Basic characteristics of the control group and the Mets group
Participants in the control group (n = 1029) and the Mets group (n = 1018) are matched by gender and age, differences of the weight, WC, body mass index (BMI), SBP, DBP, triglyceride (TG), total cholesterol (TC), low-density lipid-c (LDL-c), HDL-c, fasting plasma glucose (FPG) levels between the Control group and the Mets group are statistically significant (p < 0.001, Table 1). Frequencies of the C allele and the T allele on rs1044250 locus account for 92.1% and 7.9% respectively in the study population. Distribution of CC, CT, TT genotypes in the control group (χ2 = 0.02; p = 0.99), the Mets group (χ2 = 1.48; p = 0.48), and the study population (χ2 = 1.58; p = 0.45) are followed with Hardy -Weinberg genetic balance.
Table 1
Baseline characteristics of Control group and Mets group
| Controls (n = 1029) | Mets (n = 1018) | p |
Male % | 48.5 | 46 | 0.253 |
Age (years) | 51.29 ± 9.78 | 51.64 ± 9.80 | 0.425 |
Weight (kg) | 58.33 ± 8.30 | 72.60 ± 11.08 | < 0.001 |
WC (cm) | 75.68 ± 6.10 | 91.11 ± 8.46 | < 0.001 |
BMI (kg/m2) | 22.13 ± 3.46 | 27.32 ± 3.46 | < 0.001 |
SBP (mmHg) | 119.69 ± 9.90 | 148.50 ± 19.95 | < 0.001 |
DBP (mmHg) | 74.66 ± 6.44 | 90.53 ± 10.45 | < 0.001 |
TC (mmol/L) | 4.17 ± 0.53 | 4.68 ± 1.18 | < 0.001 |
TG (mmol/L) | 0.93 ± 0.31 | 2.32 ± 1.57 | < 0.001 |
HDL-c (mmol/L) | 1.59 ± 0.34 | 1.49 ± 0.52 | < 0.001 |
LDL-c (mmol/L) | 2.58 ± 0.52 | 3.19 ± 0.82 | < 0.001 |
FPG (mmol/L) | 4.59 ± 0.51 | 5.96 ± 2.11 | < 0.001 |
Continuous variables are recorded by \(\stackrel{-}{x}\pm S\); categorical variables are recorded in proportions; Mets, metabolic syndrome; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; TC, total cholesterol; HDL-c, high-density lipoprotein-c; LDL-c, low-density lipoprotein-c; FPG, fasting plasma glucose. |
Risks of the SNP rs1044250 on Mets and the components of Mets
The laboratory indicators among patients with CC, CT and TT genotypes at ANGPTL4 gene rs1044250 locus are compared respectively, the result indicates that the baseline data among genotypes in the control group do not show difference (p > 0.05, Supplemental Table S1), while in the Mets group, HDL-c is significantly higher in patients with TT genotype than patients with CC or CT genotypes (p < 0.05, Supplemental Table S1).
The frequencies of rs1044250 genotypes are significantly different between the control group and the Mets group (χ2 = 25.556; p < 0.001, Supplemental Table S2), and the frequency of T alleles in the control group is significantly lower than that in the Mets group (χ2 = 25.991; p < 0.001, Supplemental Table S2). The study population is subdivided into groups respectively according to the presence or absence of each of the five components of Mets. The frequencies of CC, CT, TT genotypes as well as the frequencies of C allele and T allele are significantly different between the normal WC group and the increased WC group, statistical significances were also found between the normal TG group and the elevated TG group, the normal blood pressure group and the elevated blood pressure group, the normal FPG group and the elevated FPG group (p < 0.05, Supplemental Table S2).
Multi-factor stepwise Logistic regression analysis shows the SNP rs1044250 is an independent risk factor for metabolic syndrome (OR 1.875 [95% CI 1.363–2.580]; p < 0.001, Table 2). Accordingly, the five components of Mets are studied respectively, the SNP rs1044250 is an independent risk factor for increased WC (OR 1.618 [95% CI 1.119–2.340]; p = 0.011, Table 2) and increased blood pressure (OR 1.323 [95% CI 1.002–1.747]; p = 0.048, Table 2). In addition, patients with various rs1044250 genotypes are significantly different in the numbers of Mets components (M [Q1, Q3]: CC 2 [0, 3], CT 3 [0, 3], TT 3 [3, 3]; p = 0.001). Multivariate linear regression analysis confirms that the SNP rs1044250 (β = 0.044; p = 0.007), age (β = 0.068; p < 0.001), weight (β = 0.221; p < 0.001), BMI (β = 0.387; p < 0.001) and LDL-c (β = 0.200; p < 0.001) are independent risk factors for the increased number of Mets components carried by patients.
Table 2
Logistic regression analysis of Mets and Mets components
| Independent variables | β | p | OR | 95% CI |
Lower | Upper |
Mets | | | | | | |
| Sex (male vs female) | -0.812 | < 0.001 | 0.444 | 0.313 | 0.630 |
Age (years) | 0.019 | 0.009 | 1.019 | 1.005 | 1.034 |
Weight (kg) | 0.081 | < 0.001 | 1.085 | 1.055 | 1.115 |
BMI (kg/m2) | 0.351 | < 0.001 | 1.420 | 1.308 | 1.541 |
LDL-c (mmol/L) | 1.210 | < 0.001 | 3.355 | 2.699 | 4.171 |
rs1044250 | 0.629 | < 0.001 | 1.875 | 1.363 | 2.580 |
Increased WC | | | | | | |
| Sex (male vs female) | -2.367 | < 0.001 | 0.094 | 0.059 | 0.149 |
Age (years) | 0.033 | < 0.001 | 1.034 | 1.015 | 1.053 |
Weight (kg) | 0.104 | < 0.001 | 1.110 | 1.073 | 1.148 |
BMI (kg/m2) | 0.265 | < 0.001 | 1.303 | 1.185 | 1.434 |
TG (mmol/L) | 0.328 | < 0.001 | 1.388 | 1.225 | 1.573 |
HDL-c (mmol/L) | -0.372 | 0.029 | 0.689 | 0.493 | 0.963 |
SBP (mmHg) | 0.046 | < 0.001 | 1.047 | 1.033 | 1.060 |
DBP (mmHg) | 0.068 | < 0.001 | 1.070 | 1.047 | 1.094 |
rs1044250 | 0.481 | 0.011 | 1.618 | 1.119 | 2.340 |
Elevated BP | | | | | | |
| Age (years) | 0.035 | < 0.001 | 1.036 | 1.024 | 1.048 |
BMI (kg/m2) | 0.327 | < 0.001 | 1.387 | 1.338 | 1.438 |
FPG (mmol/L) | 0.308 | < 0.001 | 1.361 | 1.237 | 1.497 |
LDL-c (mmol/L) | 0.535 | < 0.001 | 1.708 | 1.439 | 2.028 |
rs1044250 | 0.280 | 0.048 | 1.323 | 1.002 | 1.747 |
Increased TG | | | | | | |
| BMI (kg/m2) | 0.095 | < 0.001 | 1.099 | 1.051 | 1.150 |
WC (cm) | 0.065 | < 0.001 | 1.067 | 1.048 | 1.086 |
TC (mmol/L) | 0.708 | < 0.001 | 2.030 | 1.778 | 2.319 |
FPG (mmol/L) | 0.146 | < 0.001 | 1.158 | 1.079 | 1.242 |
DBP (mmHg) | 0.049 | < 0.001 | 1.050 | 1.038 | 1.062 |
rs1044250 | 0.046 | 0.752 | 1.047 | 0.786 | 1.395 |
Decreased HDL-c | | | | | | |
| Sex (male vs female) | 0.491 | < 0.001 | 1.634 | 1.332 | 2.004 |
WC (cm) | 0.028 | < 0.001 | 1.028 | 1.016 | 1.040 |
DBP (mmHg) | 0.022 | < 0.001 | 1.022 | 1.012 | 1.032 |
rs1044250 | -0.078 | 0.532 | 0.925 | 0.723 | 1.182 |
Increased FPG | | | | | | |
| WC (cm) | 0.046 | < 0.001 | 1.048 | 1.034 | 1.062 |
TC (mmol/L) | 0.647 | < 0.001 | 1.911 | 1.601 | 2.281 |
TG (mmol/L) | 0.140 | 0.002 | 1.151 | 1.054 | 1.256 |
HDL-c (mmol/L) | -0.447 | 0.016 | 0.640 | 0.444 | 0.921 |
SBP (mmHg) | 0.013 | 0.001 | 1.013 | 1.005 | 1.021 |
DBP (mmHg) | 0.018 | 0.011 | 1.018 | 1.004 | 1.032 |
rs1044250 | 0.126 | 0.361 | 1.135 | 0.866 | 1.487 |
Mets, metabolic syndrome; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; TC, total cholesterol; HDL-c, high-density lipoprotein-c; LDL-c, low-density lipoprotein-c; WC, waist circumference; FPG, fasting plasma glucose; rs1044250, (CC = 0, TC = 1, TT = 2); OR, odds ratio; 95% CI, 95% confidence interval. |
Baseline Characteristic Changes Of The Study Population
Compared with the control group, the weight, WC, BMI, SBP, DBP, TG, TC, LDL-c and FPG of the Mets group are significantly reduced in 5 years (p < 0.05, Table 3). In the Mets group, HDL-c level is significantly elevated in patients with TT genotype than that in CC genotype or CT genotype patients (p < 0.05, Table 3). Linear regression analysis shows that the SNP rs1044250 (β = -0.065; p = 0.017), Sex (β: = -0.069; p = 0.012) and TG (β = -0.611; p < 0.001) are independent risk factors for HDL-c reduction in patients with Mets in the 5-year follow-up survey.
Table 3
Baseline characteristics changes in 5-year follow-up survey of various rs1044250 genotypes in the Control group and the Mets group
| Control | | Mets |
| CC (n = 174) | CT + TT (n = 28) | Total (n = 202) | CC (n = 667) | CT (n = 151) | TT (n = 13) | Total (n = 202) |
Sex (male%) | 47.7% | 57.1% | 49.0% | | 47.5% | 39.7% | 30.8% | 45.9% |
Age (years) | 51.64 ± 9.30 | 51.07 ± 10.51 | 51.56 ± 9.45 | 51.42 ± 9.68 | 52.47 ± 10.20 | 54.00 ± 10.57 | 51.65 ± 9.79 |
ΔWeight (kg) | -0.31 ± 1.64 | -0.52 ± 1.66 | -0.37 ± 1.64 | -2.11 ± 3.11 | -1.98 ± 2.78 | -1.90 ± 1.50 | -2.08 ± 3.03‡ |
ΔBMI (kg/m2) | 0.09 ± 0.86 | -0.02 ± 0.65 | 0.07 ± 0.84 | -0.55 ± 1.08 | -0.51 ± 1.00 | -0.46 ± 0.63 | -0.54 ± 1.06‡ |
ΔWC (cm) | -0.54 ± 3.02 | -0.98 ± 2.24 | -0.60 ± 2.92 | -4.37 ± 3.36 | -3.91 ± 3.08 | -4.27 ± 3.45 | -4.28 ± 3.31‡ |
ΔSBP (mmHg) | 1.07 ± 6.79 | 0.17 ± 5.53 | 0.95 ± 6.62 | -7.16 ± 13.39 | -6.90 ± 11.75 | -4.13 ± 8.09 | -7.06 ± 13.04‡ |
ΔDBP (mmHg) | -0.27 ± 2.53 | 0.38 ± 1.59 | -0.18 ± 2.43 | -5.46 ± 6.85 | -5.17 ± 6.69 | -4.97 ± 6.96 | -5.40 ± 6.82‡ |
ΔTG (mmol/L) | 0.32 ± 0.50 | 0.23 ± 0.58 | 0.31 ± 0.51 | -0.84 ± 1.81 | -0.70 ± 1.43 | -1.02 ± 1.90 | -0.82 ± 1.75‡ |
ΔTC (mmol/L) | 0.13 ± 1.08 | -0.08 ± 1.15 | 0.10 ± 1.09 | -0.33 ± 1.31 | -0.21 ± 1.33 | -0.75 ± 1.61 | -0.32 ± 1.32‡ |
ΔHDL-c (mmol/L) | -0.24 ± 0.48 | -0.09 ± 0.36 | -0.22 ± 0.46 | -0.25 ± 0.66 | -0.32 ± 0.64 | -0.83 ± 1.12*† | -0.27 ± 0.67 |
ΔFPG (mmol/L) | 0.43 ± 1.42 | 0.59 ± 1.34 | 0.45 ± 1.41 | -0.12 ± 2.43 | -0.38 ± 2.53 | -0.10 ± 1.82 | -0.17 ± 2.44‡ |
Continuous variables are recorded by \(\stackrel{-}{x}\pm S\); Categorical variables are recorded in proportions; * statistically significant compared with CC genotype in the Mets group; †statistically significant compared with CT genotype in the Mets group; ‡ statistically significant compared with the Mets group; Δ, follow-up values minus baseline values; Mets, metabolic syndrome; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; TC, total cholesterol; HDL-c, high-density lipoprotein-c; FPG, fasting plasma glucose. |
Changes In The Number Of Mets Components
The study population is subdivided into Weight loss group (ΔWeight < 0) and Weight gain group (ΔWeight ≥ 0), the distribution of rs1044250 genotypes (fisher = 1.162; p = 0.532) and T alleles (χ2 = 0.878; p = 0.349) in these groups do not show significant difference. Among patients with CC, CT and TT genotypes at rs1044250 locus, changes of the number of Mets components do not show any difference (M [Q1, Q3]: CC 0 [-1, 1], CT 0 [-1, 1], TT 0 [-1, 1]; p = 0.529, Supplemental Table S3). However, subgroup analysis based on weight management indicates that the number changes of Mets components between CC genotype and CT or TT genotype in the weight gain group are significantly different (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [-1, 1]; p = 0.021, Supplemental Table S3), while there is no difference showed in the weight loss group (M [Q1, Q3]: CC 0 [-1, 1], CT + TT -0 [-1, 1], p = 0.732, Supplemental Table S3). Indeed, under an ordinal regression model, the SNP rs1044250 (β = -0.703; p = 0.024), TG (β = -0.337; p < 0.001) and FPG (β = -0.242; p = 0.003) are independent protective factors for the number of Mets components when the body weight is increased, which suggests that people with CC genotype are more likely to catch-up with the number of Mets components.
Interaction Of SNP rs1044250 And Weight Management
In the weight loss group, the HDL-c level is significantly decreased in patients with TT genotype at rs1044250 locus compared with CC (p = 0.002, Table 4) and CT (p = 0.008, Table 4) genotype. In the weight gain group, the SBP (p = 0.002, Table 4) and DBP (Table 4; p = 0.004) of CC genotype are significantly higher than that of CT genotype. Accordingly, the interaction of SNP rs1044250 and weight management on SBP (F = 3.291; p = 0.038, Table 4), DBP (F = 3.026; p = 0.049, Table 4) and HDL-c (F = 6.269; p = 0.002, Table 4) are statistically significant.
Table 4
Factorial analysis SNP rs1044250 and weight management on clinical characteristic changes
| Weight loss | | Weight gain | | p |
CC (n = 709) | CT (n = 146) | TT (n = 11) | | CC (n = 132) | CT (n = 32) | TT (n = 3) | | rs1044250 | ΔWeight | Rs1044250 *ΔWeight |
ΔWeight (kg) | -2.23 ± 2.81 | -2.27 ± 2.68 | -2.25 ± 1.35 | | 0.94 ± 2.24 | 0.53 ± 0.81 | 0.67 ± 1.15 | | | | |
ΔBMI (kg/m2) | -0.61 ± 0.94 | -0.61 ± 0.97 | -0.62 ± 0.51 | | 0.61 ± 1.16 | 0.36 ± 0.38 | 0.55 ± 0.54 | | | | |
ΔWC (cm) | -4.46 ± 3.11 | -4.26 ± 2.76 | -5.45 ± 2.05 | | 1.10 ± 2.33 | 0.20 ± 2.11 | 0.67 ± 2.75 | | | | |
ΔSBP (mmHg) | -6.48 ± 13.12 | -5.79 ± 10.81 | -4.55 ± 8.55 | | 0.04 ± 8.77 | -6.12 ± 13.51‡ | 0.33 ± 5.86 | | 0.113 | 0.191 | 0.038 |
ΔDBP (mmHg) | -5.06 ± 6.70 | -4.51 ± 6.40 | -5.97 ± 7.13 | | -0.78 ± 4.14 | -3.51 ± 6.99 ‡ | 0.56 ± 0.84 | | 0.285 | 0.007 | 0.049 |
ΔTG (mmol/L) | -0.69 ± 1.69 | -0.58 ± 1.39 | -1.33 ± 1.91 | | -0.14 ± 1.64 | -0.48 ± 1.33 | 0.79 ± 0.31 | | | | |
ΔTC (mmol/L) | -0.30 ± 1.28 | -0.21 ± 1.36 | -0.80 ± 1.74 | | 0.07 ± 1.22 | -0.17 ± 0.89 | 0.59 ± 1.97 | | | | |
ΔHDL-c (mmol/L) | -0.25 ± 0.64 | -0.31 ± 0.59 | -1.07 ± 0.97*† | | -0.22 ± 0.53 | -0.19 ± 0.67 | 0.41 ± 0.83 | | 0.889 | < 0.001 | 0.002 |
ΔFPG (mmol/L) | -0.04 ± 2.32 | -0.24 ± 2.47 | -0.12 ± 1.98 | | 0.16 ± 1.96 | -0.21 ± 2.16 | 0.34 ± 0.75 | | | | |
Continuous variables are recorded by \(\stackrel{-}{x}\pm S\); * statistically significant compared with CC genotype in the Weight loss group; †statistically significant compared with CT genotype in the Weight loss group; ‡ statistically significant compared with CC genotype in the Weight gain group; Δ, follow-up values minus baseline values; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; TC, total cholesterol; HDL-c, high-density lipoprotein-c; FPG, fasting plasma glucose. |
The independent variable ΔWeight*rs1044250 is included into the multi-factor stepwise linear regression equations, of which the dependent variable is ΔSBP and ΔDBP respectively. Therefore, the interaction of SNP rs1044250 and weight management is an independent risk factor for elevated SBP (β = 0.075; p < 0.001, Table 5) and elevated DBP (β = 0.097; p < 0.001, Table 5). The independent variable ΔWeight*rs1044250 is excluded from the linear regression equations of ΔHDL-c (β = 0.004, p = 0.851, Table 5).
Table 5
Linear regressions analysis of ΔSBP, ΔDBP and ΔHDL-c
| | β | p | R2 |
ΔSBP (mmHg) | | | | |
| Antihypertensive | -0.215 | 0.000 | 0.719 |
Antidiabetic | 0.058 | 0.001 |
WC (cm) | 0.135 | 0.000 |
BMI (kg/m2) | 0.052 | 0.032 |
TG (mmol/L) | 0.047 | 0.006 |
SBP (mmHg) | -0.835 | 0.000 |
DBP (mmHg) | 0.112 | 0.000 |
ΔWeight*rs1044250 | 0.075 | 0.000 |
ΔDBP (mmHg) | | | | |
| Antihypertensive | -0.373 | 0.000 | 0.696 |
Antidiabetic | 0.048 | 0.007 |
WC (cm) | 0.148 | 0.000 |
HDL-c (mmol/L) | -0.035 | 0.045 |
DBP (mmHg) | -0.621 | 0.000 |
ΔWeight*rs1044250 | 0.097 | 0.000 |
ΔHDL-c (mmol/L) | | | | |
| Antidiabetic | -0.060 | 0.003 | 0.580 |
WC (cm) | -0.072 | 0.003 |
TG (mmol/L) | -0.052 | 0.013 |
HDL-c (mmol/L) | -0.741 | 0.000 |
ΔWeight*rs1044250 | 0.004 | 0.851 |
Δ, follow-up values minus baseline values; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; HDL-c, high-density lipoprotein-c; WC, waist circumference; FPG, fasting plasma glucose; rs1044250, (CC = 0, TC = 1, TT = 2). |
A crossover analysis is conducted to study the interaction of ANGPTL4 gene SNP rs1044250 and weight management on ΔSBP, ΔDBP, ΔHDL-c under linear regression model. In the linear regression model with ΔSBP as the dependent variable, the independent variables SNP rs1044250 (β = 0.193; p < 0.001, Table 6) and rs1044250*Weight Management (β = -0.093; p = 0.013, Table 6) are included in the regression equation, meanwhile the interaction between SNP rs1044250 and weight management on ΔSBP is negative (synergy index = 0.558); in the linear regression model with ΔDBP as dependent variable, the SNP rs1044250 (β = 0.241; p < 0.001, Table 6) and rs1044250* Weight Management (β = -0.078; p = 0.035, Table 6) are included in the regression equation, and the synergistic effect between SNP rs1044250 and weight management are negative (synergy index = 0.696).
Table 6
Crossover analysis of SNP rs1044250 and WM on ΔSBP, ΔDBP and ΔHDL-c
| | β | OR | p | S |
ΔSBP | | | | | |
| WM | 0.024 | 1.024 | 0.477 | 0.558 |
| Dom | 0.193 | 1.212 | 0.000 |
| Dom*WM | -0.093 | 0.911 | 0.013 |
ΔDBP | | | | | |
| WM | 0.027 | 1.027 | 0.429 | 0.696 |
| Dom | 0.241 | 1.273 | 0.000 |
| Dom*WM | -0.078 | 0.925 | 0.035 |
ΔHDL-c | | | | | |
| WM | -0.066 | 0.936 | 0.053 | 0.106* |
| Dom | 0.017 | 1.017 | 0.620 |
| Dom*WM | 0.054 | 1.056 | 0.154 |
SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; HDL-c, high-density lipoprotein-c; WM, Weight loss = 0, Weight gain = 1; Dom, CC = 0, CT + TT = 1, OR, odds ratio; S, synergy index; S = [EXP(βWM + βDom + βDom*WM) -1] / [EXP(βWM) + EXP(βDom) − 2], * the denominator is calibrated from negative to positive |