding activity. Thus all lipoproteins containing 2 are slowly removed from the plasma and induce up-regulation of the liver LDL-C receptor and hence a low concentration of total plasma cholesterol (TC). On the other hand, 4 lipoprotein particles are removed faster from plasma, inducing down-regulation of the LDL-C receptor and, as a result, a higher concentration of circulating total cholesterol.
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How to Identify Apo E Isoforms and Genotype
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The 3 major isoforms of human Apo E (E2, E3, and E4) can be determined using isoelectric focusing phenotyping. The 3 isoforms have 0, 1+ and 2+ charges to account for electrophoretic differences derived from differences in amino acids sequence [27,32]. Apo E phenotyping can also be achieved using two-dimensional electrophoresis. In this case peptides are separated based on isoelectric pH differences in the first dimension and on molecular mass differences in the second dimension. This method offers both qualitative and quantitative analysis [27,33].
A faster and preferred method of Apo E phenotyping involves amplification by the polymerase chain reaction of the Apo E sequence at a genomic level and a subsequent HhaI endonuclease digestion. The DNA fragment amplified contains the polymorphic sites at amino acids 112 and 158, which yield a genotype-specific electrophoretic pattern on polyacrylamide gel when digested with HhaI [34].
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Gender Differences in Lipoprotein-Lipid Levels
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Plasma lipoprotein-lipid levels in the fasting state.
The plasma lipid profile in women is hormone-dependent. It has been documented that LDL-C, Apo B, and triglyceride levels are all higher in men than in pre-menopausal women. Women have lower hepatic activity and increased production rate of Apo A-I compared to men [35]. Furthermore, the level of Apo A-I can be increased with estrogen treatment [36–38]. Plasma TC concentration is determined by the hepatic synthesis of cholesterol, by the absorption of cholesterol from digested food, and by its clearance. The lipolysis rate, both basal and in response to food intake, is regulated by insulin. Women have higher circulating insulin concentrations and therefore greater suppression of lipolysis (suppressing effects of insulin on lipolysis in adipocytes) [39]. Although women have higher VLDL-C and triglyceride production rates, they also have greater hepatic clearance that re-esterifies more free fatty acids than men [40]. Furthermore, the VLDL-C particles secreted in men are larger [41], and hence more atherogenic [42], than those secreted in women. Also, plasma TC levels change over time differently in men and women [41].
Plasma lipoprotein-lipid levels while aging.
Plasma lipid levels increase with age in both genders [43–46]. It appears that men reach their peak TC level at about 50 yr of age, while women do so approximately 10 yr later. In elderly women, the mean TC level is higher than in elderly men; however TC and LDL-C levels begin to decrease in the last decades of life for both sexes. Many studies have indicated that the crossover of plasma cholesterol concentrations in men and women during aging can be attributed to a steeper rise of cholesterol levels in women after menopause [47], in addition to the possibility of a greater number of men with higher cholesterol dying [48]. Plasma HDL-C levels are higher in women than in men of all ages [49], while triglyceride levels rise with advancing age in both sexes [50].
Plasma lipoprotein-lipid levels in fed state.
The postprandial response to dietary fat intake is predominately determined by the fat content of a meal, although other factors, including body composition, visceral fat accumulation, physical activity, and as already mentioned insulin concentration, play roles. Increased visceral adipose tissue accumulation has been reported in men compared to women [51,52], which may lead to a higher plasma triglyceride concentration after fatloading in men. Couillard et al [53] found that despite having similar levels of total body fat in kilograms, men are characterized by an increased abdominal fat accumulation in relation to women. However, no difference in postprandial lipemia was found between men and women matched for visceral adipose tissue accumulation [53]. Many studies have found significant gender differences in postprandial triglyceride response to a fat-loading meal [53–57]. Plasma triglyceride levels peaked later during the postprandial period in men, suggesting impaired postprandial clearance. The explanation to this clearance delay is probably twofold: (a) an elevated fasting triglyceride level in men leads to saturation of lipoprotein lipase capacity and hence a clearance delay of chylomicron remnants, and (b) in men there is a progressive increase in plasma free fatty acid levels after a fatty meal, whereas in women plasma free fatty acid concentrations at the end of the postprandial period are close to the fasting levels (due to greater hepatic clearance and re-esterification of more free fatty acids). Moreover, Kovár et al [58] in a study comparing young men and women found that the latter adapt better to a fatty meal with respect to postprandial lipemia [58]. It is possible that what we observe during the fasting state is a result of abnormal postprandial lipemia; men are characterized by an overall less favorable plasma lipid profile, having higher triglyceride and lower HDL-C levels [35]. Taking into account the fact that the main determinant of postprandial lipemia is fasting triglyceride level [59] and that this increases with age [47,50], both men and women display a higher magnitude of postprandial lipemia as they age. Specifically, women seem to lose their normal response to a fatty meal after menopause [60].
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Gender Differences in Lipoprotein-Lipid Levels Determined by Apo E Gene Polymorphism
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Among populations, the 6 common Apo E genotypes explain about 2%–5% of the inter-individual variation in plasma TC levels and about 11%–20% of the variation in plasma Apo E concentrations [61–64]. Frikke-Schmidt et al [61] reported a significant stepwise increase as a function of genotype (22, to 32, to 42, to 33, to 43, to 44) and alleles (2, to 3, to 4) in TC. Briefly, the 2 allele reduced TC up to 30 mg/dl in women and 15 mg/dl in men. The 4 allele increased TC up to 11 mg/dl in women and 15 mg/dl in men. The absolute increase from 22 to 44 for age-adjusted levels of TC was 40 mg/dl in women and 30 mg/dl in men. Boerwinkle and Utermann [65] reported that the average effect of the 2 allele is to raise Apo E levels by 0.95 mg/dl, whereas the average effect of the 4 allele is to lower Apo E levels by 0.19 mg/dl. Normal levels of Apo E concentration are approximately 5.2±1.2 mg/dl. The 2 allele increases Apo E plasma levels by 26%, whereas 4 decreases them by 18%.
Many studies have documented that, on average, subjects with the 4 allele have higher while subjects with the 2 allele have lower Apo B, TC, and LDL-C levels, independent of gender [66–69]. Compared to 3, the 4 allele is associated with increased production and decreased catabolism of LDL-C particles [23]. The opposite tendency is observed for 2 allele carriers; however, they tend to have higher triglyceride levels [13]. Wilson et al [13] in a community-based sample of men (n = 1034) and women (n = 916) aged 40 to 77 yr, found that in comparison with the 3 allele, the 4 allele was associated with elevated LDL-C values (
160 mg/dl) in women, the 2 and 4 alleles were associated with moderately elevated triglyceride values (250 mg/dl) in men, and the 2 allele was associated with severely elevated triglyceride values (500 mg/dl) in men. The effect of the Apo E gene polymorphism on the absorption and clearance of dietary fat has been evaluated and it was found that clearance of postprandial particles is delayed in carriers of the 2 allele, compared to 4 allele carriers [31]. This may be further supported by the recent discovery of a polymorphism (–219G/T) located in the Apo E gene promoter region, which determines the level of gene expression [70,71].
Quantitative changes in gene expression could also play an important role in postprandial state variability [70]. The 4 allele is associated with a reduced binding of triglyceride-rich lipoproteins (chylomicron, VLDL-C, and their remnants) to the LDL-C receptor in men, thus leading to lipoprotein-lipid abnormalities; this could be one of the reasons explaining the more atherogenic lipid profile in men [72,73]. No significant effects of Apo E polymorphism on serum lipid levels were observed in a population of women (wide age range) selected for health [17,74]. On the contrary, in a population of women selected for menopausal status, an increase in LDL-C levels of 7.1 mg/dl was observed in women with the 4 allele. In those women, 5.0% of the LDL-C level variance was explained by Apo E polymorphism [75]. Furthermore, in the WISE (Women’s Ischemia Syndrome Evaluation) study, the 4 allele showed a significant association with increased plasma TC and LDL-C in women (Chi-square = 8.04; p = 0.0046). Additionally, in Caucasian subjects, the frequency of 4 carriers (34 and 44 genotypes) was significantly higher in the CHD group with 20% stenosis compared with the CHD group with <20% stenosis (31.3% vs 19.2%; p = 0.025) with an adjusted odds ratio (OR) of 2.40 [95% Confidence Interval (CI): 1.47–3.93; p = 0.0005] [76]. According to a study conducted by Mahley et al [77], the frequency of the 2 allele in Turkish women increased with HDL-C levels [1.5%, 5.5%, and 10%, in low (20–39 mg/dl), medium (40–49 mg/dl), and high (50–75 mg/dl) HDL-C subgroups, respectively]. Schaefer et al [75] reported that TC and LDL-C concentrations were higher (12.7% and 19.7%, respectively) in post-menopausal women with the 34 genotype compared to postmenopausal women of the 23 genotype. Moreover, the pre-menopausal women had similar TC and LDL-C values across all 3 Apo E isoforms, a finding in support of estrogen status and Apo E alleles jointly affecting plasma lipid levels.
Somekawa and Wakabayashi [78] examined the association of Apo E polymorphism and lipid profile in 3 groups of post-menopausal women. Specifically, the LDL-C/HDL-C ratio and Apo B/Apo A-I ratio were calculated to determine the risk of atherosclerosis before and 6 mo after the initiation of hormone replacement treatment (HRT) in 3 groups of patients (2, 3, and 4). The LDL-C/HDL-C ratio was improved from 2.18 before HRT to 1.58 after HRT in group 2; from 2.26 to 1.92 in group 3, and from 2.57 to 2.1 in group 4. The Apo B/Apo A-I ratio changed from 0.67 before HRT to 0.57 after HRT in group 2; from 0.74 to 0.66 in group 3, and from 0.82 to 0.68 in group 4. They concluded that women with the 4 allele had the highest, while women with the 2 the lowest, risk of CHD and suggested that in women with the 4 allele HRT should be recommended. Garry et al [79] further supported considering Apo E genotypes in treating post-menopausal women with HRT to potentially reduce CHD risk. They compared TC, triglyceride, and lipoprotein (LDLC and HDL-C) concentrations in 66 postmenopausal women receiving HRT with 174 postmenopausal women not receiving HRT, controlling for Apo E genotypes divided into 3 groups [2 (23), 3 (33), and 4 (34 + 44)] and determined CHD risk. Women with the 2 allele had the lowest risk for CHD (lowest TC and LDL-C and highest HDL-C), while women with the 4 allele had the highest risk for CHD (highest TC and LDL-C and lowest HDL-C). They also found that HRT produced a significant increase in triglyceride concentrations (~50%) in women with the 2 allele, but had a reducing effect on triglycerides (~17%) in women with the 4 allele. The authors concluded that Apo E genotypes have a differential effect on serum lipids and lipoproteins in post-menopausal women receiving HRT. Additionally, they concluded that plasma triglyceride concentrations of women in the 2 group receiving HRT may need to be monitored more closely than those in the 3 or 4 groups and finally, that 4 women should probably be targeted for HRT.
In the European Atherosclerosis Research Study [80], the 2 allele was associated with higher plasma HDL-C levels (3.1 mg/dl) and lower TC levels (–12 mg/dl) in women compared to men (population-adjusted OR by reference to phenotype 33 was estimated to be 0.23, 0.61, 0.78, 1.16, and 1.33 for 22, 32, 42, 43, and 44, respectively). Combined data for men and women from this study showed an association of the 2 allele with a 3 mg/dl increase in HDL-C levels. Various clinical studies have reported that Apo E levels tend to be highest in those with the 2 allele, intermediate in those with 3, and lowest in those with 4 [65,81, 82], although plasma Apo E concentration levels among CHD patients have been reported to be higher [83], lower [84], or no different [85,86] from those in control subjects, respectively.
In conclusion, in both men and women, as indicated by various studies (Table 1
), the 4 allele is associated with a less favorable lipid profile and an increased CHD risk, while 2 has the opposite effects. Such association seems to be stronger in women than in men and even stronger in women after menopause. However, the exact contribution of the Apo E polymorphism to CHD remains unclear.
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Gender and Apo E Gene Polymorphism According to Age
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Studies suggest that there is a greater effect of Apo E polymorphism on plasma TC, LDL-C, and Apo B levels in children of both sexes with birth weight in the lower tertile, compared to those with birth weight in higher tertiles [87,88]. Isasi et al indicated that the presence of the 2 allele (22, 23) is associated in children with a favorable plasma lipid profile characterized by increased HDL-C (17%, p = 0.001) and decreased LDL-C levels (17%, p = 0.05), increased mean HDL-C particle size (9.5 ± 0.4 vs. 9.3 ± 0.4 nm; p = 0.01), and higher levels of the large, anti-atherogenic HDL-C subpopulation (mean levels 32.8 ± 9.9 vs 27.6 ± 8.2 mg/dl, respectively; p = 0.001) compared to their 33 counterparts. The authors suggested that 2 allele is associated in children with an anti-atherogenic effect, and that the Apo E gene exerts effects, at least in childhood, beyond those reported in adults for LDL-C [89]. These children were studied at an age when sex hormones and environmental or life-style factors typical of adult age (stress, alcohol, tobacco, etc.) are not present and thus, do not complicate the effect of Apo E genotype on plasma lipids. On the other hand, Choi et al [90] studied the frequency of Apo E alleles in 103 centenarians with dementia (13 men and 90 women) and compared them with 6435 healthy adults (5008 men and 1427 women) of mean age 51±8 yr. The frequency of various genotypes and alleles of the Apo E genes of the centenarians were not significantly different from those of the control groups. Reaching an opposite conclusion, Schachter et al [91] showed that the 4 allele was significantly less frequent in centenarians than in controls (5.2% vs 11.2%, p <0.001), while the frequency of the 2 allele was significantly increased (12.8% vs 6.8%, p <0.01). Odds ratios, a measure of the relative chance of becoming a centenarian between subjects with or without a given allele, were 2 and 0.43 for the 2 and the 4 alleles, respectively. Similar results were found by Lewis and Brunner [92] when they reviewed 15 cross-sectional studies related to Apo E polymorphisms and longevity, showing that higher relative 2 frequencies and lower relative 4 allele frequencies were observed in elderly vs younger populations. Odds ratios in elderly vs control populations ranged from 0.56 (95% CI 0.23–1.39) to 2.44 (95% CI 1.18–5.06) for the presence of the 2 allele, and 0.32 (95% CI 0.10–1.01) to 2.12 (95% CI 0.79–5.66) for the presence of the 4 allele. The summary effect estimate was 1.34 (95% CI 1.19–1.35) for the presence of the 2 allele and 0.54 (95% CI 0.46–0.63) for the presence of the 4 allele in elderly vs younger individuals. Frisoni et al [93] studied 179 centenarians living in Finland (28 men and 151 women) and found that the percentages of 2 carriers in persons aged 100 to 101, 102 to 103, and 104 yr and older were 9%, 21%, and 25% (gender-adjusted for trend, p = 0.01), respectively. This effect was particularly strong in women: 8%, 18%, and 28%, respectively. Women aged 102 to 103 yr were 2.6 times more likely to carry the 2 allele, while those aged 104 yr and older were 4.4 times more likely, compared to those aged 100 to 101 yr (the 95% CI for this OR did not include 1, indicating statistical significance). Finally, Rosvall et al [94] showed an increased mortality-risk of 22% among 1094 individuals of 75 yr of age with the 4 allele; whereas a 28% decreased mortality-risk was detected in those with 2 allele compared to those with 33 genotype. The authors found that both effects of the 4 and 2 alleles were strongly modified by gender. Specifically, a 49% elevated risk of death was related to the 4 allele only in men, while a 36% decreased mortality-risk related to the 2 allele was seen in women (Relative Risks [RR] of mortality in relation to Apo E genotype for men were: 23 1.07 (95% CI 0.73–1.57), any 4 1.48 (95% CI 1.11–1.98); for women were: 23 0.63 (95% CI 0.50–0.79), any 4 1.13 (95% CI 0.96–1.33). These findings suggest different roles for the Apo E alleles in survival by gender in old age.
Taking the above studies into account (Table 2) the effect of Apo E polymorphism appears to be influenced by age. The 2 allele is associated with longevity in both sexes and its frequency increases with age. This effect seems to be stronger in women. On the contrary, the 4 allele is linked to increased mortality in the elderly, especially in men.
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Gender Relationship of CHD to Apo E Polymorphism
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The 2 allele.
The effect of Apo E polymorphism on CHD is difficult to evaluate and has been the subject of many studies (Table 3), since the frequency of Apo E alleles varies among different populations and there is ethnic variation to consider. As an example, data from Asian [95–98] and Caucasian populations [99] presented a wide range of 2 frequency. In healthy subjects from Taiwan the frequency of the 2 allele was 1.7% [100]. In contrast, Southern European populations like the Italians [101] and the French [102] had a significantly higher percentage of the 2 allele (7.3% and 7.9%, respectively). The estimated 2 allele frequency evaluated by our group in the Greek healthy population [103] was similar to the average Caucasian value (8.1%) [99]. Angiographic data from 9 observational studies suggest that 4 is associated with CHD in a similar way between men and women with an OR of 0.76 (95% CI 0.55–1.05) for 2 and an OR of 1.11 (95% CI 0.88–1.40) for 4 [104]. Comparable results were found in a meta-analysis of 48 studies, where carriers of the 4 allele had a 42% higher risk for CHD (OR of 1.42 [95% CI 1.26–1.61]) compared to 33 individuals. The 2 allele had no significant association with CHD risk (OR of 0.98 [95% CI 0.66–1.46]), even when data for each sex were analyzed separately [8]. On the other hand, our data show that the 2 allele was less frequent in Greek patients with a myocardial infarction, suggesting that the 2 allele may have a protective role against CHD (Chi-square = 18.9, d
= 4, p = 0.002) [103]. Also, in African-American, Chinese, Japanese, and Korean populations, 2 allele is associated with 5%–10% lower mortality in general than 33 genotype [105]. Frikke-Schmidt et al [73] in a study comparing 9,241 healthy men and women with 940 CHD patients, reported that the 32 genotype is protective vs 33 in women but not in men, while 43 and 44 vs 33 increased the risk of CHD in men, but not in women. After adjustments for age and other conventional cardiovascular risk factors, the equivalent ORs were for 32 women 0.38 (95% CI 0.18–0.79), for 34 men 1.35 (95% CI 1.02–1.78), and for 44 men 1.58 (95% CI 0.80–3.08). The difference between being an 32 woman and an 34 or 44 man was striking, amounting to up to a 4-fold increase in risk of CHD in men. Lahoz et al [106] examined the Framingham (Massachusetts) study population to demonstrate that, after adjustment for non-lipid risk factors, the relative odds for cardiovascular disease in the group of 2 men was 1.79 (p = 0.0098) and in the group of 4 men was 1.63 (p = 0.0086) when compared with the group 3; while in the group of 4 women it was 1.56 (p = 0.054). These results are contrary to our study where we compared the frequency of Apo E alleles in matched CHD men and women and found no difference [107].
There is still no clear conclusion on the exact gender-influence of Apo E polymorphism on CHD risk. Such influence may be ethnic-related rather than universal, which may explain the discrepancies among the various studies.
The 3 allele.
In all populations the 3 allele is the most frequent, ranging from 50% to 90%. The 3 allele appears to be the ‘normal’ allele for all known functions and for that reason the functions of the other alleles are compared to it.
The 4 allele.
The 4 allele is less prevalent in Eastern European populations [108] compared to most Northern European populations [109]; for example, 24.4% in Finland [110] and 20.3% in Sweden [111], where the 4 allele may in part account for the higher CHD mortality rates. Among the healthy group of our previous report [103], 4 allele frequency was 10.2%. The estimated odds for CHD associated with the 4 allele appear to be greater than those for any other known genetic lipid abnormality [11], while the association of the 4 allele with CHD remains significant in women and both sexes combined, after adjustment for traditional coronary risk factors and lipids. In addition, the 4 allele is associated with CHD in high-risk women (OR of 2.4 (95% CI 1.3–4.6), p = 0.0049) [112] and Australian men 40 yr of age, homozygous for the 4 allele (representing a 16-fold increase in prevalence compared to controls) [113]. Further, the 4 allele was found to be a strong independent predictor of coronary events in men, but not in women, by both Scuteri et al [72] and Frikke-Schmidt et al [73]. Scuteri et al [72] observed in men RR = 2.9 (95% CI 1.8–4.5), p <0.0001) [72]; Frikke-Schmidt et al [73] observed in men OR for 34 = 1.35 (95% CI 1.02–1.78) and for 44 1.58 (95% CI 0.80–3.08). In the WISE study, a significant association of the 4 allele with mild/significant (>20/50%) stenosis of the coronary arteries, compared to normal/minimal (<20%) stenosis, was found in women. The 4 allele was also found to be significantly correlated with an increase in vessel disease number [76]. Information from a meta-analysis of 9 studies for the 4 allele suggests an association of higher relative odds for CHD among men, women, and both sexes combined. The RR of 1.38 (95% CI 1.22–1.57) for men indicates that the risk associated with the 4 allele (24, 34, or 44) is 38% higher than in 33 men [104]. In another meta-analysis of 48 studies, carriers of the 4 allele had a 42% higher risk for CHD compared to individuals with the 33 genotype [8]. There is evident heterogeneity in the results of various studies: Utermann et al [114] suggested a decrease; the studies of Cumming and Robertson [115], Lenzen et al [116], and Yamamura et al [117] showed a non-significant increase; and the reports of Luc et al [118], Wilson et al [13], Stengard et al [119], Eto et al [120], and Eichner et al [121] demonstrated a significant increase.
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Conclusions
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Studies of the influence of Apo E polymorphism and gender on CHD indicate that no single factor can explain the observed relationships satisfactorily. The net effect is multifactorial in nature. There is a need for further corroboration using focused study design on larger population samples, with attention to avoid interpreting weak relationships of great variation as clinically important.
Apo E genotypes explain about 2%–5% of the inter-individual variation in plasma TC levels and 11%–20% of the variation in plasma Apo E concentration. Many studies document that, on average, subjects with the 4 allele have higher, while subjects with the 2 allele have lower, Apo B, total, and LDL-C values, independent of gender.
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References
|
|---|
- MacKay J, Mensah GA: The Atlas of Heart Disease and Stroke. World Health Organization, Geneva, 2004.
- Khaw KT. Epidemiology of coronary heart disease in women. Heart 2006;92 Suppl 3:iii2–4.[Free Full Text]
- Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt SC. Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2001;87:547–553.[Medline]
- Godsland IF, Wynn V, Crook D, Miller NE. Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions. Am Heart J 1987;114:1467–1503.[Medline]
- Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622–630.[Abstract/Free Full Text]
- Mahley RW, Rall SC, Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 2000;1:507–537.[Medline]
- Hallman DM, Boerwinkle E, Saha N, Sandholzer C, Menzel HJ, Csazar A, Utermann G. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Hum Genet 1991;49:338–349.[Medline]
- Song Y, Stampfer MJ, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med 2004;141:137–147.[Abstract/Free Full Text]
- Fazio S, Linton MF. Interplay between apolipoprotein E and scavenger receptor class B type I controls coronary atherosclerosis and lifespan in the mouse. Circulation 2005; 111:3349–3351.[Free Full Text]
- Rezaee F, Gijbels MJ, Offerman EH, van der Linden M, De Maat MP, Verheijen JH. Overexpression of fibrinogen in ApoE*3-Leiden transgenic mice does not influence the progression of diet-induced atherosclerosis. Thromb Haemost 2002;88:329–334.[Medline]
- Davignon J, Cohn JS, Mabile L, Bernier L. Apolipoprotein E and atherosclerosis: insight from animal and human studies. Clin Chim Acta 1999;286:115–143.[Medline]
- Kardia SL, Haviland MB, Ferrell RE, Sing CF. The relationship between risk factor levels and presence of coronary artery calcification is dependent on apolipoprotein E genotype. Arterioscler Thromb Vasc Biol 1999;19:427–435.[Abstract/Free Full Text]
- Wilson PW, Myers RH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study. JAMA 1994;272:1666–1671.[Abstract/Free Full Text]
- Rall SC Jr, Weisgraber KH, Mahley RW. Human apolipoprotein E. The complete amino acid sequence. J Biol Chem 1982;257:4171–4178.[Free Full Text]
- Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res 1999;40:1–16.[Abstract/Free Full Text]
- Taira K, Bujo H, Hirayama S, Yamazaki H, Kanaki T, Takahashi K, Ishii I, Miida T, Schneider WJ, Saito Y. LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro. Arterioscler Thromb Vasc Biol 2001;21:1501–1506.[Abstract/Free Full Text]
- Xhignesse M, Lussier-Cacan S, Sing CF, Kessling AM, Davignon J. Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health. Arterioscler Thromb 1991;11:1100–1110.[Abstract/Free Full Text]
- Huang Y, Liu XQ, Rall SC Jr, Mahley RW. Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins. J Biol Chem 1998;273:17483–17490.[Abstract/Free Full Text]
- Huang Y, Liu XQ, Rall SC Jr, Taylor JM, von Eckardstein A, Assmann G, Mahley RW. Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem 1998;273:26388–26393.[Abstract/Free Full Text]
- Rensen PC, van Berkel TJ. Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem 1996;271:14791–14799.[Abstract/Free Full Text]
- Huang Y, von Eckardstein A, Wu S, Maeda N, Assmann G. A plasma lipoprotein containing only apolipoprotein E and with gamma mobility on electrophoresis releases cholesterol from cells. PNAS USA 1994;91:1834–1838.[Abstract/Free Full Text]
- Hui DY, Harmony JA. Inhibition of Ca2+ accumulation in mitogen-activated lymphocytes: role of membrane-bound plasma lipoproteins. PNAS USA 1980;77:4764–4768.[Abstract/Free Full Text]
- Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 1988;8:1–21.[Abstract/Free Full Text]
- Luo CC, Li WH, Moore MN, Chan L. Structure and evolution of the apolipoprotein multigene family. J Mol Biol 1986;187: 325–340.[Medline]
- Scott J, Knott TJ, Shaw DJ, Brook JD. Localization of genes encoding apolipoproteins CI, CII, and E to the p13----cen region of human chromosome 19. Hum Genet 1985;71:144–146.[Medline]
- Weisgraber KH, Rall SC Jr, Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem 1981;256:9077–9083.[Free Full Text]
- Siest G, Pillot T, Regis-Bailly A, Leininger-Muller B, Steinmetz J, Galteau MM, Visvikis S. Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem 1995;41:1068–1086.[Abstract/Free Full Text]
- Hoffmann MM, Scharnagl H, Koster W, Winkler K, Wieland H, Marz W. Apolipoprotein E1 Baden (Arg(180)-->Cys). A new apolipoprotein E variant associated with hypertriglyceridemia. Clin Chim Acta 2001;303:41–48.[Medline]
- Gomez-Coronado D, Alvarez JJ, Entrala A, Olmos JM, Herrera E, Lasuncion MA. Apolipoprotein E polymorphism in men and women from a Spanish population: allele frequencies and influence on plasma lipids and apolipoproteins. Atherosclerosis 1999;147:167–176.[Medline]
- Bioletto S, Fontana P, Darioli R, James RW. Apolipoprotein E polymorphism and the distribution profile of very low density lipoproteins; an influence of the E4 allele on large (Sf > 60) particles. Atherosclerosis 1998;138:207–215.[Medline]
- Weintraub MS, Eisenberg S, Breslow JL. Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E. J Clin Invest 1987;80:1571–1577.[Medline]
- Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR, Blum C. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res 1982;23:911–914.[Medline]
- Boerwinkle E, Visvikis S, Welsh D, Steinmetz J, Hanash SM, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals. Am J Med Genet 1987;27:567–582.[Medline]
- Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31:545–548.[Abstract]
- Li Z, McNamara JR, Fruchart JC, Luc G, Bard JM, Ordovas JM, Wilson PW, Schaefer EJ. Effects of gender and menopausal status on plasma lipoprotein subspecies and particle sizes. J Lipid Res 1996;37:1886–1896.[Abstract]
- Schaefer EJ, Zech LA, Jenkins LL, Bronzert TJ, Rubalcaba EA, Lindgren FT, Aamodt RL, Brewer HB Jr. Human apolipoprotein A-I and A-II metabolism. J Lipid Res 1982;23:850–862.[Abstract]
- Schaefer EJ, Foster DM, Zech LA, Lindgren FT, Brewer HB Jr, Levy RI. The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females. J Clin Endocrinol Metab 1983;57:262–267.[Abstract/Free Full Text]
- Brinton EA. Oral estrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate. Arterioscler Thromb Vasc Biol 1996;16:431–440.[Abstract/Free Full Text]
- Williams CM. Lipid metabolism in women. Proc Nutr Soc 2004;63:153–160.[Medline]
- Mittendorfer B, Fields DA, Klein S. Excess body fat in men decreases plasma fatty acid availability and oxidation during endurance exercise. Am J Physiol Endocrinol Metab 2004;286: E354–362.[Abstract/Free Full Text]
- Freedman DS, Otvos JD, Jeyarajah EJ, Shalaurova I, Cupples LA, Parise H, D’Agostino RB, Wilson PW, Schaefer EJ. Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: the Framingham Study. Clin Chem 2004;50:1189–1200.[Abstract/Free Full Text]
- Freedman DS, Otvos JD, Jeyarajah EJ, Barboriak JJ, Anderson AJ, Walker JA. Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. Arterioscler Thromb Vasc Biol 1998;18:1046–1053.[Abstract/Free Full Text]
- Abbott RD, Garrison RJ, Wilson PW, Epstein FH, Castelli WP, Feinleib M, LaRue C. Joint distribution of lipoprotein cholesterol classes. The Framingham study. Arteriosclerosis 1983;3:260–272.[Abstract/Free Full Text]
- Connor SL, Connor WE, Sexton G, Calvin L, Bacon S. The effects of age, body weight and family relationships on plasma lipoproteins and lipids in men, women and children of randomly selected families. Circulation 1982;65:1290–1298.[Abstract/Free Full Text]
- Kottke BA, Moll PP, Michels VV, Weidman WH. Levels of lipids, lipoproteins, and apolipoproteins in a defined population. Mayo Clin Proc 1991;66:1198–1208.[Medline]
- Kritchevsky D. How aging affects cholesterol metabolism. Postgrad Med 1978;63:133–136,138.[Medline]
- Kolovou GD, Bilianou HG. Influence of aging and menopause on lipids and lipoproteins in women. Angiology 2008;59(2 Suppl):54S–57S.[Medline]
- Williams EL, Winkleby MA, Fortmann SP. Changes in coronary heart disease risk factors in the 1980s: evidence of a male-female crossover effect with age. Am J Epidemiol 1993; 137:1056–1067.[Abstract/Free Full Text]
- Johnson CL, Rifkind BM, Sempos CT, Carroll MD, Bachorik PS, Briefel RR, Gordon DJ, Burt VL, Brown CD, Lippel K, et al. Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 1993;269:3002–3008.[Abstract/Free Full Text]
- Hasegawa T, Nakasato Y, Sasaki M. Factor analysis of lifestylerelated factors in 12,525 urban Japanese subjects. J Atheroscler Thromb 2005;12:29–34.[Medline]
- Lemieux S, Despres JP. Metabolic complications of visceral obesity: contribution to the aetiology of type 2 diabetes and implications for prevention and treatment. Diabetes Metab 1994;20:375–393.
- Lemieux S, Despres JP, Moorjani S, Nadeau A, Theriault G, Prud’homme D, Tremblay A, Bouchard C, Lupien PJ. Are gender differences in cardiovascular disease risk factors explained by the level of visceral adipose tissue? Diabetologia 1994;37:757–764.[Medline]
- Couillard C, Bergeron N, Prud’homme D, Bergeron J, Tremblay A, Bouchard C, Mauriege P, Despres JP. Gender difference in postprandial lipemia : importance of visceral adipose tissue accumulation. Arterioscler Thromb Vasc Biol 1999;19:2448–2455.[Abstract/Free Full Text]
- Kolovou GD, Anagnostopoulou KK, Pavlidis AN, Salpea KD, Iraklianou SA, Tsarpalis K, Damaskos DS, Manolis A, Cokkinos DV. Postprandial lipemia in men with metabolic syndrome, hypertensives and healthy subjects. Lipids Health Dis 2005;4:21.[Medline]
- Kolovou GD, Anagnostopoulou KK, Pilatis N, Kafaltis N, Sorodila K, Psarros E, Cokkinos DV. Low fasting low high-density lipoprotein and postprandial lipemia. Lipids Health Dis 2004;3:18.[Medline]
- Cohn JS, McNamara JR, Cohn SD, Ordovas JM, Schaefer EJ. Plasma apolipoprotein changes in the triglyceride-rich lipoprotein fraction of human subjects fed a fat-rich meal. J Lipid Res 1988;29:925–936.[Abstract]
- Georgopoulos A, Rosengard AM. Abnormalities in the metabolism of postprandial and fasting triglyceride-rich lipoprotein subfractions in normal and insulin-dependent diabetic subjects: effects of sex. Metabolism 1989;38:781–789.[Medline]
- Kovar J, Poledne R. Sex differences in the response of postprandial lipemia to a change from a low-fat low-cholesterol diet to a high-fat high-cholesterol diet. Physiol Res 2000;49:233–239.[Medline]
- Kolovou GD, Daskalova D, Iraklianou SA, Adamopoulou EN, Pilatis ND, Hatzigeorgiou GC, Cokkinos DV. Postprandial lipemia in hypertension. J Am Coll Nutr 2003;22:80–87.[Abstract/Free Full Text]
- Kolovou GD, Anagnostopoulou KK, Pilatis ND, Giannopoulou M, Hoursalas IS, Pavlidis AN, Adamopoulou E, Valaora AI, Mikhailidis DP, Cokkinos DV. The influence of natural menopause on postprandial lipemia in heterozygotes for familial hypercholesterolemia. J Womens Health 2004;13:1119–1126.
- Frikke-Schmidt R, Nordestgaard BG, Agerholm-Larsen B, Schnohr P, Tybjaerg-Hansen A. Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype. J Lipid Res 2000;41:1812–1822.[Abstract/Free Full Text]
- Kamboh MI, Bunker CH, Aston CE, Nestlerode CS, McAllister AE, Ukoli FA. Genetic association of five apolipoprotein polymorphisms with serum lipoprotein-lipid levels in African blacks. Genet Epidemiol 1999;16:205–222.[Medline]
- Kaprio J, Ferrell RE, Kottke BA, Kamboh MI, Sing CF. Effects of polymorphisms in apolipoproteins E, A-IV, and H on quantitative traits related to risk for cardiovascular disease. Arterioscler Thromb 1991;11:1330–1348.[Abstract/Free Full Text]
- Stengard JH, Clark AG, Weiss KM, Kardia S, Nickerson DA, Salomaa V, Ehnholm C, Boerwinkle E, Sing CF. Contributions of 18 additional DNA sequence variations in the gene encoding apolipoprotein E to explaining variation in quantitative measures of lipid metabolism. Am J Hum Genet 2002;71:501–517.[Medline]
- Boerwinkle E, Utermann G. Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Am J Hum Genet 1988;42:104–112.[Medline]
- Lussier-Cacan S, Bolduc A, Xhignesse M, Niyonsenga T, Connelly PW, Sing CF. Impact of age and body size on inter-individual variation in measures of lipid metabolism: influence of gender and apolipoprotein E genotype. Clin Genet 2000;57:35–47.[Medline]
- Morbois-Trabut L, Chabrolle C, Garrigue MA, Lasfargues G, Lecomte P. Apolipoprotein E genotype and plasma lipid levels in Caucasian diabetic patients. Diabetes Metab 2006;32:270–275.[Medline]
- Leon AS, Togashi K, Rankinen T, Despres JP, Rao DC, Skinner JS, Wilmore JH, Bouchard C. Association of apolipoprotein E polymorphism with blood lipids and maximal oxygen uptake in the sedentary state and after exercise training in the HERITAGE family study. Metabolism 2004;53:108–116.[Medline]
- Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002;155:487–495.[Abstract/Free Full Text]
- Moreno JA, Lopez-Miranda J, Marin C, Gomez P, Perez-Martinez P, Fuentes F, Fernandez de la Puebla RA, Paniagua JA, Ordovas JM, Perez-Jimenez F. The influence of the apolipoprotein E gene promoter (–219G/T) polymorphism on postprandial lipoprotein metabolism in young normolipemic males. J Lipid Res 2003;44:2059–2064.[Abstract/Free Full Text]
- Viiri LE, Raitakari OT, Huhtala H, Kahonen M, Rontu R, Juonala M, Hutri-Kahonen N, Marniemi J, Viikari JS, Karhunen PJ, Lehtimaki T. Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults. J Lipid Res 2006;47:1298–1306.[Abstract/Free Full Text]
- Scuteri A, Bos AJ, Zonderman AB, Brant LJ, Lakatta EG, Fleg JL. Is the apoE4 allele an independent predictor of coronary events? Am J Med 2001;110:28–32.[Medline]
- Frikke-Schmidt R, Tybjaerg-Hansen A, Steffensen R, Jensen G, Nordestgaard BG. Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study. J Am Coll Cardiol 2000;35:1192–1199.[Abstract/Free Full Text]
- Stankovic S, Glisic S, Alavanatic D. The effect of a gender difference in the apolipoprotein E gene DNA polymorphism on serum lipid levels in a Serbian healthy population. Clin Chem Lab Med 2000;38:539–544.[Medline]
- Schaefer EJ, Lamon-Fava S, Johnson S, Ordovas JM, Schaefer MM, Castelli WP, Wilson PW. Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham Offspring Study. Arterioscler Thromb 1994;14: 1105–1113.[Abstract/Free Full Text]
- Chen Q, Reis SE, Kammerer CM, McNamara DM, Holubkov R, Sharaf BL, Sopko G, Pauly DF, Bairey Merz CN, Kamboh MI. APOE polymorphism and angiographic coronary artery disease severity in the Women’s Ischemia Syndrome Evaluation (WISE) study. Atherosclerosis 2003;169:159–167.[Medline]
- Mahley RW, Pepin J, Palaoglu KE, Malloy MJ, Kane JP, Bersot TP. Low levels of high density lipoproteins in Turks, a population with elevated hepatic lipase. High density lipoprotein characterization and gender-specific effects of apolipoprotein e genotype. J Lipid Res 2000;41:1290–1301.[Abstract/Free Full Text]
- Somekawa Y, Wakabayashi A. Relationship between apolipoprotein E polymorphism, menopausal symptoms, and serum lipids during hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol 1998;79:185–191.[Medline]
- Garry PJ, Baumgartner RN, Brodie SG, Montoya GD, Liang HC, Lindeman RD, Williams TM. Estrogen replacement therapy, serum lipids, and polymorphism of the apolipoprotein E gene. Clin Chem 1999;45:1214–1223.[Abstract/Free Full Text]
- Tiret L, de Knijff P, Menzel HJ, Ehnholm C, Nicaud V, Havekes LM. ApoE polymorphism and predisposition to coronary heart disease in youths of different European populations. The EARS Study. European Atherosclerosis Research Study. Arterioscler Thromb 1994;14:1617–1624.[Abstract/Free Full Text]
- Lehtinen S, Lehtimaki T, Sisto T, Salenius JP, Nikkila M, Jokela H, Koivula T, Ebeling F, Ehnholm C. Apolipoprotein E polymorphism, serum lipids, myocardial infarction and severity of angiographically verified coronary artery disease in men and women. Atherosclerosis 1995;114:83–91.[Medline]
- Reilly SL, Ferrell RE, Kottke BA, Kamboh MI, Sing CF. The gender-specific apolipoprotein E genotype influence on the distribution of lipids and apolipoproteins in the population of Rochester, MN. I. Pleiotropic effects on means and variances. Am J Hum Genet 1991;49:1155–1166.[Medline]
- Chivot L, Mainard F, Bigot E, Bard JM, Auget JL, Madec Y, Fruchart JC. Logistic discriminant analysis of lipids and apolipoproteins in a population of coronary bypass patients and the significance of apolipoproteins C-III and E. Atherosclerosis 1990;82:205–211.[Medline]
- Couderc R, Mahieux F, Bailleul S, Fenelon G, Mary R, Fermanian J. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study. Stroke 1993;24:661–664.[Abstract/Free Full Text]
- Buring JE, O’Connor GT, Goldhaber SZ, Rosner B, Herbert PN, Blum CB, Breslow JL, Hennekens CH. Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction. Circulation 1992;85:22–29.[Abstract/Free Full Text]
- Bittolo Bon G, Cazzolato G, Saccardi M, Kostner GM, Avogaro P. Total plasma apo E and high density lipoprotein apo E in survivors of myocardial infarction. Atherosclerosis 1984;53:69–75.[Medline]
- Garces C, Benavente M, Ortega H, Rubio R, Lasuncion MA, Rodriguez Artalejo F, Fernandez Pardo J, de Oya M. Influence of birth weight on the apo E genetic determinants of plasma lipid levels in children. Pediatr Res 2002;52:873–878.[Medline]
- Infante-Rivard C, Levy E, Rivard GE, Guiguet M, Feoli-Fonseca JC. Small babies receive the cardiovascular protective apolipoprotein epsilon 2 allele less frequently than expected. J Med Genet 2003;40:626–629.[Free Full Text]
- Isasi CR, Shea S, Deckelbaum RJ, Couch SC, Starc TJ, Otvos JD, Berglund L. Apolipoprotein epsilon2 allele is associated with an anti-atherogenic lipoprotein profile in children: The Columbia University BioMarkers Study. Pediatrics 2000;106:568–575.[Abstract/Free Full Text]
- Choi YH, Kim JH, Kim DK, Kim JW, Lee MS, Kim CH, Park SC. Distributions of ACE and APOE polymorphisms and their relations with dementia status in Korean centenarians. J Gerontol A Biol Sci Med Sci 2003;58:227–231.[Medline]
- Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994;6:29–32.[Medline]
- Lewis SJ, Brunner EJ. Methodological problems in genetic association studies of longevity–the apolipoprotein E gene as an example. Int J Epidemiol 2004;33:962–970.[Abstract/Free Full Text]
- Frisoni GB, Louhija J, Geroldi C, Trabucchi M. Longevity and the epsilon2 allele of apolipoprotein E: the Finnish Centenarians Study. J Gerontol A Biol Sci Med Sci 2001;56:M75–78.[Abstract/Free Full Text]
- Rosvall L, Rizzuto D, Wang HX, Winblad B, Graff C, Fratiglioni L. APOE-related mortality: Effect of dementia, cardiovascular disease and gender. Neurobiol Aging 2008 (in press).
- Evans AE, Zhang W, Moreel JF, Bard JM, Ricard S, Poirier O, Tiret L, Fruchart JC, Cambien F. Polymorphisms of the apolipoprotein B and E genes and their relationship to plasma lipid variables in healthy Chinese men. Hum Genet 1993; 92:191–197.[Medline]
- Eto M, Watanabe K, Ishii K. A racial difference in apolipoprotein E allele frequencies between the Japanese and Caucasian populations. Clin Genet 1986;30:422–427.[Medline]
- Asakawa J, Takahashi N, Rosenblum BB, Neel JV. Two-dimensional gel studies of genetic variation in the plasma proteins of Amerindians and Japanese. Hum Genet 1985;70: 222–230.[Medline]
- Tsuchiya S, Yamanouchi Y, Onuki M, Yamakawa K, Miyazaki R, Taya T, Kondo I, Ohnuki M, Hamaguchi H. Frequencies of apolipoproteins E5 and E7 in apparently healthy Japanese. Jinrui Idengaku Zasshi 1985;30:271–278.[Medline]
- Baroni MG, Berni A, Romeo S, Arca M, Tesorio T, Sorropago G, Di Mario U, Galton DJ. Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD. BMC Med Genet 2003;4:8.[Medline]
- Hsieh MC, Lin SR, Yang YC, Chen HC, Lin JN, Shin SJ. Higher frequency of apolipoprotein E2 allele in type 2 diabetic patients with nephropathy in Taiwan. J Nephrol 2002;15:368–373.[Medline]
- James RW, Boemi M, Giansanti R, Fumelli P, Pometta D. Underexpression of the apolipoprotein E4 isoform in an Italian population. Arterioscler Thromb 1993;13:1456–1459.[Abstract/Free Full Text]
- Bailleul S, Couderc R, Landais V, Lefevre G, Raichvarg D, Etienne J. Direct phenotyping of human apolipoprotein E in plasma: application to population frequency distribution in Paris (France). Hum Hered 1993;43:159–165.[Medline]
- Kolovou G, Yiannakouris N, Hatzivassiliou M, Malakos J, Daskalova D, Hatzigeorgiou G, Cariolou MA, Cokkinos DV. Association of apolipoprotein E polymorphism with myocardial infarction in Greek patients with coronary artery disease. Curr Med Res Opin 2002;18:118–124.[Medline]
- Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 1996;16:1250–1255.[Abstract/Free Full Text]
- Eubank DC. Differences in the association between apolipoprotein E genotype and mortality across populations. J Gerontol A Biol Sci Med Sci 2007;62:899–907.[Abstract/Free Full Text]
- Lahoz C, Schaefer EJ, Cupples LA, Wilson PW, Levy D, Osgood D, Parpos S, Pedro-Botet J, Daly JA, Ordovas JM. Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis 2001;154:529–537.[Medline]
- Kolovou GD, Anagnostopoulou KK, Salpea KD, Panagiotakos DB, Hoursalas IS, Cariolou MA, Koniavitou K, Cokkinos DV. Apolipoprotein E genotype in matched men and women with coronary heart disease. Ann Clin Lab Sci 2005;35:391–396.[Abstract/Free Full Text]
- Gerdes LU, Klausen IC, Sihm I, Faergeman O. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol 1992;9:155–167.[Medline]
- Kolovou GD, Anagnostopoulou KK, Cokkinos DV. Apolipoprotein E gene polymorphism and myocardial infarction. Int J Cardiol 2008 (in press).
- Ehnholm C, Lukka M, Kuusi T, Nikkila E, Utermann G. Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res 1986;27:227–235.[Abstract]
- Eggertsen G, Tegelman R, Ericsson S, Angelin B, Berglund L. Apolipoprotein E polymorphism in a healthy Swedish population: variation of allele frequency with age and relation to serum lipid concentrations. Clin Chem 1993;39:2125–2129.[Abstract/Free Full Text]
- Hirashiki A, Yamada Y, Murase Y, Suzuki Y, Kataoka H, Morimoto Y, Tajika T, Murohara T, Yokota M. Association of gene polymorphisms with coronary artery disease in low-or high-risk subjects defined by conventional risk factors. J Am Coll Cardiol 2003;42:1429–1437.[Abstract/Free Full Text]
- van Bockxmeer FM, Mamotte CD. Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease. Lancet 1992;340:879–880.[Medline]
- Utermann G, Hardewig A, Zimmer F. Apolipoprotein E phenotypes in patients with myocardial infarction. Hum Genet 1984;65:237–241.[Medline]
- Cumming AM, Robertson FW. Polymorphism at the apoprotein-E locus in relation to risk of coronary disease. Clin Genet 1984;25:310–313.[Medline]
- Lenzen HJ, Assmann G, Buchwalsky R, Schulte H. Association of apolipoprotein E polymorphism, low-density lipoprotein cholesterol, and coronary artery disease. Clin Chem 1986;32:778–781.[Abstract/Free Full Text]
- Yamamura T, Tajima S, Miyake Y, Nomura S, Yamamoto A, Haze K, Hiramori K. Hyperlipoproteinemia as a risk factor for ischemic heart disease. Jpn Circ J 1990;54:448–456.[Medline]
- Luc G, Bard JM, Arveiler D, Evans A, Cambou JP, Bingham A, Amouyel P, Schaffer P, Ruidavets JB, Cambien F, et al. Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study. Arterioscler Thromb 1994;14:1412–1419.[Abstract/Free Full Text]
- Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF. Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation 1995;91:265–269.[Abstract/Free Full Text]
- Eto M, Watanabe K, Makino I. Increased frequencies of apolipoprotein epsilon 2 and epsilon 4 alleles in patients with ischemic heart disease. Clin Genet 1989;36:183–188.[Medline]
- Eichner JE, Kuller LH, Ferrell RE, Meilahn EN, Kamboh MI. Phenotypic effects of apolipoprotein structural variation on lipid profiles. III. Contribution of apolipoprotein E phenotype to prediction of total cholesterol, apolipoprotein B, and low density lipoprotein cholesterol in the healthy women study. Arteriosclerosis 1990;10:379–385.[Abstract/Free Full Text]
- Kolovou GD, Anagnostopoulou KK, Mikhailidis DP, Panagiotakos DB, Pilatis ND, Cariolou MA, Yiannakouris N, Degiannis D, Stavridis G, Cokkinos DV. Association of apolipoprotein E genotype with early onset of coronary heart disease in Greek men. Angiology 2005;56:663–670.[Medline]
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Abstract
Introduction
