Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity

SUN Hua Lei ZHAO Tong ZHANG Dong Dong FENG Ming Ming XU Ze HUANG Hao Yue ZHANG Luo Ya LI Wen Jie LI Xing DUAN Jia Yu LI Jia

SUN Hua Lei, ZHAO Tong, ZHANG Dong Dong, FENG Ming Ming, XU Ze, HUANG Hao Yue, ZHANG Luo Ya, LI Wen Jie, LI Xing, DUAN Jia Yu, LI Jia. Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity[J]. Biomedical and Environmental Sciences, 2023, 36(2): 196-200. doi: 10.3967/bes2023.022
Citation: SUN Hua Lei, ZHAO Tong, ZHANG Dong Dong, FENG Ming Ming, XU Ze, HUANG Hao Yue, ZHANG Luo Ya, LI Wen Jie, LI Xing, DUAN Jia Yu, LI Jia. Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity[J]. Biomedical and Environmental Sciences, 2023, 36(2): 196-200. doi: 10.3967/bes2023.022

doi: 10.3967/bes2023.022

Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity

Funds: This study is supported by grants from the National Natural Science Foundation of China [grant numbers 82003454, 81903314, and 81872626]; National Natural Science Foundation of Henan Province [grant number 222300420337]; Chinese Nutrition Society - Bright Moon Seaweed Group Nutrition and Health Research Fund [grant number CNS-BMSG2020A63]; Chinese Nutrition Society Zhendong National Physical Fitness and Health Research Fund [grant number CNS-ZD2019066]; key R&D and promotion projects in Henan Province [grant numbers 212102310219, 212102310110, and 202102310120]; and National Natural Science Foundation of China [grant number 81903314]
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    Author Bio:

    SUN Hua Lei, male, born in 1988, Doctor, majoring in nutrition and chronic diseases

    ZHAO Tong, female, born in1997, MPH, majoring in nutrition and mechanisms of nutrition-related metabolic diseases

    Corresponding author: DUAN Jia Yu, E-mail: jyduan@zzu.edu.cnLI Jia, E-mail: deerlijia@163.com Tel: 86-371-67781305.
  • &These authors contributed equally to this work.
  • &These authors contributed equally to this work.
    注释:
  • Figure  1.  Flow diagram of the screening process. A total of 1,014 subjects who met the exclusion criteria were excluded, and 1,364 participants were finally included in this study. HTN, Hypertension; T2DM, type 2 diabetes mellitus

    Table  1.   Genotypic distribution of vitamin D receptor polymorphisms and their association with HDC risk

    SNPsNo-HDCHDCχ2POR (95% CI)aPHWE
    rs22285700.2760.8710.267
    TT236 (20.92%)53 (22.46%)1
    CT580 (51.42%)119 (50.42%)0.874 (0.597−1.279)0.487
    CC312 (27.66%)64 (27.12%)0.766 (0.497−1.182)0.228
    TT/CT+CC0.835 (0.582−1.198)0.328
    TT+CT/CC0.843 (0.599−1.186)0.327
    rs384798710.1080.0060.805
    CC725 (64.27%)128 (54.24%)1
    CA357 (31.65%)91 (38.56%)1.559 (1.133−2.146)0.006
    AA46 (4.08%)17 (7.20%)1.972 (1.043−3.730)0.037
    CC/CA+AA1.610 (1.186−2.185)0.002
    CC+CA/AA1.664 (0.893−3.100)0.109
    rs22391790.0950.9540.342
    AA685 (60.73%)144 (61.02%)1
    AG395 (35.02%)83 (35.17%)0.940 (0.683−1.294)0.706
    GG48 (4.26%)9 (3.81%)0.946 (0.433−2.068)0.889
    AA/AG+GG0.941 (0.691−1.281)0.699
    AA+AG/GG0.967 (0.446−2.097)0.932
    rs7398376.2320.0440.691
    GG637 (56.47%)113 (47.88%)1
    GT418 (37.06%)102 (43.22%)1.412 (1.029−1.937)0.033
    TT73 (6.47%)21 (8.90%)1.681 (0.954−2.962)0.072
    GG/GT+TT1.451 (1.072−1.963)0.016
    GG+GT/TT1.441 (0.834−2.488)0.190
      Note. CI, confidence interval; HWE, Hardy-Weinberg equilibrium; OR, odds ratio. aAdjusted for age, sex, smoking, alcohol drinking, family history of HTN, and family history of diabetes.
    下载: 导出CSV

    S2.   Results of association analysis of metabolic indicators with HDC risk

    IndicatorOR (95% CI)aP
    BMI
    < 18.500.873 (0.192−3.974)0.861
    18.50−23.991
    24.00−27.993.396 (2.258−5.106)< 0.001
    ≥ 28.007.553 (4.799−11.889)< 0.001
    HTGb3.673 (2.676−5.041)< 0.001
    Abnormal WCc4.368 (3.004−6.352)< 0.001
    Abnormal WHRc 4.138 (2.724−6.284)< 0.001
    Abnormal TCd1.710 (1.230−2.378)0.001
    Abnormal HDL-Ce1.352 (0.972−1.879)0.073
    25(OH)D3f
    VDD (< 20)1.204 (0.820−1.768)0.343
    VDI (20−30)0.827 (0.527−1.299)0.411
    VDS (> 30)1
      Note. aAdjusted for age, sex, smoking, alcohol drinking, family history of HTN, and family history of diabetes. bHTG, hypertriglyceridemia (TG ≥ 2.26 mmol/L). cWC > 85 cm or waist-hip ratio WHR ≥ 0.90 for men and > 80 cm or ≥ 0.85 for women are defined as abnormal WC and abnormal WHR. d TC ≥ 5.18 mmol/L was determined to be abnormal TC. eHDL-C < 1.04 mmol/L was defined as abnormal HDL-C. fVDD-vitamin D deficiency (< 20 ng/mL); VDI-vitamin D insufficient (20−30 ng/mL); VDS-vitamin D sufficient (≥ 30 ng/mL).
    下载: 导出CSV

    S3.   The interactions between VDR variants and environment indicators on the HDC risk

    SNPsRERIAPSI
    rs2228570
     BMI−3.27 (−9.03−2.48)−0.42 (0.99−0.14)0.67 (0.44−1.04)
     WC−2.39 (−6.19−1.40)−0.44 (−1.04−0.17)0.65 (0.40−1.06)
     WHR−0.80 (−3.51−1.90)−0.16 (−0.67−0.35)0.83 (0.49−1.41)
     TC−0.04 (−1.59−1.50)−0.02 (−0.76−0.72)0.96 (0.25−3.71)
     TG0.61 (−1.43−2.65)0.19 (−0.41−0.79)1.37 (0.43−4.41)
     HDL-C−0.08 (−0.99−0.82)−0.11 (−1.34−1.12)1.49 (0.01−281.05)
     25(OH)D30.18 (−0.53−0.88)0.18 (−0.61−0.97)0.13 (0.01−1.91)
    rs3847987
     BMI−0.58 (−3.28−2.12)−0.08 (−0.48−0.31)0.91 (0.60−1.39)
     WC0.96 (−1.04−2.97)0.17 (−0.15−0.48)1.25 (0.78−2.01)
     WHR2.54 (0.53−4.55)0.41 (0.18−0.64)1.96 (1.14−3.39)
     TC1.33 (−0.04−2.69)0.43 (0.11−0.75)2.76 (0.85−8.97)
     TG2.67 (0.05−5.29)0.48 (0.18−0.77)2.37 (1.11−5.07)
     HDL-C−1.10 (−3.12−0.93)−0.42 (−1.13−0.29)0.60 (0.30−1.19)
     25(OH)D3−0.59 (−1.97−0.78)−0.28 (−0.92−0.36)0.65 (0.29−1.46)
    rs2239179
     BMI−1.03 (−3.05−0.98)−0.23 (−0.69−0.23)0.77 (0.49−1.23)
     WC−1.47 (−3.63−0.69)−0.32 (−0.81−0.18)0.71 (0.45−1.13)
     WHR−2.82 (−6.23−0.60)−0.43 (−0.94−0.07)0.66 (0.44−0.99)
     TC−1.33 (−2.68−0.01)−0.79 (−1.81−0.24)0.34 (0.10−1.21)
     TG−0.34 (−2.30−1.61)−0.10 (−0.72−0.51)0.87 (0.40−1.91)
     HDL-C0.01 (−0.88−0.91)0.01 (−0.63−0.65)1.03 (0.10−10.48)
     25(OH)D30.17 (−0.55−0.89)0.13 (−0.41−0.66)1.93 (0.02−152.78)
    rs739837
     BMI−1.44 (−4.58−1.71)−0.19 (−0.60−0.23)0.82 (0.55−1.22)
     WC0.58 (−1.48−2.64)0.10 (−0.23−0.43)1.13 (0.72−1.77)
     WHR1.70 (−0.22−3.63)0.28 (0.01−0.55)1.50 (0.92−2.45)
     TC1.10 (−0.18−2.38)0.38 (0.03−0.73)2.40 (0.74−7.76)
     TG2.01 (−0.37−4.38)0.38 (0.05−0.72)1.91 (0.92−3.97)
     HDL-C−0.10 (−2.96−0.97)−0.36 (−1.01−0.28)0.64 (0.34−1.20)
     25(OH)D3−0.58 (−1.90−0.74)−0.28 (−0.88−0.33)0.66 (0.31−1.40)
      Note. SNPs: Single nucleotide polymorphisms; RERI, relative excess risk due to interaction; AP, attributable proportion due to interaction; SI, synergy index; BMI, body mass index; WC, waist circumference; WHR, waist–hip ratio; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol.
    下载: 导出CSV

    Table  2.   Interactions between VDR variants and HTG and abdominal obesity and HDC risk

    SNPsStatusOR (95% CI)P
    rs3847987
    CCNormal TGa1
    AA+CANormal TG1.338 (0.911−1.966) 0.137
    CCHTG3.026 (1.913−4.788)< 0.001
    AA+CAHTG7.749 (4.685−12.817)< 0.001
    RERI2.666 (0.045−5.286)
    AP0.475 (0.183−0.766)
    SI
    rs3847987
    2.367 (1.106−5.065)
    CCNon-abdominal obesity1
    AA+CANon-abdominal obesity0.849 (0.382−1.890) 0.689
    CCabdominal obesityb3.028 (1.800−5.094)< 0.001
    AA+CA
    RERI
    AP
    SI
    abdominal obesity5.742 (3.355−9.828)
    2.544 (0.534−4.554)
    0.412 (0.179−0.644)
    1.964 (1.137−3.392)
    < 0.001
      Note. RERI, relative excess risk due to interaction; AP, attributable proportion due to interaction; SI, synergy index. aNormal TG (< 2.26 mmol/L); HTG (≥ 2.26 mmol/L). bAbdominal obesity was diagnosed as having a waist-hip ratio (WHR) of ≥ 0.90 for men and ≥ 0.85 for women.
    下载: 导出CSV

    S1.   Demographic and clinical characteristics of the study participants

    CharacteristicsNon-HDC (n = 1,128)HDC (n = 236)P
    Male513 (45.48%)82 (34.75%)0.003
    Age (years)48.00 (37.00−60.00)61.00 (54.50−68.00)< 0.001
    Smoking386 (34.22%)60 (25.42%)0.009
    Alcohol drinking252 (22.42%)33 (14.04%)0.004
    Family history of diabetes214 (18.97%)43 (18.22%)0.932
    Family history of hypertension391 (34.66%)83 (35.17%)0.833
    FPG (mmol/L)4.66 (4.14−5.15)8.37 (6.59−10.62)< 0.001
    SBP (mm Hg)116.67 (108.33−123.33)143.17 (133.33−153.33)< 0.001
    DBP (mm Hg)75.67 (70.00−80.00)86.00 (80.00−91.67)< 0.001
    TC (mmol/L)4.27 (3.68−4.97)4.71 (4.07−5.52)< 0.001
    TG (mmol/L)1.14 (0.76−1.79)1.87 (1.26−2.94)< 0.001
    HDL-C (mmol/L)1.24 (1.04−1.46)1.17 (1.00−1.39)0.018
    LDL-C (mmol/L)2.40 (1.89−2.93)2.57 (2.00−3.17)0.028
    BMI (kg/m2)24.16 (21.65−26.60)26.86 (24.93−28.98)< 0.001
    WHR0.88 (0.83−0.93)0.94 (0.90−0.98)< 0.001
    WC (cm)83.00 (75.90−90.50)92.00 (86.00−98.00)< 0.001
    25(OH)D30.080
    VDD (< 20 ng/mL)550 (48.76%)133 (56.36%)
    VDI (20−30 ng/mL)279 (24.73%)54 (22.88%)
    VDS (> 30 ng/mL)299 (26.51%)49 (20.76%)
      Note. HDC, hypertension and diabetes comorbidity; FPG, fasting plasma glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BMI, body mass index; WHR, waist–hip ratio; WC, waist circumference; VDD, vitamin D deficiency; VDI, vitamin D insufficiency; VDS, vitamin D sufficiency. Data are given as the mean ± SD, n (%) or median (interquartile range), with the significance of differences between groups evaluated using t test, the χ2 test, or Wilcoxon ranks teat, respectively.
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出版历程
  • 收稿日期:  2022-10-23
  • 录用日期:  2022-12-09
  • 网络出版日期:  2023-03-02
  • 刊出日期:  2023-02-20

Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity

doi: 10.3967/bes2023.022
    基金项目:  This study is supported by grants from the National Natural Science Foundation of China [grant numbers 82003454, 81903314, and 81872626]; National Natural Science Foundation of Henan Province [grant number 222300420337]; Chinese Nutrition Society - Bright Moon Seaweed Group Nutrition and Health Research Fund [grant number CNS-BMSG2020A63]; Chinese Nutrition Society Zhendong National Physical Fitness and Health Research Fund [grant number CNS-ZD2019066]; key R&D and promotion projects in Henan Province [grant numbers 212102310219, 212102310110, and 202102310120]; and National Natural Science Foundation of China [grant number 81903314]
    作者简介:

    SUN Hua Lei, male, born in 1988, Doctor, majoring in nutrition and chronic diseases

    ZHAO Tong, female, born in1997, MPH, majoring in nutrition and mechanisms of nutrition-related metabolic diseases

    通讯作者: DUAN Jia Yu, E-mail: jyduan@zzu.edu.cnLI Jia, E-mail: deerlijia@163.com Tel: 86-371-67781305.
注释:

English Abstract

SUN Hua Lei, ZHAO Tong, ZHANG Dong Dong, FENG Ming Ming, XU Ze, HUANG Hao Yue, ZHANG Luo Ya, LI Wen Jie, LI Xing, DUAN Jia Yu, LI Jia. Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity[J]. Biomedical and Environmental Sciences, 2023, 36(2): 196-200. doi: 10.3967/bes2023.022
Citation: SUN Hua Lei, ZHAO Tong, ZHANG Dong Dong, FENG Ming Ming, XU Ze, HUANG Hao Yue, ZHANG Luo Ya, LI Wen Jie, LI Xing, DUAN Jia Yu, LI Jia. Interactions of Vitamin D Receptor Polymorphisms with Hypertriglyceridemia and Obesity in Chinese Individuals Susceptible to Hypertension and Diabetes Comorbidity[J]. Biomedical and Environmental Sciences, 2023, 36(2): 196-200. doi: 10.3967/bes2023.022
  • Hypertension (HTN) and type 2 diabetes mellitus (T2DM) are interconnected metabolic diseases [1, 2] that considerably increase susceptibility to microvascular and macrovascular disorders. In many patients, HTN and diabetes comorbidity (HDC) is caused by mutual pathogenic pathways, such as endothelial dysfunction, atherosclerosis, oxidative stress, and vascular inflammation [1]. Hence, it is crucial to identify risk factors, especially ones that can be treated, for HDC and provide essential information for further health management. Based on previous research, generalized and abdominal obesity are linked to a higher risk of HDC. In individuals with obesity, adipocyte dysfunction can lead to vascular and systemic insulin resistance and renin-angiotensin-aldosterone system and sympathetic nervous system dysfunction[2]. A possible indicator of HDC is dyslipidemia, which includes hypertriglyceridemia (HTG), and abnormal levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC).

    In addition to modifiable indicators of HDC, including unhealthy diet, low levels of physical activity, and overweight or obesity, nonmodifiable risk factors, such as genetic polymorphisms and family history, should be addressed. One example is the vitamin D receptor (VDR) gene, which consists of 14 exons and is situated on human chromosome 12q13.11. Previous studies [3] found that VDR mutations may hasten the disease process of HTN and T2DM. However, few studies have focused on the relationship between VDR single nucleotide polymorphisms (SNPs) and HDC predisposition. Therefore, this study aimed to assess the potential correlations between VDR SNPs, HTG, abnormal waist-hip ratio (WHR), and HDC to show the physiological relevance of the combined effects. This can aid in the development of new treatment approaches to prevent HDC in Chinese populations.

    Stratified random cluster sampling was used to recruit a total of 1,364 individuals in this cross-sectional study (Figure 1). The Zhengzhou University Life Science Ethics Committee approved the study protocol. We collected demographic and anthropometric data from the subjects and conducted a biochemical analysis (Supplementary Table S1, available in www.besjournal.com). We chose four associated SNPs based on the selection criteria of the minor allele frequency (MAF) > 0.01, linkage disequilibrium (r2 > 0.8), and position in major gene functional and nonfunctional areas (rs2228570, rs3847987, rs2239179, and rs739837). Assuming additive, dominant, and recessive models of inheritance, logistic regression models were used to appraise the associations between VDR or metabolic factors (i.e., obesity and dyslipidemia) and HDC susceptibility. In the dominant model, the additive interaction model was applied to evaluate the effect of interaction between gene and environmental factors on HDC risk.

    Figure 1.  Flow diagram of the screening process. A total of 1,014 subjects who met the exclusion criteria were excluded, and 1,364 participants were finally included in this study. HTN, Hypertension; T2DM, type 2 diabetes mellitus

    Multiple logistic regression analysis showed that rs3847987 and rs7398379 polymorphisms were associated with HDC risk after adjusting for age, sex, smoking, drinking, and family history of diabetes and HTN (Table 1). Participants with the “CA” and “AA” genotypes of rs3847987 were more likely to develop HDC (1.559, 95% CI 1.133–2.146 and 1.972, 95% CI 1.043–3.730) when compared with the “CC” genotype. Furthermore, subjects with the “GT+TT” genotype of rs7398379 had higher HDC susceptibility compared with the “GG” genotype (OR = 1.451, 95% CI 1.072–1.963). Our findings are in line with numerous studies [3, 4] that found a correlation between VDR mutations and an increase in the prevalence of T2DM and HTN. The 3’ untranslated region of VDR is where the SNPs rs3847987 and rs739837 are both found. This region has little effect on the amino acid sequence and is unlikely to affect gene function. However, through the modification of mRNA stability, this region is implicated in the control of gene expression. Variations in rs739837 may affect the levels of VDR mRNA and protein, which may be linked to a decreased risk of developing diabetes.

    Table 1.  Genotypic distribution of vitamin D receptor polymorphisms and their association with HDC risk

    SNPsNo-HDCHDCχ2POR (95% CI)aPHWE
    rs22285700.2760.8710.267
    TT236 (20.92%)53 (22.46%)1
    CT580 (51.42%)119 (50.42%)0.874 (0.597−1.279)0.487
    CC312 (27.66%)64 (27.12%)0.766 (0.497−1.182)0.228
    TT/CT+CC0.835 (0.582−1.198)0.328
    TT+CT/CC0.843 (0.599−1.186)0.327
    rs384798710.1080.0060.805
    CC725 (64.27%)128 (54.24%)1
    CA357 (31.65%)91 (38.56%)1.559 (1.133−2.146)0.006
    AA46 (4.08%)17 (7.20%)1.972 (1.043−3.730)0.037
    CC/CA+AA1.610 (1.186−2.185)0.002
    CC+CA/AA1.664 (0.893−3.100)0.109
    rs22391790.0950.9540.342
    AA685 (60.73%)144 (61.02%)1
    AG395 (35.02%)83 (35.17%)0.940 (0.683−1.294)0.706
    GG48 (4.26%)9 (3.81%)0.946 (0.433−2.068)0.889
    AA/AG+GG0.941 (0.691−1.281)0.699
    AA+AG/GG0.967 (0.446−2.097)0.932
    rs7398376.2320.0440.691
    GG637 (56.47%)113 (47.88%)1
    GT418 (37.06%)102 (43.22%)1.412 (1.029−1.937)0.033
    TT73 (6.47%)21 (8.90%)1.681 (0.954−2.962)0.072
    GG/GT+TT1.451 (1.072−1.963)0.016
    GG+GT/TT1.441 (0.834−2.488)0.190
      Note. CI, confidence interval; HWE, Hardy-Weinberg equilibrium; OR, odds ratio. aAdjusted for age, sex, smoking, alcohol drinking, family history of HTN, and family history of diabetes.

    In Table 1, we found that rs2228570 polymorphisms were not associated with HDC risk after adjusting for confounding factors. The rs2228570 is located at the 5’ end of the gene, close to the promoter region. The T→C mutation at this position will result in a mutation of the first start codon from ATG to ACG, which may interfere with the binding effectiveness of vitamin D and VDR and restrict the complete function of vitamin D. Ultimately, this may affect the course of T2DM by influencing the function of vitamin D. However, rs2228570 and HDC were not found to be associated in this study. One study [5] discovered that the rs2228570 was not related to diabetes in the Chinese Han population. Conversely, another study [6] indicated an inverse association between rs2228570 and a greater chance of developing HTN. Thus, further research is required to establish the correlation between rs2228570 and HDC. Another gene, Rs2239179, is located in the VDR coding region, where the variation from A to G may impact the amino acid sequence. Similarly, we discovered no connection between rs2239179 and HDC risk. Future research should verify the findings and investigate the mechanisms of activation.

    We used logistic regression analysis to examine the relationships between metabolic indicators (TC, TG, HDL-C, BMI, WC, and WHR) and HDC risk (Supplementary Table S2, available in www.besjournal.com). Except for the level of HDL-C, significant associations between other indicators and HDC susceptibility were found after adjusting for confounding factors. Compared with participants with normal weight, those with overweight and obesity presented an elevated risk of HDC (OR = 3.396, 95% CI 2.258–5.106 and OR = 7.553, 95% CI 4.799–11.889, respectively). HDC susceptibility was positively correlated to TG level with an OR of 3.673 (95% CI 2.676–5.041). Similarly, abnormal WC, WHR, and TC increased the risk of HDC (OR = 4.368 [3.004–6.352], 4.138 [2.724–6.284], and 1.710 [1.230–2.378], respectively; P < 0.001). Consistent with other findings [7], high blood pressure and decreased sensitivity to insulin are linked to complicated and uncomplicated obesity.

    Table S2.  Results of association analysis of metabolic indicators with HDC risk

    IndicatorOR (95% CI)aP
    BMI
    < 18.500.873 (0.192−3.974)0.861
    18.50−23.991
    24.00−27.993.396 (2.258−5.106)< 0.001
    ≥ 28.007.553 (4.799−11.889)< 0.001
    HTGb3.673 (2.676−5.041)< 0.001
    Abnormal WCc4.368 (3.004−6.352)< 0.001
    Abnormal WHRc 4.138 (2.724−6.284)< 0.001
    Abnormal TCd1.710 (1.230−2.378)0.001
    Abnormal HDL-Ce1.352 (0.972−1.879)0.073
    25(OH)D3f
    VDD (< 20)1.204 (0.820−1.768)0.343
    VDI (20−30)0.827 (0.527−1.299)0.411
    VDS (> 30)1
      Note. aAdjusted for age, sex, smoking, alcohol drinking, family history of HTN, and family history of diabetes. bHTG, hypertriglyceridemia (TG ≥ 2.26 mmol/L). cWC > 85 cm or waist-hip ratio WHR ≥ 0.90 for men and > 80 cm or ≥ 0.85 for women are defined as abnormal WC and abnormal WHR. d TC ≥ 5.18 mmol/L was determined to be abnormal TC. eHDL-C < 1.04 mmol/L was defined as abnormal HDL-C. fVDD-vitamin D deficiency (< 20 ng/mL); VDI-vitamin D insufficient (20−30 ng/mL); VDS-vitamin D sufficient (≥ 30 ng/mL).

    Lipolysis, which triggers the release of free fatty acids and causes metabolic irregularities, oxidative stress, and vascular dysfunction, is not prevented by postprandial hyperinsulinemia. In earlier research, abdominal obesity increased the risk of HDC more than general obesity, presumably due to the significant link between visceral and abdominal obesity [8]. Two mechanisms may be at play in the connection between obesity, metabolic syndrome, and their sequelae [9]. First, increased free fatty acids may cause insulin resistance by favoring highly sensitive visceral adipose tissue lipolysis in hypertrophied areas. Second, higher levels of free testosterone and lower levels of sex hormone-binding globulin may stimulate the accumulation of belly fat and decrease the proportion of insulin extracted by the liver. Consequently, the increased visceral fat depot that drains free fatty acids into the portal vein and systemic circulation may influence the relationship between adiposity and HDC. In other words, weight control is of great importance for patients with T2DM and HTN, especially those with abdominal obesity.

    As a dietary factor, vitamin D is also crucial for the development of HDC. Theoretically, vitamin D can affect insulin sensitivity in several ways. The expression of insulin receptors appears to be stimulated by 1,25(OH)2D and, therefore, influences insulin sensitivity. In insulin-responsive cells, 1,25(OH)2D enters and interacts with VDR, boosting the transcriptional activity of insulin receptor genes and the number of insulin receptors overall without changing their affinity. As 1,25(OH)2D activates the peroxisome-activated receptor delta, it may also improve insulin sensitivity. Patients with 25(OH)D levels of < 21 ng/mL in the National Health and Nutrition Examination Survey had a 1.3-fold increased risk of developing HTN than those with levels of ≥37 ng/mL. Currently, no experimental trials support a correlation between vitamin D intervention and HDC risk. Additionally, we were unable to detect a significant relationship between 25(OH)D3 level and HDC risk (Supplementary Table S2).

    Both HTN and T2DM are chronic systemic disorders caused by the combination of various genes and environmental risk factors [10]. In both T1DM and T2DM, only a minority of cases are caused by either genetic or environmental factors alone. Moreover, 95% of these cases are multifactorial, induced by the interaction of environmental, genetic, and behavioral risk factors. Individuals with genetic susceptibility are more likely to develop T2DM owing to metabolic factors, such as obesity, reduced physical activity, high-sucrose diet, and low physical activity. In this study, the interaction of VDR with obesity and dyslipidemia was analyzed (Supplementary Table S3, available in www.besjournal.com), and we found that the interaction of rs3847987 with TG and WHR can increase the risk of developing HDC.

    Table S3.  The interactions between VDR variants and environment indicators on the HDC risk

    SNPsRERIAPSI
    rs2228570
     BMI−3.27 (−9.03−2.48)−0.42 (0.99−0.14)0.67 (0.44−1.04)
     WC−2.39 (−6.19−1.40)−0.44 (−1.04−0.17)0.65 (0.40−1.06)
     WHR−0.80 (−3.51−1.90)−0.16 (−0.67−0.35)0.83 (0.49−1.41)
     TC−0.04 (−1.59−1.50)−0.02 (−0.76−0.72)0.96 (0.25−3.71)
     TG0.61 (−1.43−2.65)0.19 (−0.41−0.79)1.37 (0.43−4.41)
     HDL-C−0.08 (−0.99−0.82)−0.11 (−1.34−1.12)1.49 (0.01−281.05)
     25(OH)D30.18 (−0.53−0.88)0.18 (−0.61−0.97)0.13 (0.01−1.91)
    rs3847987
     BMI−0.58 (−3.28−2.12)−0.08 (−0.48−0.31)0.91 (0.60−1.39)
     WC0.96 (−1.04−2.97)0.17 (−0.15−0.48)1.25 (0.78−2.01)
     WHR2.54 (0.53−4.55)0.41 (0.18−0.64)1.96 (1.14−3.39)
     TC1.33 (−0.04−2.69)0.43 (0.11−0.75)2.76 (0.85−8.97)
     TG2.67 (0.05−5.29)0.48 (0.18−0.77)2.37 (1.11−5.07)
     HDL-C−1.10 (−3.12−0.93)−0.42 (−1.13−0.29)0.60 (0.30−1.19)
     25(OH)D3−0.59 (−1.97−0.78)−0.28 (−0.92−0.36)0.65 (0.29−1.46)
    rs2239179
     BMI−1.03 (−3.05−0.98)−0.23 (−0.69−0.23)0.77 (0.49−1.23)
     WC−1.47 (−3.63−0.69)−0.32 (−0.81−0.18)0.71 (0.45−1.13)
     WHR−2.82 (−6.23−0.60)−0.43 (−0.94−0.07)0.66 (0.44−0.99)
     TC−1.33 (−2.68−0.01)−0.79 (−1.81−0.24)0.34 (0.10−1.21)
     TG−0.34 (−2.30−1.61)−0.10 (−0.72−0.51)0.87 (0.40−1.91)
     HDL-C0.01 (−0.88−0.91)0.01 (−0.63−0.65)1.03 (0.10−10.48)
     25(OH)D30.17 (−0.55−0.89)0.13 (−0.41−0.66)1.93 (0.02−152.78)
    rs739837
     BMI−1.44 (−4.58−1.71)−0.19 (−0.60−0.23)0.82 (0.55−1.22)
     WC0.58 (−1.48−2.64)0.10 (−0.23−0.43)1.13 (0.72−1.77)
     WHR1.70 (−0.22−3.63)0.28 (0.01−0.55)1.50 (0.92−2.45)
     TC1.10 (−0.18−2.38)0.38 (0.03−0.73)2.40 (0.74−7.76)
     TG2.01 (−0.37−4.38)0.38 (0.05−0.72)1.91 (0.92−3.97)
     HDL-C−0.10 (−2.96−0.97)−0.36 (−1.01−0.28)0.64 (0.34−1.20)
     25(OH)D3−0.58 (−1.90−0.74)−0.28 (−0.88−0.33)0.66 (0.31−1.40)
      Note. SNPs: Single nucleotide polymorphisms; RERI, relative excess risk due to interaction; AP, attributable proportion due to interaction; SI, synergy index; BMI, body mass index; WC, waist circumference; WHR, waist–hip ratio; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol.

    HDC risk in participants with HTG having the “CC” allele of rs3847987 increased by 203% (OR = 3.026, 95% CI 1.913–4.788; P < 0.001), whereas HDC risk in those carrying the mutational allele of rs3847987 increased by 675% (OR = 7.749, 95% CI 4.685–12.817; P < 0.001, Table 2). For participants with abdominal obesity, those who carried “CC” or “TT+TC” of rs3847987 showed an increased risk of HDC by 203% (OR = 3.028, 95% CI 1.800–5.094; P < 0.001) or 474% (OR = 5.742, 95% CI 3.355–9.828; P < 0.0001) compared to wild-type gene carriers with regular WHR. The additive interaction analysis provided more proof that VDR-HTG or gene-WHR interaction may be a crucial factor in the rising HDC susceptibility among the Chinese population. Although we conducted a gene-environment interaction study, future research should confirm the interactions of other genes and environmental variables on HDC risk.

    Table 2.  Interactions between VDR variants and HTG and abdominal obesity and HDC risk

    SNPsStatusOR (95% CI)P
    rs3847987
    CCNormal TGa1
    AA+CANormal TG1.338 (0.911−1.966) 0.137
    CCHTG3.026 (1.913−4.788)< 0.001
    AA+CAHTG7.749 (4.685−12.817)< 0.001
    RERI2.666 (0.045−5.286)
    AP0.475 (0.183−0.766)
    SI
    rs3847987
    2.367 (1.106−5.065)
    CCNon-abdominal obesity1
    AA+CANon-abdominal obesity0.849 (0.382−1.890) 0.689
    CCabdominal obesityb3.028 (1.800−5.094)< 0.001
    AA+CA
    RERI
    AP
    SI
    abdominal obesity5.742 (3.355−9.828)
    2.544 (0.534−4.554)
    0.412 (0.179−0.644)
    1.964 (1.137−3.392)
    < 0.001
      Note. RERI, relative excess risk due to interaction; AP, attributable proportion due to interaction; SI, synergy index. aNormal TG (< 2.26 mmol/L); HTG (≥ 2.26 mmol/L). bAbdominal obesity was diagnosed as having a waist-hip ratio (WHR) of ≥ 0.90 for men and ≥ 0.85 for women.

    Table S1.  Demographic and clinical characteristics of the study participants

    CharacteristicsNon-HDC (n = 1,128)HDC (n = 236)P
    Male513 (45.48%)82 (34.75%)0.003
    Age (years)48.00 (37.00−60.00)61.00 (54.50−68.00)< 0.001
    Smoking386 (34.22%)60 (25.42%)0.009
    Alcohol drinking252 (22.42%)33 (14.04%)0.004
    Family history of diabetes214 (18.97%)43 (18.22%)0.932
    Family history of hypertension391 (34.66%)83 (35.17%)0.833
    FPG (mmol/L)4.66 (4.14−5.15)8.37 (6.59−10.62)< 0.001
    SBP (mm Hg)116.67 (108.33−123.33)143.17 (133.33−153.33)< 0.001
    DBP (mm Hg)75.67 (70.00−80.00)86.00 (80.00−91.67)< 0.001
    TC (mmol/L)4.27 (3.68−4.97)4.71 (4.07−5.52)< 0.001
    TG (mmol/L)1.14 (0.76−1.79)1.87 (1.26−2.94)< 0.001
    HDL-C (mmol/L)1.24 (1.04−1.46)1.17 (1.00−1.39)0.018
    LDL-C (mmol/L)2.40 (1.89−2.93)2.57 (2.00−3.17)0.028
    BMI (kg/m2)24.16 (21.65−26.60)26.86 (24.93−28.98)< 0.001
    WHR0.88 (0.83−0.93)0.94 (0.90−0.98)< 0.001
    WC (cm)83.00 (75.90−90.50)92.00 (86.00−98.00)< 0.001
    25(OH)D30.080
    VDD (< 20 ng/mL)550 (48.76%)133 (56.36%)
    VDI (20−30 ng/mL)279 (24.73%)54 (22.88%)
    VDS (> 30 ng/mL)299 (26.51%)49 (20.76%)
      Note. HDC, hypertension and diabetes comorbidity; FPG, fasting plasma glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BMI, body mass index; WHR, waist–hip ratio; WC, waist circumference; VDD, vitamin D deficiency; VDI, vitamin D insufficiency; VDS, vitamin D sufficiency. Data are given as the mean ± SD, n (%) or median (interquartile range), with the significance of differences between groups evaluated using t test, the χ2 test, or Wilcoxon ranks teat, respectively.

    No potential conflicts of interest were disclosed.

    SUN Hua Lei and ZHAO Tong substantially contributed to the study design, gathered the data, and wrote the manuscript; ZHANG Dong Dong conducted data collection and established the methodology; FENG Ming Ming, XU Ze, HUANG Hao Yue, and ZHANG Luo Ya conducted data collection; LI Wen Jie, LI Xing, and DUAN Jia Yu supervised the study and contributed to data curation. Li Jia and DUAN Jia Yu reviewed and revised the manuscript.

参考文献 (10)
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