Apolipoprotein E Gene Polymorphism Effects on Lipid Metabolism and Risk of Cerebral Infarction in Northwest Han Chinese Population

doi:10.21203/rs.3.rs-1094744/v1

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Apolipoprotein E Gene Polymorphism Effects on Lipid Metabolism and Risk of Cerebral Infarction in Northwest Han Chinese Population

https://doi.org/10.21203/rs.3.rs-1094744/v1

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Background: The apolipoprotein E (ApoE) genetic variation may be involved in the development of Cerebral Infarction (CI). Serum lipid levels are known risk factors for CI, but the effect of the ApoE gene polymorphism on lipid metabolism remains unclear. This retrospective cohort study aimed to determine the role of ApoE genotypes in CI risk and the relationships between ApoE gene polymorphism and serum lipid levels among the population of northwest China.

patients and methods: 517 CI patients and 517 non-CI controls were enrolled in the study. Polymerase chain reaction and hybridization were used to test the ApoE gene polymorphisms.

results: Patients with CI had a significantly higher frequency of ε3/ε4 genotype (OR =2.057, 95% CI = 1.477–2.864, P<0.001) and ε4 allele (OR =1.818, 95% CI = 1.364–2.424, P<0.001) than control participants. When stratifying by age and sex, it was found that statistically significant differences in the distribution and frequencies of the ε3/ε4 genotype(OR =3.067, 95% CI = 1.675–5.614, P<0.001 in age ≤60 years; OR =1.735, 95% CI = 1.156–2.604, P=0.008 in age >60 years and OR =2.206, 95% CI = 1.474–3.301, P<0.001 in males) and ε4 allele (OR =1.709, 95% CI = 1.201–2.432, P=0.001) in males and ε4 allele (OR =2.072, 95% CI = 1.281–3.353, P=0.003 in age ≤60 years; OR =1.704, 95% CI = 1.189–2.444, P=0.003 in age>60 years; OR =1.709, 95% CI = 1.201–2.432, P=0.001 in males and OR =2.046, 95% CI = 1.246–3.361, P=0.004 in females ) were observed between patients and controls. ε4 carriers had significantly lower ApoE level and higher low-density lipoprotein cholesterol (LDL-C), ApoB and ApoB/ApoA-I levels than ε2 carriers in both two groups. Additionally, control participants with ε4 carriers had significantly higher levels of lipoprotein and lower total cholesterol (TC) levels than ε2 carriers, CI patients with ε4 carriers had significantly lower level of ApoA-I than ε2 carriers. After adjusting for other established risk factors, drinking, hypertension, lipoprotein, triglycerides (TG) and ε4 allele were significant independent risk factor for CAD. ε4 allele presence was associated with a nearly two-fold higher CI risk.

Conclusions: This study provides evidence that ε4 allele, drinking, hypertension, lipoprotein and TG levels are independent risk factor for CI among patients in Northwest China. Also, these data might be clinically useful in allowing for more individualized preventive and therapeutic strategies.

Cardiac & Cardiovascular Systems

Endocrinology & Metabolism

Apolipoprotein E

Cerebral Infarction

Gene polymorphism

Northwest China

CI also called ischemic stroke and is the most commonly reported cerebral vascular diseases, accounting for 70–80% of all strokes[1]. CI is a complex disease caused by multiple susceptibility genes and environmental factors[2]. A number of candidate genes have been investigated in CI through association studies, but with controversial results[3].

Recently, mounting evidence indicates that ApoE is a candidate gene in the development of CI. ApoE is an arginine-rich alkaline protein, which is present in plasma chylomicron, low-density lipoprotein and very low-density lipoprotein[4]. In humans, the APOE gene is located at chromosome 19q13.2 and is also found to be extensively expressed in the brain. Genotypes were also determined for the two functional single nucleotide polymorphisms (SNPs) rs429358 (388T > C) and rs7412 (526C > T), resulting in three different alleles (ε2, ε3 and ε4) and six different genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4 and ε4/ε4). ApoE plays an important role in cholesterol transport, plasma lipoprotein metabolism and thus affects the serum lipid profiles in the body[4]. Several studies indicate that ε4 allele was associated with significantly higher serum TC and LDL-C and it thereby contributes to the increasing burden of cardiovascular diseases, including CI[5]. Although the mechanism responsible for the association between ApoE polymorphisms and CI, but the exact mechanism is still controversial. The distribution of ApoE allele frequencies can vary across different ethnic groups [6]. Furthermore, there are no studies that have addressed the relationship between ApoE polymorphism and the risk of developing CI in the Northwest of China. Therefore, the aim of the present study was to investigate the role of ApoE genotypes in the risk of CI in Northwest Chinese Han population.

Subjects

A total of 517 Chinese CI patients (males: females = 344:173) and 517 controls (males: females = 332:185) were enrolled into the study. These two groups were gender and age matched. All participants were enrolled from May 2018 to May 2019 in the First Affiliated Hospital of Xi’an Jiao Tong University. Most of the study participants are ethnically Han Chinese and residents living in Northwest China. The demographic and clinical characteristics of study participants are presented in Table 1. Diagnostic criteria of CI patients were as referred to in the Fourth National Cerebrovascular Disease Conference of China, and the diagnosis was confirmed by computed tomography or Magnetic Resonance Imaging. The exclusion criteria were as follows: patients with malignancy, autoimmune disease, chronic kidney disease, and incomplete heart function. This study was approved by the Ethical Committee of the First Affiliated Hospital of Xi’an Jiao Tong University and we got the informed consent of each patients.

Table 1

Characteristics of the Study Population
Factors	Controls	CI	P value
Age(years)	61.26±14.29	61.52±11.24	0.742 ^a
Males/Females	332/185	344/173	0.472 ^b
Smoking	187(36.17%)	189(36.56%)	0.948 ^b
Drinking	99(19.15%)	142(27.47%)	0.002 ^b
Diabetes	119(23.02%)	162(31.33%)	0.003 ^b
Hypertension	265(51.26%)	356(68.86%)	<0.001 ^b
TC	3.78±0.86	3.81±0.92	0.560 ^a
HDL	1.03±0.26	1.02±0.25	0.416 ^a
LDL-C	2.19±0.73	2.21±0.79	0.740 ^a
TG	1.37±0.76	1.50±0.95	0.011 ^a
Cr	69.14±53.10	67.39±34.97	0.552 ^a
Apolipoprotein A	1.15±0.21	1.15±0.20	0.994 ^a
Apolipoprotein B	0.74±0.20	0.75±0.20	0.175 ^a
ApoB/ApoA	0.66±0.28	0.67±0.21	0.321 ^a
Apolipoprotein E	36.89±13.97	35.58±14.10	0.135 ^a
Lipoprotein	194.88±202.30	211.94±205.38	0.179 ^a
DB	4.71±4.72	4.50±2.37	0.395 ^a
IB	9.15±4.79	9.13±4.75	0.996 ^a
CI: cerebral infarction, TC: total cholesterol, HDL: high-density lipoproteins, LDL-C: low-density lipoprotein cholesterol, TG: triglyceride, Cr: creatinine, DB: direct bilirubin, IB: indirect bilirubin
aP values were calculated by Student’s t-tests.
bP values were calculated from two-sided chi-square test.

DNA extraction and genotyping

Blood samples from each participant were obtained from the cubital vein and collected in tubes containing ethylene diamine tetra acetic acid (EDTA). Genomic DNA was extracted using DNA isolation kits (Sinochips Bioscience Co., Ltd., Zhuhai, Guangdong, China) for peripheral blood and stored at -20°C. The genotypes of ApoE were detected using a commercially available kit (Sinochips Bioscience Co., Ltd., Zhuhai, Guangdong, China). PCR analysis was performed according to the manufacturer’s instructions: 50°C for two minutes, pre-denaturation at 95°C for 15 minutes, followed by 45 cycles at 94°C for 30 seconds and 65°C for 45 seconds. PCR products were then reversely hybridized with gene chip technology. Finally, we used a gene chip scanner to help interpret the data.

Statistical analyses

Data analysis was performed using SPSS statistical software version 16.0. Continuous variable data are presented as means ± standard deviation and as numbers and percentages for categorical variables. Student's t test and χ2 test were initially used to test the difference between CI and control groups. ApoE genotype and allele frequencies were tested for Hardy-Weinberg equilibrium by chi-square test. The chi-square test and ANOVA were used to analyze the association between specific ApoE genotypes and clinical characteristics. Logistic regression analysis was used to assess the interactions between ApoE genotypes and various factors. A value of p<0.05 was considered statistically significant.

Baseline clinical characteristics of the CI and control groups

Baseline clinical characteristics of the patients with CI and control groups are summarized in Table 1. A total of 517 Chinese patients with CI, consisting of 344 males and 173 females aged 26-91 years (mean=61.52 years, SD=11.24), and 517 controls participants, comprising 332 males and 185 females aged 23-93 years (mean=61.26 years, SD=14.29), were included in the present study. Most of the study participants originate from northwest China. Age and sex distribution were not significantly different between the two groups (P=0.742 and 0.472, respectively). The proportions of drinking (P=0.002), hypertension (P=0.003) and diabetes (P<0.001) were significantly higher in the CI group than in the control group. TG level was significantly higher in the CI group compared to the control group (P=0.011), no significant differences were found in TC, high-density lipoprotein (HDL), LDL-c, creatinine (Cr), ApoA-I, ApoB, ApoB/A-I, ApoE, lipoprotein, direct bilirubin (DB) and indirect bilirubin (IB) levels between the two groups (all P > 0.05).

Allele And Genotype Frequencies Of Apoe And Ci Risk

The distribution of the ApoE genotype and allele frequencies in CI cases and control subjects is summarized in Table 2. The genotype distribution of this polymorphism in patients with CAD and control participants was in concordance with Hardy-Weinberg equilibrium (P = 0.45 and 0.50, respectively). Genotype ε3/ε3 (63.8%) was the most common type in CI groups, followed by ε3/ε4 (22.8%), ε2/ε3 (9.9%), ε4/ε4 (1.5%), ε2/ε4 (1.2%), and ε2/ε2 (0.8%), whereas those in control participants were ε3/ε3 (71.0%), followed by ε2/ε3 (13.3%), ε3/ε4 (12.6%), ε2/ε4 (2.1%), ε4/ε4 (0.6%) and ε2/ε2 (0.4%). The allele frequency of ε2, ε3, and ε4 was 6.3%, 80.2% and 13.5% respectively in patients with CI; 8.1%, 83.9% and 7.9% respectively in control participants. The distribution of ApoE genotypes and alleles in the two groups was significantly different (χ2=24.424 and P<0.001, χ2=18.472 and P<0.001, respectively).

Table 2

The distributions of genotypes and alleles of the ApoE gene in the CAD patients and controls
Genotype, n (%)	CI group(n=617)	Control group(n=308)	OR (95% CI)	P^a	χ2	P
E2/E2	4(0.8%)	2(0.4%)	2.010(0.366,11.010)	0.687	24.424	0.000
E2/E3	51(9.9%)	69(13.3%)	0.711(0.484,1.044)	0.099
E2/E4	6(1.2%)	11(2.1%)	0.540(0.198,1.472)	0.328
E3/E3	330(63.8%)	367(71.0%)	0.721(0.555,0.937)	0.017
E3/E4	118(22.8%)	65(12.6%)	2.057(1.477,2.864)	0.000
E4/E4	8(1.5%)	3(0.6%)	2.693(0.710,10.208)	0.224
HWE	χ2 = 3.70, P = 0.45	χ2 = 3.33, P =0.50
Alleles, n (%)
E2	65(6.3%)	84(8.1%)	0.759(0.542,1.062)	0.126	18.472	0.000
E3	829(80.2%)	868(83.9%)	0.773(0.617,0.969)	0.029
E4	140(13.5%)	82(7.9%)	1.818(1.364,2.424)	0.000
CI: cerebral infarction, HWE: Hardy-Weinberg equilibrium.
ap and OR (95% CI) values were calculated by logistic regression adjusted for age, gender, and traditional cardiovascular risk factors.
bp values were calculated from two-sided chi-square tests or Fisher’s exact tests.

The frequencies of ε3/ε4 genotype (OR =2.057, 95% CI = 1.477–2.864, P<0.001) and ε4 allele (OR =1.818, 95% CI = 1.364–2.424, P<0.001) were significantly higher in CI patients than in control participants. Further, patients with CAD had a significantly lower ε3/ε3 (OR =0.721, 95% CI = 0.555–0.937, P=0.017) genotype and ε3 allele (OR =0.773, 95% CI = 0.617–0.969, P=0.029) frequencies than did the control participants. (P < 0.05)

To explore the relationship between ApoE genotype and CI, we conducted further analysis stratified by age(dichotomized into ≤60 years and >60 years) and sex. The results showed that ε3/ε4 frequency was significantly higher in patients with CI compared to the control participants (OR =3.067, 95% CI = 1.675–5.614, P<0.001 in age ≤60 years; OR =1.735, 95% CI = 1.156–2.604, P=0.008 in age >60 years and OR =2.206, 95% CI = 1.474–3.301, P<0.001 in males), but not in females (OR =1.746, 95% CI = 0.973–3.134, P=0.078). Additionally, the variance in allele ε4 between patients with CI and controls was also statistically significant (OR =2.072, 95% CI = 1.281–3.353, P=0.003 in age ≤60 years; OR =1.704, 95% CI = 1.189–2.444, P=0.003 in age>60 years; OR =1.709, 95% CI = 1.201–2.432, P=0.001 in males and OR =2.046, 95% CI = 1.246–3.361, P=0.004 in females) (Table 3).

Relationships between serum lipid profile and ApoE alleles.

Table 4 describe the association between serum lipid profiles and allelic carrier status (ε2, ε3 and ε4 groups). Participants with ε2/ε4 genotype (n= 17) were excluded because play opposing roles in lipid metabolism and the incidence of CI. In the patients with CAD, ε4 carriers had significantly higher LDL-C, ApoB and ApoB/ApoA-I and lower levels of ApoA-I and ApoE levels than ε2 carriers. LDL-C, ApoB, ApoB/ApoA-I and ApoE levels of the control participants showed similar trends to those in CI groups. Additionally, control participants with ε4 carriers had significantly higher levels of lipoprotein and TC levels than ε2 carriers.

Table 4

Relationships between serum lipid profile and ApoE allele in CI patients and control participants
CI patient								Control participants
Factors	ε2(ε2ε2 + ε2ε3)	ε3(ε3)	ε4(ε3ε4 + ε4ε4)	P ^a	P ^b	P ^c	P ^d	ε2(ε2ε2 + ε2ε3)	ε3(ε3)	ε4(ε3ε4 + ε4ε4)	P ^a	P ^b	P ^c	P ^d
TC	3.59±0.87	3.86±0.94	3.78±0.90	0.112	0.046	0.423	0.183	3.55±0.87	3.82±0.84	3.85±0.93	0.043	0.014	0.822	0.042
HDL	1.07±0.26	1.02±0.24	1.00±0.27	0.220	0.208	0.329	0.107	1.01±0.21	1.04±0.27	1.04±0.27	0.620	0.326	0.923	0.466
LDL-C	1.89±0.54	2.27±0.82	2.18±0.79	0.004	0.001	0.266	0.014	1.98±0.77	2.23±0.71	2.29±0.77	0.023	0.009	0.589	0.043
TG	1.55±1.23	1.45±0.80	1.61±1.16	0.245	0.435	0.090	0.740	1.55±0.84	1.36±0.76	1.23±0.60	0.039	0.057	0.184	0.011
Cr	64.91±20.61	67.69±36.85	68.36±34.85	0.854	0.622	0.870	0.537	65.53±21.07	70.03±60.95	69.91±26.78	0.820	0.553	0.987	0.302
Apolipoprotein A	1.26±0.23	1.16±0.20	1.12±0.21	0.000	0.002	0.061	0.000	1.17±0.18	1.16±0.21	1.13±0.22	0.514	0.710	0.139	0.263
Apolipoprotein B	0.64±0.14	0.77±0.20	0.77±0.21	0.000	0.000	0.944	0.000	0.66±0.21	0.75±0.20	0.76±0.21	0.001	0.000	0.535	0.003
ApoB/ApoA	0.54±0.14	0.68±0.21	0.70±0.20	0.000	0.000	0.274	0.000	0.56±0.20	0.67±0.31	0.68±0.21	0.012	0.005	0.807	0.001
Apolipoprotein E	49.03±21.64	34.61±10.89	32.04±14.05	0.000	0.000	0.039	0.000	50.24±17.97	34.99±11.75	32.11±12.09	0.000	0.000	0.066	0.000
Lipoprotein	215.81±213.97	210.85±207.31	212.14±201.12	0.986	0.870	0.952	0.912	133.86±109.56	203.59±216.48	213.16±182.36	0.021	0.008	0.732	0.002
DB	4.58±2.26	4.45±2.25	4.58±2.74	0.863	0.729	0.626	0.990	4.73±2.50	4.65±5.19	5.14±4.14	0.737	0.904	0.460	0.472
IB	9.08±5.26	9.14±4.58	9.13±5.12	0.998	0.943	0.991	0.959	9.14±4.41	9.06±4.79	9.78±5.04	0.526	0.890	0.263	0.434
CI: cerebral infarction, TC: total cholesterol, HDL: high-density lipoproteins, LDL-C: low-density lipoprotein cholesterol, TG: triglyceride, Cr: creatinine, DB: direct bilirubin, IB: indirect bilirubin
ap value shows the differences compared between groups (ε2, ε3, ε4)
bp values obtained when comparing ε2 subjects with ε3 subjects.
cp values obtained when comparing ε4 subjects with ε3 subjects.
dp values obtained when comparing ε2 subjects with ε4 subjects.

Logistic Regression Analysis Of Ci Risk Factors

We performed a multivariate logistic regression analysis to identify which variables with statistical significance from the univariate analysis could act as independent predictors of CI. Univariate logistic analysis showed that drinking (OR =1.701, 95% CI = 1.167–2.478, P=0.006), hypertension (OR =1.885, 95% CI = 1.417–2.508, P<0.001), ApoE levels (OR =0.983, 95% CI = 0.969–0.997, P=0.017), lipoprotein (OR =1.001, 95% CI = 1.000–1.001, P=0.046), TG (OR =1.363, 95% CI = 1.035–1.797, P=0.028) and ε4 allele (OR =1.954, 95% CI = 1.359–2.810; P<0.001) were significant independent risk factors for CI (Table 5). Furthermore, to exclude the confounding effect of age (≤60 years and >60 years) and sex, multivariate logistic regression analysis stratified according to age and sex was performed. In both age groups, ε4 carriers were associated with increased risk of CI (age ≤60 years: OR = 2.970, 95% CI = 1.553–5.678, P = 0.001; age >60 years: OR = 1.715, 95% CI = 1.082–2.719, P = 0.022). Also, ε4 carriers was significantly associated with a higher risk of CI in males (OR =2.182, 95% CI = 1.398–3.407, P=0.022), but not in females (OR =1.500, 95% CI = 0.779–2.887, P=0.225) (Table 6).

Table 5

Logistic regression analysis of the risk of CI in Northwest of China population.
Variables	P- value	OR (95% CI)
Drinking	0.006	1.701(1.167-2.478)
Hypertension	0.000	1.885(1.417-2.508)
Lipoprotein	0.046	1.001(1.000-1.001)
TG	0.028	1.363(1.035-1.797)
ApoE	0.017	0.983(0.969-0.997)
ε4	0.000	1.954(1.359-2.810)
CI: cerebral infarction, TG: triglyceride

Table 6

Multiple logistic regression analysis for CI patients and control subjects
ε4
	OR (95% CI)	P-value
Age≤60	2.970(1.553-5.678)	0.001
Age༞60	1.715(1.082-2.719)	0.022
males	2.182(1.398-3.407)	0.001
females	1.500(0.779-2.887)	0.225

The strength of this study is that this is the first study about the relationship of CI and ApoE gene polymorphism in Northwest Han Chinese population. Association of lipid levels with ApoE gene polymorphisms included in the final analysis and have excluded confounding factors or comorbidities affecting the results. There were some inherent limitations presented in our study. (1) Most ofthe present participants may receive lipid-lowering therapy at the time of inclusion, which may have potential impacts on the association of blood lipid profiles with adverse events. (2) As this is a large retrospective study, original data shortage constrained assessment of potential gene-environment interactions. (3) The small sample size of this study, which may lead to the instability of the results to some extent. (4) The study was conducted only in northwest Chinese populations, and whether these findings will also be true in other populations needs further investigation.

In conclusion, the present study suggests that ɛ4 allele is associated with CI in the Northwest Han Chinese population. When stratifying by age and sex, it was found that statistically significant differences in the distribution and frequencies of the ε3/ε4 genotype and ε4 allele in males and ε4 allele in females were observed between patients and controls; ε4 allele was a significant and independent risk factors in elderly and young patients. ApoE gene polymorphisms may be related to lipid metabolism in patients with CI. Since the limited sample size, and thus further studies with larger sample population are needed to clear our findings.

ApoE

apolipoprotein E

cerebral infarction

total cholesterol

HDL

high-density lipoproteins

LDL-C

low-density lipoprotein cholesterol

triglyceride

creatinine

direct bilirubin

indirect bilirubin

HWE

Hardy-Weinberg equilibrium

Acknowledgments

We gratefully acknowledge all sample donors who participated in this study.

Authors’ contributions

Wenbing Ma and Xiaoyun Lu conceived and designed the experiments; Wenbing Ma and Weiyi Feng contributed to the writing of the manuscript. Liting Zhang, Shuang Yang, Houli Li and Suya Zhang recruited subjects and collected clinical data. Haiyan Dong and Weihua Dong helped to analyze the data. All authors read and approved the final manuscript.

Funding

This work was supported by the Key R & D Plan Projects in Shaanxi Province (grant number 2021-SF-130) and the Foundation of the First Affiliated Hospital of Xi'an Jiaotong University (grant number 2020ZYTS-08).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Ethics approval and consent to participate

This study was approved by the Ethical Committee of the First Affiliated Hospital of Xi’an Jiao Tong University and we got the informed consent of each patients.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

¹Department of Pharmacology, The First Affliated Hospital of Xi'an Jiaotong University, Xi'an, People’s Republic of China; ²The school of Life Science and technonlogy, Xi'an Jiaotong University, Xi'an, People’s Republic of China.

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Apolipoprotein E Gene Polymorphism Effects on Lipid Metabolism and Risk of Cerebral Infarction in Northwest Han Chinese Population

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Abstract

Introduction

Methods

Subjects

DNA extraction and genotyping

Statistical analyses

Results

Baseline clinical characteristics of the CI and control groups

Allele And Genotype Frequencies Of Apoe And Ci Risk

Logistic Regression Analysis Of Ci Risk Factors

Study Strength And Limitations

Conclusions

Abbreviations

Declarations

References

Table

Supplementary Files

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