A positive relationship between Apo ε2 allele and high-density lipoprotein cholesterol

Nutrition Research 26 (2006) 443 – 449 www.elsevier.com/locate/nutres

A positive relationship between Apo E2 allele and high-density lipoprotein cholesterol Yung-Chieh Yena,b, Bih-Ching Shuc, Chien-Shu Wangd, Ming-Jen Yange,f, Wei-Tsung Kaod, Chun-Hua Shihe, For-Wey Lungd,e,g,4 a

Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA b Calo Psychiatric Center, Pingtung 925, Taiwan c Institute of Allied Health Sciences and School of Nursing, National Cheng-Kung University, Tainan 701, Taiwan d Department of Psychiatry, Military Kaohsiung General Hospital, Kaohsiung 802, Taiwan e Graduate Institute of Behavioral Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan f Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan g Department of Psychiatry, National Defense Medical University, Taipei 114, Taiwan Received 11 April 2006; revised 23 June 2006; accepted 17 July 2006

Abstract This study explored the relationship between ApoE genotypes and the fasting serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triacylglycerol in an elderly Chinese population. A total of 500 subjects aged 65 to 74 years were randomly selected in southern Taiwan from April to June 2001. Two hundred fifty-six participants, who agreed to have additional venous blood withdrawal for genetic study, were regarded as the participant group, and the other 244 participants, who disagreed to have additional venous blood withdrawal, were included in the control group. In the participant group, the most prevalent ApoE allele was the E3 allele (89.65%), followed by the E4 allele (7.81%), and the E2 allele (2.54%). After holding sex, age, education, and income factors as constant, only the E2 allele associated with plasma HDL-C was statistically significant. Elderly women tended to have higher plasma total cholesterol and HDL-C than elderly men. The Apo E2 allele had an increasing effect on plasma HDL-C relative to the non–Apo E2 allele. Such a relationship is particularly important in investigating the roles of genetic and environmental factors in cardiovascular disease. D 2006 Elsevier Inc. All rights reserved. Keywords:

ApoE genotypes; Cholesterol; High-density lipoprotein cholesterol; Low-density lipoprotein cholesterol; Verylow-density lipoprotein cholesterol; Triacylglycerol; ApoE allele

1. Introduction The cognitive impairment rate among the elderly population is 4.92% in Taiwan [1], and the odds ratio of the presence of the Apo E4 allele in patients with Alzheimer

4 Corresponding author. Department of Psychiatry, Military Kaohsiung General Hospital, Kaohsiung 802, Taiwan. Tel.: +886 7 7490056; fax: +886 7 7498706. E-mail address: [email protected] (F.-W. Lung). 0271-5317/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nutres.2006.07.003

disease in Taiwan is 3.226, which is similar to that in the general population [2,3]. In addition, the inheritance of an E2 allele has been associated with a significantly lower risk of inheriting an E4 allele, which might in turn lower the risk for Alzheimer disease [3]. Alzheimer disease is a progressively degenerative disease that results in the irreversible loss of neurons, particularly in the cortex and hippocampus [4]. The role of the apolipoprotein E (ApoE) polymorphism in the pathogenesis of Alzheimer disease is still unknown, but studies reveal that genetic factors play an important role.

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One such factor, the APOE gene [5], which is located on human chromosome 19, plays a pivotal role in the transport of cholesterol and other lipids between peripheral tissues and the liver [6-9]. Three common variants of ApoE have been described and designated as Apo E2 (Cys 112, Cys 158), Apo E3 (Cys 112, Arg 158), and Apo E4 (Arg 112, Arg 158) [10,11]. These are coded as the E2, E3, and E4 alleles, respectively [12]. Different populations exhibit various frequency distributions of the ApoE isoforms; so far, the most frequent allele in all populations examined is the isoform Apo E3, and its frequency is always negatively correlated with that of Apo E4 [13]. The Apo E4 allele is widely accepted to be a risk factor in late-onset Alzheimer disease, in a dose-dependent manner [14], whereas the presence of the Apo E2 allele might be a protective factor against Alzheimer disease [15,16]. In a Taiwanese study, the presence of an Apo E2 allele might have decreased the risk of inheriting the Apo E4 allele, which in turn lowered the risk for Alzheimer disease [3]. Recently, ApoE has played an important role in lipid metabolism, which mediates the cellular uptake of specific lipoproteins, such as intermediate-density lipoprotein and the chylomicron remnant [17]. Three common alleles, the E2, E3, and E4 alleles, have quantitative effects on lipid and lipoprotein levels, which are the major risk determinants of cardiovascular disease [18]. In particular, positive associations of the E4 allele with plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and the negative associations of the E2 allele with TC and LDL-C have been well established in several European and American white populations [19-29]. In addition, the positive association of the E2 allele with serum concentrations of highdensity lipoprotein cholesterol (HDL-C) is suggested [30,31]. However, the association of the E4 allele with HDL-C is not confirmed because of conflicting results [26,30,32, 33]. On the other hand, the E4 and E2 alleles are generally considered to be positively related to plasma very-lowdensity lipoprotein cholesterol (VLDL-C) and triacylglycerol (TG) [22,25,33-37]. For Asians, positive associations of the E4 allele with serum TC and LDL-C and negative associations of the E2 allele with TC and LDL-C can be found in Japan [38-41]. However, the role of the ApoE polymorphism in HDL-C, VLDL-C, and TG remains uncertain [38,40,42]. For the Chinese, the negative associations of the E2 allele with TC and LDL-C and the positive associations of the E4 allele with TC and LDL-C are found in some research [43-47]. The positive association of the E2 allele with HDL-C and the negative association of the E4 allele with HDL-C have also been noted [44,47]. The positive association of the E4 allele with VLDL-C and TG can be found in one Chinese study [48], which has not been replicated. The relationship between elevated serum TC and LDL-C concentrations, low HDL-C concentrations, and coronary heart disease in middle age [49-52] and early old age has been established [53]. Therefore, we aimed to explore the

relationship between the ApoE polymorphism and the lipid profile in an elderly Chinese population. 2. Methods and materials 2.1. Participants This research was approved by the Institutional Research Board of a teaching general hospital in southern Taiwan. Employing a multilevel stratified sampling strategy, we selected subjects from the official household records of an entire prefecture in southern Taiwan. Three hierarchical household classifications below the county level were sequentially, randomly, sampled. A total of 500 subjects aged 65 to 74 years from the general population of Chiayi City in southern Taiwan were recruited for this interview survey between April and June in 2001. Of 500 participants, 256 agreed to have additional venous blood withdrawal for DNA extraction for genetic study (they were regarded as the participant group), and the other 244 participants who disagreed to have additional venous blood withdrawal were included in the control group. Informed consent was obtained, and the surveys were conducted by trained social workers. 2.2. Data collection and laboratory methods All personal information was obtained during the face-toface interviews. Blood samples were obtained on the morning after a 12-hour fast. Cholesterol and TG levels were determined in plasma, and lipoproteins were determined by enzymatic methods. LDL-C was calculated using the equation of Friedewald et al [54], and VLDL-C was derived from TC after subtracting LDL-C and HDL-C. We used a polymerase chain reaction (PCR) technique to identify the ApoE genotypes. The genomic DNA extracted from the peripheral leukocytes was amplified by PCR, along with an upstream primer, 5V-GAA TTC GCC CCG GCC TGG TA-3V, and a downstream primer, 5V-AAG CTT GGC ACG GCT GTC CA-3V. This method was based on the fact that nucleotide substitutions accounting for ApoE allelic variation result in polymorphic restriction sites for HhaI [55]. The primers were designed to amplify 2 fragments, both of which carry only one restriction site for HhaI or not, depending on the allelic polymorphism. Both PCR products were digested with HhaI, and fragments were separated by electrophoresis on an 8% polyacylamide gel. DNA fragments were visualized by ultraviolet illumination. ApoE genotypes for the subjects were determined in a blinded fashion by scoring for a unique combination of fragment sizes [56]. 2.3. Statistical analysis The data were analyzed by using the SPSS 10.0 for Windows software package (SPSS, Chicago, Ill). Subjects were classified into 1 of 3 groups (the E2, E3, and E4 groups). The E2 group consisted of subjects with an E2E2 or E2E3 phenotype, the E3 group consisted of those with an E3E3 phenotype, and the E4 group consisted of those with an E3E4

Y.-C. Yen et al. / Nutrition Research 26 (2006) 443–449 Table 1 Comparison of participant and control groups among unrelated elderly Chinese individuals Variable Age, mean (SD), y Sex, n (%) Men Women Education, n (%) Illiterate Primary school or higher Monthly income in USD, n (%) b 860 860–2000 2001–2860 N 2860

Participant group (n = 256) 69.2 (2.7)

Control group (n = 244) 69.3 (2.8)

150 (58.6) 117 (41.4)

123 (50.4) 121 (49.6)

114 (44.5) 142 (55.5)

131 (53.9) 112 (46.1)

P .849 .066

.036

.076 185 56 12 3

(72.3) (21.9) (4.7) (1.2)

199 34 7 3

(81.9) (14.0) (2.9) (1.2)

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3. Results 3.1. Demographic characteristics Of the 500 participants, 256 agreed to have additional venous blood withdrawal for DNA extraction for genetic study, and their blood samples successfully completed further examinations. The response rate was 51.2%. A comparison of the sociodemographic characteristics of our respondents with the data from the Ministry of the Interior, Taiwan, revealed that our survey sample did not substantially differ from the national sample [57]. The mean age, sex, and monthly income were not statistically significant between the participant and control group (Table 1). The participant group included more educated persons than the control group ( P = .036). 3.2. ApoE genotypes and allele frequencies

The P values for the percentages of sex, education, and monthly income refer to v 2 tests of differences between participating and nonparticipating subjects. For age, the P value refers to the t test of differences between participant and control groups. USD indicates US dollar.

or E4E4 phenotype. Two subjects with an E2E4 phenotype were excluded from the analysis because of the potentially opposing effects of the E2 and E4 alleles. The outcomes identified were (1) TC, (2) HDL-C, (3) LDL-C, (4) VLDL-C, and (5) TG levels. Continuous variables were expressed as mean F SD and categorical variables as proportions. An unpaired t test was used for comparison between groups for continuous variables, and Pearson v 2 test was used for categorical variables. Hardy-Weinberg equilibrium was tested by means of gene counting and v 2 analysis. Multiple linear regression models examined the associations of serum lipids and the 3 groups. The analyses examined the lipid profile as continuous outcome variables. Potential confounding variables (sex, age education, and income) were included; the average levels of plasma lipid were compared between different genotypes using an analysis of variance. Finally, logistic regression was used to compare Apo E2 and non–Apo E2 participants in several factors, such as sex, age, HDL level, and so on.

Genotypes of ApoE were in Hardy-Weinberg equilibrium (HWE) in the elderly Chinese population in this study (HWE v 2 = 4.828 b 11.07). Genotype E3E3 appeared most frequently (82.03%), followed by E3E4 (11.72%), E2E3 (3.52%), E4E4 (1.56%), E2E4 (0.78%), and E2E2 (0.39%). The most prevalent Apo E allele was the E3 allele (89.65%), followed by the E4 allele (7.81%) and the E2 allele (2.54%). The data were not shown. 3.3. Association with plasma lipid levels Mean values of the overall plasma lipid levels in the elderly Chinese population across all ApoE genotypes are shown in Table 2. The only statistical significance noted was in HDL-C ( P b .001). As we further group by phenotypes (E2, E3, and E4 in Table 2), HDL-C still appeared significantly different among the different ApoE alleles ( P b .001). Yet, no significant difference was noted between the ApoE genotypes and Apo E alleles in the other plasma lipids. For TC, only the total effect of sex was significant. When other factors were controlled, we found that the positive direct effect of female sex was still significant. For HDL-C, the total effects of the E2 allele and female sex were significant. After adjusting all other factors, the direct

Table 2 ApoE genotypes and allele frequencies and plasma lipids according to ApoE genotypes among unrelated elderly Chinese individuals Genotype

Allele variation

ApoE 22 23 24 33 34 44 P 2 3 4 P

Values are expressed as mean (SD). 4 P b 0.001.

TC 183.0 230.4 236.0 212.6 217.5 246.0 .337 225.7 212.8 219.9 .420

(56.9) (67.9) (38.4) (45.7) (14.0) (55.7) (38.4) (44.7)

HDL-C 33.0 72.3 (26.7) 54.5 (10.6) 51.3 (14.3) 47.0 (10.5) 46.3 (5.7) .0004 68.4 (28.1) 51.2 (14.3) 47.1 (10.1) .0004

LDL-C 114.0 137.4 (50.0) 153.0 (53.7) 134.8 (33.1) 145.6 (39.6) 155.3 (34.2) .463 135.1 (47.7) 135.0 (33.2) 145.7 (38.8) .255

VLDL-C 36.0 20.7 (6.6) 28.5 (3.5) 26.7 (16.7) 24.8 (16.2) 44.5 (26.4) .263 22.2 (7.9) 26.7 (16.7) 27.1 (18.6) .694

TG 182.0 102.1 (32.3) 142.0 (17.0) 133.8 (83.8) 124.3 (80.7) 224.3 (133.2) .238 110.1 (39.6) 133.9 (83.4) 135.9 (93.1) .667

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Variable

Apoe vs non–Apoe Apoe vs non–Apoe Women vs Men Age in years Education z 12 y vs b 12 y Income V 860 USD vs N 860 USD

TC Total Coefficient ( P value) 11.917 (.356) 7.587 (.304) 13.722 (.007) 1.722 (.066) 3.367 (.505) 2.554 (.649)

HDL-C Direct

Total

13.530 (.293) 5.898 (.423) 14.239 (.008) 1.618 (.085) 3.289 (.537)

17.744 5.129 5.455 .235 3.555

1.298 (.815)

LDL-C

Direct

(.000) (.062) (.004) (.502) (.058)

2.629 (.207)

16.311 4.745 5.378 .146 1.025

Total

(.001) (.076) (.006) (.666) (.596)

3.223 (.110)

1.343 11.978 7.502 1.785 2.005

(.905) (.060) (.088) (.028) (.647)

4.621 (.341)

Note: Linear regression analysis with robust variance applied to total and direct effects of all variables.

VLDL-C

Direct

.967 10.325 7.189 1.594 1.596

Total

(.931) (.107) (.124) (.051) (.731)

4.123 (.393)

4.566 647 .954 .174 2.334

TG

Direct

(.397) (.834) (.652) (.656) (.265)

.454 (.845)

3.801 .194 1.953 .175 2.955

Total

(.488) (.951) (.392) (.660) (.194)

.257 (.914)

24.048 3.266 4.483 .914 11.999

Direct

(.373) (.832) (.672) (.640) (.252)

2.180 (.852)

20.115 .915 9.551 .924 15.000

(.143) (.463) (.403) (.643) (.187)

1.193 (.920)

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Table 3 Total and direct effects of multiple linear regression in average serum lipids among unrelated elderly Chinese individuals

Y.-C. Yen et al. / Nutrition Research 26 (2006) 443–449 Table 4 The parsimonious model of logistic regression coefficients for comparing Apo 2 subjects and non–Apo 2 subjects Variables Women vs Men HDL level Constant

B .020 .058 6.593

SE .678 .018 1.473

Wald .001 10.561 20.032

df 1 1 1

Sig .977 .001 .000

Exp(B) 1.020 1.059 .001

B indicates coefficient; SE, standard error; Wald, Wald v 2; df, degrees of freedom; Sig, P value; Exp(B), odds ratio.

effects of the E2 allele and female sex remained significant. Using the full model (Table 3) and parsimonious model (Table 4) of logistic regression, the HDL-C level was still statistically significantly different between Apo E2 subjects and non–Apo E2 subjects ( P = .001; Table 4). For LDL-C, only the total effect of age was significant. When adjusted with all other factors, the direct effect of age was not statistically significant. For VLDL-C and TG, the total and direct effects of all variables were not significant. 4. Discussion A significant effect of the ApoE genotype on plasma HDL-C was observed. The presence of the E2 allele is associated with substantially increased HDL-C. However, our finding that only the E2 allele tends to increase plasma HDL-C differs from that of previous Chinese research [4347]. Possible reasons include different sampling sources (community-based general population vs hospital-based population or healthy subjects) and different subject characteristics (eg, age, socioeconomic status). Failure to control for certain physical conditions (eg, diabetes, obesity), daily physical activity, or diet may also result in different outcomes. However, the subjects with an ApoE genotype in this study were in Hardy-Weinberg equilibrium for a suitable parameter estimate. The presence of the E2 or E4 allele in our participants was not significantly associated with differences in VLDL-C and TG. This is in contrast with the finding of Evans et al [48], wherein the E4 allele is associated with elevated plasma VLDL-C and TG in healthy Chinese men. The difference may be the result of different study subject characteristics. The E4 allele and E2 allele are generally considered positively related to plasma VLDL-C and TG in Western research [21,25,33-37], and the E4 allele had a tendency to lower VLDL-C and TG in one Japanese study [38]. Our findings were not the same as those of the above-mentioned studies. The different effects of the ApoE polymorphism on lipid profiles across ethnicity have been noted [58-60]. The results of our study also suggest that the same ApoE genotype may have qualitatively or quantitatively different effects on lipid profiles across ethnicity. The differences in Apo E allele frequencies between the general Chinese population of our study and American or European whites are marked and have been confirmed in previous studies [45,46,48,61], and the E2

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and E4 allelic frequencies of the Chinese were far less than those of whites. The implication of this marked difference is that the same manifestations of a disease (eg, cardiovascular diseases) may derive from various predispositional and environmental factors. Thus, we need to explore the slightly different distribution frequencies of Apo E alleles that are exhibited in different populations. The allelic frequency for Apo E4 allele was highest (0.368) for Papua New Guineans [62], followed by Nigerian blacks (frequency, 0.31) [63], American blacks and Australian aborigines (both with a frequency of 0.26) [63], and Greenland Inuits (frequency, 0.23) [64]. In Amerindian, Greenland Inuit, and Australian aborigine populations, no Apo E2 allele was found [64-66]. Alaskan natives displayed 0.02 Apo E2 and 0.193 Apo E4 [67]. Whites displayed a high frequency (0.09) of the Apo E2 allele and a relatively low frequency (0.15) of the Apo E4 allele [68]. In a survey of European and African populations, Sanghera et al [69] found that the strength of linkage disequilibrium was highest for the Apo E2 allele and lowest for the Apo E4 allele. This finding suggests that the origin of the ApoE polymorphism has followed a 4Y3Y2 pathway; this concept was suggested earlier by Gerdes et al [64]. The advantage of Apo E4 allele in our ancestors was the efficient use of nutrients in a period of food scarcity, whereas the disadvantage of Apo E4 allele in the modern world is its association with Alzheimer disease. Whether this association of plasma lipid and ApoE genotype is important in Alzheimer disease needs further investigation. In this study, the alleles were under the Hardy-Weinberg equilibrium. However, some limitations require mentioning. First, because the subjects of this study were restricted to byoungQ elderly Chinese in a rural area, the generalizability of this study is limited. Second, the characteristics of the respondents were significantly different from the nonrespondents in educational-level distribution. Therefore, our study sample was composed of fewer educated subjects than the general population. Third, education and income may not be perfect surrogates of socioeconomic status; therefore, residual bias will appear. Fourth, our 256 subjects were all elderly, so they hardly represent the general population. Lastly, lifestyle, physical activity, diet, and physical diseases are factors that may potentially confound the effect of ApoE polymorphism on plasma lipids, but these were not controlled in our study. This factor might further influence our results. The Apo E2 allele has more associations with HDL-C than the Apo E4 allele because the Apo E4 is catabolized 3 times faster than the ApoE2 allele [70,71]. The current study suggested that the Apo E2 allele had an increasing effect on plasma HDL-C as compared with the non–Apo E2 allele. The interaction among ApoE polymorphism, plasma lipids, Alzheimer disease, atherosclerosis, and depression is complex, as suggested by this study and our previous studies [1-3]. In addition, our previous study had evidence that Apo E2 allele is likely to be the protective effect against major depressive disorder in Taiwanese [72]. Further studies are therefore needed to address the impact of the variation of the

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