Abstract
Little is known about the association of monoacylglycerol acyltransferase 1 gene (MGAT1) rs634501 single nucleotide polymorphism (SNP) and serum lipid profiles in the Chinese populations. The aim of this study was to detect the association of the MGAT1 rs634501 SNP and several environmental factors with serum lipid levels in the Chinese Maonan and Han populations. Genotypes of the SNP in 2014 unrelated participants (Han, 986; Maonan, 1028) were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and confirmed by direct sequencing. The genotypic and allelic frequencies of the MGAT1 rs634501 SNP were significantly different between the Han and Maonan populations as well as between males and females in the Maonan population. The A allele carriers had lower serum apolipoprotein (Apo) A1 levels, the ApoA1/ApoB ratio and higher ApoB levels in Maonans; and lower high-density lipoprotein cholesterol, ApoA1 levels, ApoA1/ApoB ratio, and higher triglyceride levels in Han than the A allele non-carriers. There were also different associations of the MGAT1 rs634501 SNP and serum lipid profiles between males and females in the both ethnic groups. Serum lipid parameters in the two ethnic groups were also associated with several environmental factors. These results suggest that the association of the MGAT1 rs634501 SNP and serum lipid parameters might have ethnic- and/or sex-specificity.
Keywords: Mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase; single nucleotide polymorphism; lipids; environmental factors
Introduction
Coronary heart disease (CHD) is the main cause of death and disability worldwide, and it is a huge drain on public health expenditure [1-3]. CHD in the United States leads to 502,000 deaths each year [4], while the number of deaths per year in China is higher than 700,000 [5]. It is a truth universally acknowledged that dyslipidemia plays a vital role in CHD [6]. Dyslipidemia includes increased serum or plasma total cholesterol (TC) [7], triglyceride (TG) [8], low-density lipoprotein cholesterol (LDL-C) [9], and apolipoprotein (Apo) B [10] levels, together with decreased levels of ApoA1 [10], high-density lipoprotein cholesterol (HDL-C) [11] and the ratio of ApoA1 to ApoB (ApoA1/ApoB) [12].
To date, many studies have shown that dyslipidemia is a multi-factorial disease influenced by both environmental and genetic factors [13,14]. Accumulating evidence has shown that the heritability estimates of the inter-individual variation give rise to a considerable genetic contribution [15,16]. Recently genome-wide association studies (GWASes), which could display genetic contribution to dyslipidemia, have identified multiple lipid-related loci and provided valuable information to develop novel therapeutic interventions for dyslipidemia [17,18].
Mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase gene (MGAT1), localizes on chromosome 5, and is a key enzyme involved in glycosylation of proteins and lipids [19]. It has been found that a variant of the MGAT1 rs12517906, rs4285184 SNPs is associated with body weight and obesity [20,21]. Recently, GWASes have identified that genetic variant of MGAT1 rs634501 SNP is associated with serum HDL-C level in East Asians [22]. However, the effect of MGAT1 rs634501 SNP on serum lipid levels is not functionally validated and the mechanism is yet unclear. Furthermore, the reproducibility of this association has not been detected in the Chinese populations to date.
China is a multi-ethnic country since ancient times. Han is the largest one and Maonan ethnic group is one of the 55 ethnic minorities with a population of 101,192 according to the sixth national census statistics of China in 2010. Maonan nationality mainly settled in the Huanjiang Maonan Autonomous County, Guangxi Zhuang Autonomous Region. In a previous study, we have shown significant association of several SNPs [23] and serum lipid levels in the Maonan population. To date, the association of rs634501 SNP and serum lipid levels has not been explored in the Chinese populations. Therefore, the aim of the present study was to assess the association of the MGAT1 rs634501 SNP and several environmental factors with serum lipid phenotypes in the Han and Maonan populations.
Materials and methods
Study population
The present study included 2,014 unrelated subjects who were randomly selected from our previous stratified randomized samples. The sample comprised 986 Han Chinese (480 males, 48.68%; 506 females, 51.32%) and 1028 Maonan subjects (503 males, 48.93%; 525 females, 51.07%). They lived in the Huanjiang Maonan Autonomous County, Guangxi, China. Age ranged from 16 to 92 years, with a mean age of 56.25 ± 13.93 years (Han) and 57.19 ± 14.86 years (Maonan). The two ethnic groups showed similar age distribution and gender ratio. All participants were healthy and showed no evidence of diabetes, CHD, or atherosclerosis. None of the subjects was taking medications known to affect serum lipid levels, such as statins, hormones, diuretics, or beta-blockers. This study was approved by the Ethics Committee of the First Affiliated Hospital, Guangxi Medical University (Lunshen-2014-KY-Guoji-001, 07 March 2014). Informed consent was obtained from all subjects.
Epidemiological survey
The present study was carried out using internationally standardized methods [24,25]. Standardized questionnaire was used to collect the information on socioeconomic status, lifestyle factors, and demographics. Cigarette smoking was categorized into groups of 0 (non-smoker), ≤ 20 or > 20 cigarettes/day. Alcohol intake was quantified as the number of liang (50 g) of corn wine, rice wine, beer, rum, or liquor consumed during the preceding 12 months. Alcohol consumption was categorized based on grams consumed per day: 0 (non-drinker), ≤ 25/day or > 25/day. In the physical examination, several parameters covering body height, weight, body mass index (BMI), waist circumference, and blood pressure (BP) were measured. Height was measured, to the nearest 0.5 cm, using a stadiometer. Weight, to the nearest 50 g, was estimated by a portable weighing machine. BMI (kg/m2) was calculated. Waist circumference was measured by a non-stretchable measuring tape. Sitting BP was measured three times with the using of a mercury sphygmomanometers. Systolic BP (SBP) was determined by the first Korotkoff sound, and diastolic BP (DBP) by the fifth Korotkoff sound.
Clinical specimen analysis
Venous blood sample (5 ml) was extracted from all subjects after at least 12 h of fasting. From the total sample, 2-ml was used to determine serum lipid levels, and the remaining 3-ml was used to extract deoxyribonucleic acid (DNA). Measurements of serum TC, TG, HDL-C, and LDL-C levels were performed enzymatically using commercially available kits (Randox Laboratories, Crumlin, UK; Daiichi Pure Chemicals, Tokyo, Japan). Serum ApoA1 and ApoB levels were assayed using a commercial turbidimetric immunoassay. All determinations were made on an auto-analyzer (Type 7170A; Hitachi, Tokyo, Japan) at the Clinical Science Experiment Center of the First Affiliated Hospital, Guangxi Medical University [26,27].
Diagnostic criteria
The normal ranges of serum clinical values based on routine practice at our Clinical Science Experimental Center were: TC, 3.10-5.17 mmol/L; TG, 0.56-1.70 mmol/L; HDL-C, 1.16-1.42 mmol/L; LDL-C, 2.70-3.10 mmol/L; ApoA1, 1.20-1.60 g/L; ApoB, 0.80-1.05 g/L; and ApoA1/ApoB ratio, 1.00-2.50. Individuals with TC > 5.17 mmol/L and/or TG > 1.70 mmol/L were defined as hyperlipidemic. Normal weight, overweight and obesity were defined, respectively, as a BMI < 24, 24-28 or > 28 kg/m2.
DNA amplification and genotyping
Genomic DNA was extracted from peripheral blood leukocytes by the phenol-chloroform method [26,27]. The extracted DNA was stored at 4°C until analysis. The MGAT1 rs634501 SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. PCR amplification was performed using 5’-TTCCTGCTTAATACCCCGCA-3’ and 5’-GGTGGAGAAAGTGAGGACCA-3’ as the forward and reverse primer pairs. Each amplification reaction was performed in a total volume of 25 μl, which contained 2.5 μl of 10 × PCR buffer (1.8 mM MgCl2), 1 U of Taq polymerase, 2.0 μl of 2.5 mmol/L dNTPs (Tiangen, Beijing, China), 20 pmol/L of each primer and 50 ng of genomic DNA. Reactions were heated at 95°C for 5 min, followed by 33 cycles of denaturation for 30 s at 95°C, annealing for 30 s at 59°C and elongation for 35 s at 72°C. After electrophoresis on a 2.0% (w/v) agarose gel with 0.5 μg/ml ethidium bromide, the amplified products were visualized under UV light. Then amplification, TspRI restriction enzyme was added directly to the PCR products (10 μl) at digested at 65°C for 0.5 h. Digests were run on agarose gels, stained with 2% ethidium bromide and visualized by ultraviolet illumination. Genotypes were scored by an experienced reader blinded to epidemiological and lipid results. Three samples with each rs634501 genotypes as determined by PCR-RFLP (nine samples total) were confirmed by direct sequencing. PCR products were purified on low-melting-point agarose gel, phenol-extracted, and sequenced on an ABI Prism 3100 sequencer (Applied Biosystems) by Shanghai Sango Biological Engineering Technology & Services (Shanghai, China).
Statistical analyses
Epidemiological data were recorded on a predesigned form and managed using Microsoft Excel. Statistical analyses were performed using SPSS 17.0 (IBM, Chicago, IL, USA). Quantitative variables were expressed as mean ± standard deviation, and qualitative variables were expressed as percentages. Allele frequency was determined by direct counting, while accordance with predictions of Hardy-Weinberg equilibrium was assessed based on standard goodness-of-fit. Differences in general characteristics between the two ethnic groups were assessed for significance using Student’s unpaired t-test. Differences in genotype distribution between the groups were assessed using the chi-square test. Association between genotype and serum lipid parameters was tested by analysis of covariance (ANCOVA). Data were adjusted for age, BMI, sex, BP, cigarette smoking, and alcohol consumption during statistical analyses. Multivariate linear regression analysis with stepwise modeling was performed to evaluate the association of serum lipid levels with genotypes (AA = 1, AG = 2, GG = 3) and with several environmental factors in the combined Han and Maonan populations. A P < 0.05 was considered significant.
Results
General characteristics and serum lipid profiles
Serum lipid levels and general characteristics of the Han and Maonan populations are summarized in Table 1. Maonan subjects had higher weight, BMI, SBP, DBP, pulse pressure, cigarette smoking, TG, HDL-C, ApoA1 and the ApoA1/ApoB ratio than the Han participants (P < 0.05 for all). There were no differences in gender ratio, age, height, waist circumference, glucose, alcohol consumption, TC, LDL-C and ApoB levels between the two ethnic groups (P > 0.05 for all).
Table 1.
Comparison of demographic, and lifestyle characteristics and serum lipid profiles between the Maonan and Han populations
| Characteristics | Han | Maonan | t (x 2) | P |
|---|---|---|---|---|
| Number (n) | 986 | 1028 | ||
| Gender (Male/Female) | 480/506 | 503/525 | 0.012 | 0.911 |
| Age (years) | 56.25 ± 13.93 | 57.19 ± 14.86 | -1.465 | 0.143 |
| Height (cm) | 157.20 ± 8.14 | 156.12 ± 8.18 | 0.417 | 0.677 |
| Weight (kg) | 53.88 ± 10.60 | 55.16 ± 9.27 | 2.881 | 0.004 |
| Body mass index (kg/m2) | ||||
| Underweight (BMI < 18.5) | 48 (4.87) | 65 (6.32) | ||
| Normal weight (18.5 ≤ BMI < 24) | 248 (25.15) | 206 (20.04) | 8.960 | 0.030 |
| Overweight (24 ≤ BMI < 28) | 608 (61.67) | 660 (64.20) | ||
| Obesity (28 ≤ BMI) | 82 (8.31) | 97 (9.44) | ||
| Waist circumference (cm) | 76.47 ± 8.36 | 76.75 ± 9.21 | -0.732 | 0.464 |
| Systolic blood pressure (mmHg) | 130.24 ± 18.94 | 135.89 ± 23.93 | -5.860 | 0.000 |
| Diastolic blood pressure (mmHg) | 81.59 ± 10.82 | 82.65 ± 12.16 | -2.061 | 0.039 |
| Pulse pressure (mmHg) | 48.65 ± 14.84 | 53.24 ± 18.12 | -6.209 | 0.000 |
| Smoking status (n%) | ||||
| Nonsmoking | 738 (74.85) | 859 (83.56) | ||
| ≤ 20 cigarettes/day | 183 (18.56) | 128 (12.45) | 23.463 | 0.000 |
| > 20 cigarettes/day | 65 (6.59) | 41 (3.99) | ||
| Alcohol consumption (n%) | ||||
| Non-drinker | 783 (79.41) | 818 (79.57) | ||
| ≤ 25 g/day | 148 (15.01) | 125 (12.16) | 1.259 | 0.196 |
| > 25 g/day | 55 (5.58) | 85 (8.27) | ||
| Glucose (mmol/L) | 6.40 ± 1.55 | 6.26 ± 1.44 | 1.541 | 0.215 |
| Total cholesterol (mmol/L) | 4.95 ± 1.06 | 4.98 ± 1.40 | -0.657 | 0.511 |
| Triglyceride (mmol/L) | 1.66 (0.60) | 1.70 (0.79) | -2.678 | 0.007 |
| HDL-C (mmol/L) | 1.70 ± 0.41 | 1.75 ± 0.46 | 3.806 | 0.002 |
| LDL-C (mmol/L) | 2.85 ± 0.66 | 2.82 ± 0.72 | 1.327 | 0.185 |
| Apo A1 (g/L) | 1.34 ± 0.28 | 1.37 ± 0.31 | -2.955 | 0.003 |
| ApoB (g/L) | 0.89 ± 0.20 | 0.87 ± 0.20 | 1.321 | 0.143 |
| ApoA1/ApoB | 1.58 ± 0.49 | 1.64 ± 0.64 | -2.014 | 0.044 |
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Apo, Apolipoprotein; ApoA1/ApoB, ratio of ApoA1 to ApoB. Triglyceride values are presented as median (interquartile range). Based on the Wilcoxon-Mann-Whitney test.
Results of electrophoresis and genotyping
The expected 465-bp PCR product was identified in all subjects (Figure 1), and the genotype was determined based on the presence of a TspRI restriction site (G allele) or its absence (A allele). Subjects with a GG genotype showed only a band of 465 bp; subjects with a AG genotype showed bands of 465-, 273- and 192-bp; those with a AA genotype showed bands of 273- and 192-bp (Figure 2). The accuracy of PCR-RFLP genotyping was confirmed by direct sequencing (Figure 3). The genotypes of the rs634501 SNP followed the Hardy-Weinberg equilibrium.
Figure 1.
Electrophoresis of PCR products of the samples. Lane M, 100-bp marker ladder. Lanes 1-6, samples. The target amplicon is 465 bp long.
Figure 2.
Genotyping of the MGAT1 rs634501 SNP. Lane M, 100-bp marker ladder; lanes 1 and 2, GG genotype (465 bp); lanes 3 and 4, AA genotype (273- and 192-bp); and lanes 5 and 6, AG genotype (465-, 273- and 192-bp).
Figure 3.
Partial nucleotide sequence of the MGAT1 rs634501 SNP. (A) AA genotype, (B) AG genotype, and (C) GG genotype.
Genotypic and allelic frequencies
The genotypic and allelic frequencies of the MGAT1 rs634501 SNP in both ethnic groups are shown in Table 2. Genotypic and allelic frequencies were significantly different between the two ethnic groups, as well as between Maonan males and females (P < 0.05 for all), but not between Han males and females (P > 0.05).
Table 2.
Comparison of genotypic and allelic frequencies at MGAT1 rs634501 SNP between the two ethnic groups and between males and females
| Group | n | Genotype | Allele | |||
|---|---|---|---|---|---|---|
|
|
|
|||||
| AA | AG | GG | A | G | ||
| Han | 986 | 203 (20.59) | 502 (50.91) | 281 (28.50) | 908 (46.04) | 1064 (53.96) |
| Maonan | 1028 | 143 (13.91) | 455 (44.26) | 430 (41.83) | 741 (36.04) | 1315 (63.96) |
| x2 | 43.081 | 41.608 | ||||
| P | 0.000 | 0.000 | ||||
| Maonan | ||||||
| Male | 503 | 62 (12.33) | 211 (41.95) | 230 (45.72) | 335 (33.30) | 671 (66.70) |
| Female | 525 | 81 (15.43) | 244 (46.48) | 200 (38.09) | 406 (38.67) | 644 (61.34) |
| x2 | 6.543 | 6.419 | ||||
| P | 0.038 | 0.011 | ||||
| Han | ||||||
| Male | 480 | 105 (21.88) | 253 (52.71) | 122 (25.41) | 463 (48.23) | 497 (51.77) |
| Female | 506 | 98 (19.37) | 249 (49.21) | 159 (31.42) | 445 (43.97) | 567 (56.03) |
| x2 | 4.463 | 3.593 | ||||
| P | 0.107 | 0.058 | ||||
Genotypes and serum lipid profiles
Table 3 summarizes the associations between genotypes and serum lipid levels in Maonan and Han ethnic groups. Serum ApoA1, ApoB levels and the ApoA1/ApoB ratio in Maonans were different among the AA, AG and GG genotypes (P < 0.05). The A allele carriers had lower levels of ApoA1, the ApoA1/ApoB ratio, as well as higher level of ApoB than the A allele non-carriers. Serum TG, HDL-C, ApoA1 levels and the ApoA1/ApoB ratio in Han were different among the three genotypes (P < 0.05). The A allele carriers had lower HDL-C, ApoA1 levels and ApoA1/ApoB ratio, and higher TG than the A allele non-carriers. Subgroup analysis according to sex found that the three genotypes were associated with different levels of TG among Maonan males; TG, ApoA1, ApoB as well as ApoA1/ApoB ratio among Maonan females; TG among Han males; and TG and HDL-C among Han females (P < 0.05 for all).
Table 3.
Comparison of MGAT1 rs634501 genotypes and serum lipid levels in Han and Maonan populations
| Gentoype | N | TC (mmol/L) | TG (mmol/L) | HDL-C (mmol/L) | LDL-C (mmol/L) | ApoA1 (g/L) | ApoB (g/L) | ApoA1/ApoB |
|---|---|---|---|---|---|---|---|---|
| Maonan | ||||||||
| AA | 143 | 5.06 ± 1.30 | 1.82 (0.90) | 1.66 ± 0.41 | 2.81 ± 0.77 | 1.32 ± 0.24 | 0.89 ± 0.19 | 1.57 ± 0.45 |
| AG | 455 | 5.01 ± 1.03 | 1.76 (0.84) | 1.67 ± 0.41 | 2.88 ± 0.84 | 1.39 ± 0.35 | 0.90 ± 0.21 | 1.63 ± 0.62 |
| GG | 430 | 4.99 ± 1.89 | 1.58 (0.72) | 1.72 ± 0.40 | 2.78 ± 0.75 | 1.41 ± 0.24 | 0.86 ± 0.21 | 1.70 ± 0.52 |
| F | 0.139 | 4.503 | 2.671 | 1.945 | 4.611 | 3.660 | 6.276 | |
| P | 0.870 | 0.105 | 0.070 | 0.143 | 0.010 | 0.026 | 0.002 | |
| Male | ||||||||
| AA | 62 | 4.98 ± 1.00 | 1.87 (0.56) | 1.64 ± 0.45 | 2.77 ± 0.81 | 1.33 ± 0.25 | 0.90 ± 0.17 | 1.53 ± 0.42 |
| AG | 211 | 4.91 ± 0.93 | 1.78 (0.94) | 1.66 ± 0.42 | 2.78 ± 0.85 | 1.37 ± 0.45 | 0.90 ± 0.22 | 1.63 ± 0.77 |
| GG | 230 | 4.81 ± 1.31 | 1.61 (0.98) | 1.74 ± 0.43 | 2.70 ± 0.67 | 1.38 ± 0.26 | 0.88 ± 0.21 | 1.67 ± 0.55 |
| F | 0.511 | 6.778 | 2.770 | 0.699 | 0.693 | 0.442 | 1.126 | |
| p | 0.600 | 0.034 | 0.064 | 0.498 | 0.500 | 0.643 | 0.325 | |
| Female | ||||||||
| AA | 81 | 5.13 ± 1.49 | 1.83 (1.22) | 1.68 ± 0.38 | 2.85 ± 0.74 | 1.32 ± 0.23 | 0.88 ± 0.20 | 1.58 ± 0.46 |
| AG | 244 | 5.10 ± 1.10 | 1.70 (0.81) | 1.69 ± 0.39 | 2.97 ± 0.83 | 1.40 ± 0.22 | 0.89 ± 0.20 | 1.63 ± 0.44 |
| GG | 200 | 5.08 ± 1.29 | 1.58 (0.67) | 1.71 ± 0.37 | 2.88 ± 0.81 | 1.43 ± 0.20 | 0.84 ± 0.20 | 1.80 ± 0.49 |
| F | 0.043 | 6.117 | 0.362 | 1.174 | 8.078 | 4.832 | 9.7769 | |
| P | 0.958 | 0.047 | 0.697 | 0.310 | 0.000 | 0.008 | 0.000 | |
| Han | ||||||||
| AA | 203 | 5.06 ± 0.94 | 1.76 (0.57) | 1.66 ± 0.41 | 2.89 ± 0.86 | 1.30 ± 0.22 | 0.90 ± 0.21 | 1.54 ± 0.49 |
| AG | 502 | 4.94 ± 1.09 | 1.66 (0.62) | 1.75 ± 0.49 | 2.84 ± 0.66 | 1.35 ± 0.23 | 0.91 ± 0.23 | 1.56 ± 0.49 |
| GG | 281 | 4.87 ± 1.09 | 1.61 (0.51) | 1.83 ± 0.43 | 2.84 ± 0.43 | 1.36 ± 0.19 | 0.89 ± 0.23 | 1.65 ± 0.50 |
| F | 2.056 | 18.236 | 8.587 | 0.522 | 5.061 | 2.021 | 3.597 | |
| P | 0.129 | 0.000 | 0.000 | 0.594 | 0.007 | 0.133 | 0.028 | |
| Male | ||||||||
| AA | 105 | 5.05 ± 0.87 | 1.76 (0.81) | 1.61 ± 0.39 | 2.91 ± 0.83 | 1.29 ± 0.24 | 0.91 ± 0.20 | 1.50 ± 0.48 |
| AG | 253 | 4.91 ± 0.96 | 1.64 (0.69) | 1.73 ± 0.55 | 2.87 ± 0.58 | 1.34 ± 0.24 | 0.94 ± 0.24 | 1.53 ± 0.54 |
| GG | 122 | 4.90 ± 0.67 | 1.63 (0.76) | 1.82 ± 0.44 | 2.89 ± 0.46 | 1.37 ± 0.21 | 0.90 ± 0.25 | 1.66 ± 0.56 |
| F | 0.996 | 7.495 | 5.172 | 0.066 | 3.449 | 2.255 | 3.544 | |
| P | 0.370 | 0.024 | 0.006 | 0.844 | 0.051 | 0.106 | 0.030 | |
| Female | ||||||||
| AA | 98 | 5.08 ± 1.01 | 1.72 (0.42) | 1.70 ± 0.43 | 2.86 ± 0.90 | 1.30 ± 0.20 | 0.89 ± 0.23 | 1.57 ± 0.53 |
| AG | 249 | 4.96 ± 1.20 | 1.68 (0.56) | 1.77 ± 0.42 | 2.80 ± 0.74 | 1.34 ± 0.23 | 0.89 ± 0.21 | 1.58 ± 0.43 |
| GG | 159 | 4.84 ± 1.33 | 1.61 (0.36) | 1.83 ± 0.42 | 2.79 ± 0.40 | 1.35 ± 0.17 | 0.88 ± 0.21 | 1.62 ± 0.44 |
| F | 1.254 | 17.464 | 3.114 | 0.343 | 2.372 | 0.160 | 0.498 | |
| P | 0.286 | 0.000 | 0.045 | 0.710 | 0.094 | 0.852 | 0.608 |
TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ApoA1, Apolipoprotein A1; ApoB, Apolipoprotein B; ApoA1/ApoB, the ratio of Apolipoprotein A1 to Apolipoprotein B. Triglyceride values are presented as median (interquartile range). Differences among the genotypes were assessed for significance using the Kruskal-Wallis test.
Environmental factors and serum lipid traits
Tables 4, 5 describe the associations between some environmental factors and serum lipid parameters in the two ethnic groups. Several environmental factors such as gender, age, weight, height, waist circumference, cigarette smoking, and alcohol consumption were correlated with serum lipid parameters. Similarly, several traditional cardiovascular risk factors included BMI, blood glucose, SBP, and DBP were also correlated with serum lipid traits (P < 0.05-0.001).
Table 4.
Factors influencing serum lipid parameters in Han and Maonan populations
| Lipid | Risk factor | B | Std.error | Beta | t | P |
|---|---|---|---|---|---|---|
| Han & Maonan | ||||||
| TC | Gender | -0.220 | 0.086 | -0.088 | -2.542 | 0.011 |
| Cigarette smoking | 0.018 | 0.004 | 0.127 | 4.313 | 0.000 | |
| Alcohol consumption | 0.003 | 0.001 | 0.068 | 2.420 | 0.016 | |
| Waist circumference | 0.028 | 0.006 | 0.201 | 4.887 | 0.000 | |
| Systolic blood pressure | 0.005 | 0.002 | 0.082 | 2.215 | 0.027 | |
| TG | Gender | -0.179 | 0.070 | -0.090 | -2.560 | 0.011 |
| Genotype | -0.125 | 0.035 | -0.089 | -3.571 | 0.000 | |
| Waist circumference | 0.011 | 0.005 | 0.096 | 2.301 | 0.022 | |
| Blood glucose | 0.061 | 0.017 | 0.093 | 3.647 | 0.000 | |
| HDL-C | Gender | -0.076 | 0.029 | -0.089 | -2.596 | 0.010 |
| Genotype | 0.068 | 0.015 | 0.113 | 4.650 | 0.000 | |
| Age | 0.002 | 0.001 | 0.081 | 2.800 | 0.005 | |
| Alcohol consumption | 0.002 | 0.000 | 0.145 | 5.230 | 0.000 | |
| Height | 0.007 | 0,004 | 0.142 | 2.026 | 0.043 | |
| Systolic blood pressure | -0.002 | 0.001 | -0.080 | -2.201 | 0.028 | |
| Waist circumference | -0.009 | 0.002 | -0.187 | -4.608 | 0.000 | |
| LDL-C | Gender | 0.642 | 0.059 | 0.352 | 10.918 | 0.000 |
| Genotype | -0.065 | 0.029 | -0.051 | -2.212 | 0.027 | |
| Alcohol consumption | -0.004 | 0.001 | -0.135 | -5.135 | 0.000 | |
| Blood glucose | 0.061 | 0.014 | 0.101 | 4.294 | 0.000 | |
| ApoA1 | Gender | 0.156 | 0.023 | 0.225 | 6.877 | 0.000 |
| Cigarette smoking | 0.004 | 0.001 | 0.087 | 3.144 | 0.002 | |
| Alcohol consumption | 0.002 | 0.000 | 0.160 | 5.993 | 0.000 | |
| ApoB | Genotype | 0.045 | 0.016 | 0.066 | 2.855 | 0.004 |
| Age | 0.002 | 0.001 | 0.056 | 2.038 | 0.042 | |
| Height | -0.011 | 0.004 | -0.190 | -2.834 | 0.005 | |
| Weight | 0.013 | 0.005 | 0.277 | 2.598 | 0.009 | |
| BMI | -0.029 | 0.011 | -0.206 | -2.688 | 0.007 | |
| ApoA1/ApoB | Genotype | 0.096 | 0.022 | 0.124 | 4.417 | 0.000 |
| Age | -0.003 | 0.001 | -0.095 | -2.818 | 0.005 | |
| Alcohol consumption | 0.003 | 0.000 | 0.197 | 6.288 | 0.000 | |
| Weight | -0.018 | 0.006 | -0.311 | -2.773 | 0.006 | |
| Waist circumference | -0.007 | 0.003 | -0.112 | -2.190 | 0.029 | |
| Maonan | ||||||
| TC | Gender | -0.511 | 0.128 | -0.192 | -3.984 | 0.000 |
| Genotype | 0.158 | 0.066 | 0.081 | 2.408 | 0.016 | |
| Cigarette smoking | 0.021 | 0.006 | 0.149 | 3.671 | 0.000 | |
| Alcohol consumption | 0.004 | 0.001 | 0.092 | 2.388 | 0.017 | |
| Height | -0.067 | 0.026 | -0.427 | -2.577 | -0.010 | |
| Weight | 0.082 | 0.036 | 0.662 | 2.280 | 0.023 | |
| BMI | -0.194 | 0.078 | -0.511 | -2.481 | 0.013 | |
| Waist circumference | 0.035 | 0.008 | 0.241 | 4.382 | 0.000 | |
| TG | Gender | -0.237 | 0.120 | -0.113 | -2.269 | 0.024 |
| Genotype | -0.134 | 0.062 | -0.076 | -2.171 | 0.030 | |
| Diastolic blood pressure | 0.008 | 0.004 | 0.077 | 2.056 | 0.040 | |
| Blood glucose | 0.095 | 0.031 | 0.108 | 3.032 | 0.003 | |
| HDL-C | Genotype | 0.062 | 0.020 | 0.105 | 3.087 | 0.002 |
| Age | 0.003 | 0.001 | 0.106 | 2.656 | 0.008 | |
| Alcohol consumption | 0.003 | 0.000 | 0.215 | 5.547 | 0.000 | |
| Waist circumference | -0.009 | 0.002 | -0.206 | -3.740 | 0.000 | |
| Pulse pressure | -0.002 | 0.001 | -0.096 | -2.496 | 0.013 | |
| LDL-C | Gender | 1.325 | 0.054 | 0.758 | 24.427 | 0.000 |
| Age | 0.003 | 0.001 | 0.056 | 2.161 | 0.031 | |
| Cigarette smoking | 0.008 | 0.002 | 0.086 | 3.271 | 0.001 | |
| Alcohol consumption | -0.005 | 0.001 | -0.199 | -7.968 | 0.000 | |
| Height | -0.029 | 0.011 | -0.286 | -2.675 | 0.008 | |
| Weight | 0.049 | 0.015 | 0.600 | 3.206 | 0.001 | |
| BMI | -0.098 | 0.033 | -0.395 | -2.969 | 0.003 | |
| ApoA1 | Gender | 0.423 | 0.030 | 0.543 | 14.328 | 0.000 |
| Cigarette smoking | 0.003 | 0.001 | 0.063 | 1.979 | 0.048 | |
| Alcohol consumption | 0.002 | 0.000 | 0.164 | 5.387 | 0.000 | |
| ApoB | Gender | -0.831 | 0.038 | -0.742 | -21.872 | 0.000 |
| Genotype | 0.077 | 0.019 | 0.095 | 3.974 | 0.000 | |
| Height | -0.029 | 0.008 | -0.448 | -3.835 | 0.000 | |
| Weight | 0.048 | 0.011 | 0.920 | 4.496 | 0.000 | |
| BMI | -0,098 | 0.023 | -0.618 | -4.251 | 0.000 | |
| Waist circumference | -0.009 | 0.002 | -0.156 | -4.029 | 0.000 | |
| Pulse pressure | -0.003 | 0.001 | -0.081 | -2.999 | 0.003 | |
| ApoA1/ApoB | Genotype | 0.117 | 0.050 | 0.117 | 2.327 | 0.021 |
| Age | -0.005 | 0.003 | -0.123 | -2.033 | 0.043 | |
| Alcohol consumption | 0.004 | 0.001 | 0.254 | 4.908 | 0.000 | |
| Waist circumference | -0.019 | 0.006 | -0.263 | -2.931 | 0.004 | |
| Blood glucose | -0.062 | 0.025 | -0.127 | -2.512 | 0.012 | |
| Han | ||||||
| TC | Diastolic blood pressure | 0.006 | 0.004 | 0.062 | 2.662 | 0.043 |
| TG | Genotype | -0.077 | 0.036 | -0.082 | -2.125 | 0.034 |
| Blood glucose | 0.039 | 0.016 | 0.094 | 2.531 | 0.012 | |
| HDL-C | Genotype | 0.098 | 0.023 | 0.159 | 4.245 | 0.000 |
| Height | 0.009 | 0.005 | 0.166 | 2.040 | 0.042 | |
| LDL-C | Genotype | -0.075 | 0.037 | -0.077 | -2.029 | 0.043 |
| Age | 0.004 | 0.002 | 0.092 | 2.148 | 0.032 | |
| Waist circumference | 0.011 | 0.005 | 0.130 | 2.028 | 0.043 | |
| Blood glucose | 0.035 | 0.016 | 0.082 | 2.246 | 0.025 | |
| ApoA1 | Genotype | 0.041 | 0.012 | 0.131 | 2.535 | 0.000 |
| Cigarette smoking | 0.004 | 0.001 | 0.118 | 2.853 | 0.004 | |
| Alcohol consumption | 0.002 | 0.000 | 0.221 | 5.657 | 0.000 | |
| ApoB | Age | 0.002 | 0.001 | 0.128 | 3.018 | 0.003 |
| Weight | 0.007 | 0.003 | 0.299 | 2.457 | 0.014 | |
| Blood glucose | 0.011 | 0.005 | 0.079 | 2.188 | 0.029 | |
| ApoA1/ApoB | Genotype | 0.079 | 0.025 | 0.117 | 3.184 | 0.002 |
| Cigarette smoking | 0.006 | 0.003 | 0086 | 2.101 | 0.036 | |
| Alcohol consumption | 0.002 | 0.001 | 0.116 | 3.005 | 0.003 | |
| Weight | -0.021 | 0.006 | -0.391 | -3.266 | 0.001 | |
| Blood glucose | -0.026 | 0.011 | -0.086 | -2.431 | 0.015 |
TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ApoA1, Apolipoprotein A1; ApoB, Apolipoprotein B; ApoA1/ApoB, the ratio of Apolipoprotein A1 to Apolipoprotein B.
Table 5.
Factors influencing serum lipid parameters in the males and females of Han and Maonan populations
| Lipid | Risk factor | B | Std.error | Beta | t | P |
|---|---|---|---|---|---|---|
| Moanan/Male | 0.003 | |||||
| TC | Age | -0.018 | 0.006 | -0.181 | -3.025 | 0.003 |
| Cigarette smoking | 0.020 | 0.006 | 0.167 | 3.174 | 0.002 | |
| Waist circumference | 0.046 | 0.014 | 0.288 | 3.221 | 0.001 | |
| TG | Blood glucose | 0.105 | 0.059 | 0.150 | 2.781 | 0.006 |
| HDL-C | Genotype | 0.073 | 0.032 | 0.116 | 2.321 | 0.021 |
| Alcohol consumption | 0.003 | 0.000 | 0.282 | 5.495 | 0.000 | |
| Waist circumference | -0.020 | 0.004 | -0.451 | -5.052 | 0.000 | |
| LDL-C | Alcohol consumption | -0.005 | 0.001 | -0.303 | -5.720 | 0.000 |
| Cigarette smoking | 0.008 | 0.003 | 0.129 | 2.382 | 0.018 | |
| ApoA1 | Alcohol consumption | 0.002 | 0.000 | 0.226 | 4.189 | 0.000 |
| Waist circumference | -0.012 | 0.004 | -0.305 | -3.255 | 0.001 | |
| ApoB | Age | 0.002 | 0.001 | 0.152 | 2.605 | 0.010 |
| Alcohol consumption | 0.000 | 0.000 | -0.127 | -2.522 | 0.012 | |
| Height | -0.025 | 0.012 | -0.780 | -2.179 | 0.030 | |
| Weight | 0.038 | 0.015 | 1.803 | 2.496 | 0.013 | |
| BMI | -0.080 | 0.040 | -1.170 | -1.994 | 0.047 | |
| Blood glucose | 0.024 | 0.008 | 0.158 | 3.211 | 0.001 | |
| ApoA1/ApoB | Genotype | 0.116 | 0.049 | 0.118 | 2.362 | 0.019 |
| Age | -0.005 | 0.003 | -0.121 | -2.037 | 0.042 | |
| Alcohol consumption | 0.004 | 0.001 | 0.254 | 4.948 | 0.000 | |
| Waist circumference | -0.019 | 0.006 | -0.265 | -2.967 | 0.003 | |
| Blood glucose | -0.062 | 0.024 | -0.013 | -2.597 | 0.010 | |
| Maonan/female | ||||||
| TC | Age | 0.013 | 0.004 | 0.153 | 2.956 | 0.003 |
| Waist circumference | 0.032 | 0.009 | 0.217 | 3.371 | 0.001 | |
| Blood glucose | -0.123 | 0.040 | -0.138 | -3.071 | 0.002 | |
| TG | Waist circumference | 0.017 | 0.006 | 0.170 | 2.611 | 0.009 |
| Diastolic blood pressure | 0.007 | 0.003 | 0.099 | 2.105 | 0.036 | |
| HDL-C | Age | 0.003 | 0.001 | 0.106 | 2.026 | 0.043 |
| Pulse pressure | -0.002 | 0.001 | -0.106 | -2.090 | 0.037 | |
| LDL-C | Waist circumference | 0.031 | 0.010 | 0.219 | 3.298 | 0.001 |
| ApoA1 | Genotype | 0.060 | 0.014 | 0.193 | 4.265 | 0.000 |
| Height | 0.014 | 0.006 | 0.383 | 2.201 | 0.028 | |
| ApoB | Genotype | -0.042 | 0.012 | -0.144 | -3.415 | 0.001 |
| Age | 0.002 | 0.001 | 0.126 | 2.567 | 0.011 | |
| Waist circumference | 0.008 | 0.001 | 0.355 | 5.829 | 0.000 | |
| Pulse pressure | 0.002 | 0.001 | 0.330 | 2.814 | 0.005 | |
| ApoA1/ApoB | Genotype | 0.157 | 0.029 | 0.231 | 5.450 | 0.000 |
| Waist circumference | -0.016 | 0.003 | -0.290 | -4.760 | 0.000 | |
| Pulse pressure | -0.004 | 0.001 | -0.132 | -2.793 | 0.005 | |
| Han/Male | ||||||
| TC | Weight | -0.031 | 0.015 | -0.299 | -2.017 | 0.045 |
| Waist circumference | 0.024 | 0.011 | 0.211 | 2.070 | 0.039 | |
| Diastolic blood pressure | 0.011 | 0.005 | 0.145 | 2.304 | 0.022 | |
| TG | Age | 0.002 | 0.001 | 0.313 | 2.812 | 0.004 |
| HDL-C | Genotype | 0.160 | 0.044 | 0.235 | 3.685 | 0.000 |
| ApoA1 | Genotype | 0.070 | 0.022 | 0.193 | 3.160 | 0.002 |
| Cigarette smoking | 0.004 | 0.002 | 0.161 | 2.598 | 0.010 | |
| Alcohol consumption | 0.002 | 0.000 | 0.272 | 4.574 | 0.000 | |
| ApoB | Diastolic blood pressure | 0.003 | 0.001 | 0.162 | 2.711 | 0.007 |
| ApoA1/ApoB | Genotype | 0.095 | 0.045 | 0.126 | 2.110 | 0.036 |
| Cigarette smoking | 0.007 | 0.003 | 0.131 | 2.164 | 0.031 | |
| Alcohol consumption | 0.003 | 0.001 | 0.196 | 3.370 | 0.001 | |
| Weight | -0.023 | -.008 | -0.387 | -2.827 | 0.005 | |
| Blood glucose | -0.045 | 0.019 | -0.140 | -2.444 | 0.015 | |
| Han/Female | ||||||
| TC | Genotype | -0.183 | 0.085 | -0.106 | -2.162 | 0.031 |
| TG | Genotype | -0.089 | 0.039 | -0.110 | -2.263 | 0.024 |
| Blood glucose | 0.047 | 0.016 | 0.135 | 2.908 | 0.004 | |
| HDL-C | Genotype | 0.072 | 0.028 | 0.119 | 2.527 | 0.012 |
| LDL-C | Genotype | -0.119 | 0.046 | -0.121 | -2.617 | 0.009 |
| Age | 0.013 | 0.003 | 0.273 | 4.940 | 0.000 | |
| ApoA1 | Genotype | 0.029 | 0.014 | 0.096 | 1.997 | 0.046 |
| Alcohol consumption | 0.004 | 0.001 | 0.133 | 2.865 | 0.004 | |
| ApoB | Age | 0.003 | 0.001 | 0.223 | 3.947 | 0.000 |
| Diastolic blood pressure | -0.002 | 0.001 | -0.107 | -2.222 | 0.027 | |
| ApoA1/ApoB | Genotype | 0.065 | 0.031 | 0.100 | 2.100 | 0.036 |
| Age | -0.005 | 0.002 | -0.158 | -2.776 | 0.006 | |
| Diastolic blood pressure | 0.006 | 0.002 | 0.131 | 2.720 | 0.007 |
TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ApoA1, Apolipoprotein A1; ApoB, Apolipoprotein B; ApoA1/ApoB, the ratio of Apolipoprotein A1 to Apolipoprotein B.
Multiple linear regression analysis showed that serum TG, HDL-C, LDL-C ApoB levels and the ApoA1/ApoB ratio in both ethnic groups; TC, TG, HDL-C, ApoB levels and the ApoA1/ApoB ratio in Maonans; and TG, HDL-C, LDL-C, ApoA1 levels and the ApoA1/ApoB ratio in Hans were correlated with the genotypes (P < 0.05 for all; Table 4).
As shown in Table 5, when serum lipid data were analyzed according to gender, serum HDL-C levels and the ApoA1/ApoB ratio in Maonan males; ApoA1, ApoB levels and the ApoA1/ApoB ratio in Maonan females; HDL-C, ApoA1 levels and the ApoA1/ApoB ratio in Han males; and TC, TG, HDL-C, LDL-C, ApoA1 levels and the ApoA1/ApoB ratio in Han females were correlated with genotypes (P < 0.05 for all).
Discussion
In the current study, we demonstrated that serum TG, HDL-C, ApoA1 levels, and the ApoA1/ApoB ratio were higher in the Maonan subjects than in Han participants. There were no significant differences in TC, LDL-C, and ApoB levels between the two ethnic groups. It is well-known that dyslipidemia is a complex trait caused by environmental and genetic factors. Family and twin studies suggest that in numerous populations, 40-60% of the variation in serum lipid profiles is genetically determined [28,29]. Maonan is a famous mountain nationality as well as a relatively conservative minority in China. Maonan nationality has a huge different culture and life habits from the Han Chinese. To date, they still conserve the original culture and life habits and lack communication with other nationalities. Rice and corn foods are their staple diet, supplemented by sorghum, sweet potatoes, and pumpkin. Marriages arranged by their parents were common and strict intra-ethnic marriages are also popular in this minority. At the same time, the brides do not live with their husbands until the first child is born. Therefore, we considered that the hereditary characteristics and genotypes of certain lipid metabolism-related genes in this population may be different from those in the Han Chinese.
The genotypic and allelic frequencies of the MGAT1 rs634501 SNP in diverse racial/ethnic groups are different, which can be found on the International HapMap project website (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs = 634501). The frequency of AA, AG and GG genotypes was 5.3%, 35.4% and 59.3% in Utah residents with ancestry from Northern and Western Europe (CEU); 8.1%, 45.35% and 46.55% in Japanese in Tokyo, Japan (JPT); 0, 14.16% and 85.84% in Sub-Saharan African (YRI); and 25.58%, 39.53% and 34.89% in Han Chinese in Beijing, China (CHB). The frequency of A and G alleles was 23.0% and 77.0% in CEU; 30.8% and 69.2% in JPT; 7.0% and 93.0% in YRI and 45.35% and 54.65% in CHB. In the current study, the frequency of AA, AG, GG genotypes was 20.59%, 50.91% and 28.50% in Han Chinese; and 13.91%, 44.26% and 41.83% in Maonan nationality. The frequency of A and G alleles was 46.04% and 53.96% in Han; and 36.04% and 63.96% in Maonans. The frequencies of AA genotype and A allele were lower in the Maonans than in the Han Chinese (P < 0.05). According to these results, we conclude that MGAT1 rs634501 SNP may have racial/ethnic specificity in our study populations.
There were scarcely any previous studies showing a direct relationship between the rs634501 SNP and lipid levels in humans except a new GWAS which showed that the rs634501 was significantly associated with HDL-C in the population of East Asians [22]. In the present study, we showed that the A allele carriers had higher ApoB levels and lower ApoA1 levels as well as the ApoA1/ApoB ratio in Maonans; higher TG levels and lower HDL-C, ApoA1 levels as well as the ApoA1/ApoB ratio in Han Chinese; higher TG levels in Maonan males; higher TG, ApoB levels and lower ApoA1 level and the ApoA1/ApoB ratio in Maonan females; higher TG levels in Han males; higher TG levels and lower HDL-C levels in Han females than the A allele non-carriers. These findings indicated that the association of the MGAT1 rs634501 SNP and serum lipid levels may have racial/ethnic and /or sex specificity. As far as we know, our study is the first replication of GWAS signals about the association of the MGAT1 rs634501 SNP with serum lipid levels in the Chinese populations. Therefore, further studies with large sample size are still needed to confirm these associations.
In addition, we also showed that several environmental factors such as age, gender, BMI, waist circumference, SBP, DBP, blood glucose, alcohol consumption and cigarette smoking were associated with serum lipid levels in both ethnic groups. Maonan nationality settles in mountainous areas and has similar eating habits. They like acidic food, such as sour meat, sour snail, and sauerkraut. Maonan people also prefer to eating vegetables, such as peas, cabbages, bittersweet vegetables, as well as pumpkin. At the same time, they consume too many animal offals which contain abundant saturated fatty acid. Several previous studies have shown a correlation between diet and changes in blood lipid levels [30,31] including serum ApoB, ApoA1 levels and the ApoA1/ApoB ratio which can result in the risk of CHD [32-34]. Many other previous studies have reported that diets rich in polyunsaturated fatty acids (PUFAs), high carbohydrates, or saturated fatty acid, and even stearic acid can reduce LDL-C levels [35,36]. In the present study, we also found that different lifestyles, dietary habits, or environmental factors probably further modified the effect of genetic variation on serum lipid levels in Han Chinese and Maonan populations. These findings might be partly attributed to the difference in daily eating habits in our study populations.
There are several limitations in this study. First, the general characteristics of the both ethnic groups were different. Although these characteristics have been adjusted for statistical analysis, we could not completely eliminate the effects of these factors on serum lipid levels among different genotypes in Han Chinese and Maonan populations. Secondly, diet was not adjusted for statistical analysis. In the present study, however, the diet in this isolated population is consistent throughout the year and among individuals because of the Maonans’ reliance on a limited number of locally available food items. Finally, the interactions of gene-gene, gene-environment, and environment-environment on serum lipid levels remain to be determined.
Conclusion
The present study showed that the MGAT1 rs634501 SNP and several environmental factors were associated with some serum lipid parameters in the Chinese Han and Maonan populations, but the associated trends of the SNP and serum lipid parameters are different. There is a sex-specific association of the MGAT1 rs634501 and serum lipid parameters in both ethnic groups.
Acknowledgements
This work was supported by a grant from the National Natural Science Foundation of China (No. 81460169). All procedures of the investigation were carried out following the rules of the Declaration of Helsinki of 1975 (http://www.wma.net/en/30publications/10policies/b3/), revised in 2008. The study design was approved by the Ethics Committee of the First Affiliated Hospital, Guangxi Medical University (No. Lunshen-2014-KY-Guoji-001, Mar. 7, 2014).
Informed consent was obtained from all participants.
Disclosure of conflict of interest
None.
Abbreviations
- ANCOVA
Analysis of covariance
- Apo
Apolipoprotein
- BMI
Body mass index
- CHD
Coronary heart disease
- GWAS
Genome-wide association study
- HDL-C
High-density lipoprotein cholesterol
- HWE
Hardy-Weinberg equilibrium
- LDL-C
Low-density lipoprotein cholesterol
- PCR
Polymerase chain reaction
- RFLP
Restriction fragment length polymorphism
- SNP
Single nucleotide polymorphism
- MGAT1
Mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
- TC
Total cholesterol
- TG
Triglyceride
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