Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population

WANG Yan HAN Han WANG Jun SHEN Fang YU Fei WANG Ling YU Song Cheng ZHANG Dong Dong SUN Hua Lei XUE Yuan BA Yue WANG Chong Jian LI Wen Jie

WANG Yan, HAN Han, WANG Jun, SHEN Fang, YU Fei, WANG Ling, YU Song Cheng, ZHANG Dong Dong, SUN Hua Lei, XUE Yuan, BA Yue, WANG Chong Jian, LI Wen Jie. Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population[J]. Biomedical and Environmental Sciences, 2019, 32(7): 550-553. doi: 10.3967/bes2019.072
Citation: WANG Yan, HAN Han, WANG Jun, SHEN Fang, YU Fei, WANG Ling, YU Song Cheng, ZHANG Dong Dong, SUN Hua Lei, XUE Yuan, BA Yue, WANG Chong Jian, LI Wen Jie. Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population[J]. Biomedical and Environmental Sciences, 2019, 32(7): 550-553. doi: 10.3967/bes2019.072

doi: 10.3967/bes2019.072
基金项目: 

the National Nature Science Foundation of China 81573151

the National Nature Science Foundation of China U1204823

the National Nature Science Foundation of China 81573243

the National Nature Science Foundation of China 81872626

Science and Technology Foundation for Innovation Talent of Henan Province 154200510010

Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population

Funds: 

the National Nature Science Foundation of China 81573151

the National Nature Science Foundation of China U1204823

the National Nature Science Foundation of China 81573243

the National Nature Science Foundation of China 81872626

Science and Technology Foundation for Innovation Talent of Henan Province 154200510010

More Information
    Author Bio:

    WANG Yan, born in 1991, Doctor, majoring in nutrition and food hygiene

    Corresponding author: LI Wen Jie, Professor, Tel:86-371-67781305, E-mail:lwj@zzu.edu.cn
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出版历程
  • 收稿日期:  2019-01-28
  • 录用日期:  2019-05-21
  • 刊出日期:  2019-07-20

Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population

doi: 10.3967/bes2019.072
    基金项目:

    the National Nature Science Foundation of China 81573151

    the National Nature Science Foundation of China U1204823

    the National Nature Science Foundation of China 81573243

    the National Nature Science Foundation of China 81872626

    Science and Technology Foundation for Innovation Talent of Henan Province 154200510010

    作者简介:

    WANG Yan, born in 1991, Doctor, majoring in nutrition and food hygiene

    通讯作者: LI Wen Jie, Professor, Tel:86-371-67781305, E-mail:lwj@zzu.edu.cn

English Abstract

WANG Yan, HAN Han, WANG Jun, SHEN Fang, YU Fei, WANG Ling, YU Song Cheng, ZHANG Dong Dong, SUN Hua Lei, XUE Yuan, BA Yue, WANG Chong Jian, LI Wen Jie. Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population[J]. Biomedical and Environmental Sciences, 2019, 32(7): 550-553. doi: 10.3967/bes2019.072
Citation: WANG Yan, HAN Han, WANG Jun, SHEN Fang, YU Fei, WANG Ling, YU Song Cheng, ZHANG Dong Dong, SUN Hua Lei, XUE Yuan, BA Yue, WANG Chong Jian, LI Wen Jie. Polymorphisms in CYP2R1 Gene Associated with Serum Vitamin D Levels and Status in a Chinese Rural Population[J]. Biomedical and Environmental Sciences, 2019, 32(7): 550-553. doi: 10.3967/bes2019.072
  • Vitamin D, a fat-soluble vitamin and endocrine hormone, and it impacts various bone and extra-bone health, such as osteoporosis, diabetes, and cancer. The main circulating form of vitamin D is 25-hydroxyvitamin D [25(OH)D] and it is a useful clinical biomarker of vitamin D status. The Institute of Medicine (IOM) defines as vitamin D deficiency (VDD) when serum 25(OH)D concentration is less than 20 ng/mL[1]. Worldwide, VDD is recognized as a severe public health problem. In 2007, Holick estimated that globally over one billion people suffered from VDD or vitamin D insufficiency (VDI). In China, it has been reported that the prevalence of VDD ranged from 38.8% to 91.2% in different regions[2, 3].

    The CYP2R1 gene encodes 25-hydroxylase, which is the foremost enzyme in hepatic microsome to convert vitamin D to 25(OH)D. Tom reported that CYP2R1 gene mutation impaired 25-hydroxylase activity and caused an atypical VDD. Genome-wide-association studies (GWAS) identified that the SNPs of CYP2R1 were associated with vitamin D levels[4]. Also some previous studies have shown a significant association of CYP2R1 variants with 25(OH)D levels[3, 5]. However, to date, there is paucity in the literature addressing the involvement of vitamin D levels and status in the Chinese rural population. Therefore, we conducted this cross-sectional study to investigate the current status of VDD in rural area and the associations of genetic factors with vitamin D levels and status in a Chinese rural population.

    From June to July in 2013, a total of 2, 378 Han ethnic subjects were recruited from Zhengzhou, Luoyang and Jiaozuo cities in Henan province. All subjects completed a standardized questionnaire, detailed information has been described in our previous study[6]. After over-night fasting, samples of blood were drawn from the subjects for the measurements of glucose, lipid profile, and 25(OH)D concentrations.

    Inclusion criterion were subjects aged between 14 and 80 years old and in good health. Subjects who suffered from diseases affecting vitamin D metabolism were excluded from the study. Other exclusion criterion were lacking of biological sample information and subjects who supplemented with vitamin D within the past 3 months. Based on these exclusion criterion, a total of 1, 559 participants were included in the present analysis. The Ethics Committee of Zhengzhou University approved the study protocol according to the Declaration of Helsinki.

    Four single nucleotide polymorphisms (SNPs) of CYP2R1 (rs1279414, rs1993116, rs10766197, rs10741657) were selected for genotyping in this study. The basic characteristics of these SNPs are listed in Supplementary Table S1 (available in www.besjournal.com) in the supplementary material. Deviation from Hardy-Weinberg equilibrium (HWE) was tested for vitamin D sufficient subjects using Chi-square test. No significant deviation from HWE was observed. (Supplementary Table S2, available in www.besjournal.com).

    Table Supplementary Table S1.  The Basic Characteristics of CYP2R1 Gene

    Chromosome Location Gene Full Name Selected SNPs
    11 11p15.2 CYP2R1 Cytochrome P450, family 2, subfamily R, polypeptide 1 4
    rs1279414
    rs1993116
    rs10766197
    rs10741657
    Note. SNP: signal nucleotide polymorphism; CYP2R1: cytochrome P450, family 2, subfamily R, polypeptide 1 (vitamin D 25-hydroxylase).

    Table Supplementary Table S2.  The HWE Test in the Vitamin D Sufficient Participants

    SNP Genotype Observed Frequency Expected Frequency χ2 P
    rs1279414 GG 294 (37.4%) 313 (39.8%) 4.629 0.10
    AG 405 (51.5%) 366 (46.6%)
    AA 87 (11.1%) 107 (13.6%)
    rs1993116 GG 292 (37.2%) 299 (38.0%) 0.467 0.792
    AG 385 (49.0%) 372 (47.3%)
    AA 109 (13.8%) 115 (14.7%)
    rs10741657 GG 291 (37.0%) 299 (38.0%) 0.707 0.702
    AG 388 (49.4%) 372 (47.3%)
    AA 107 (13.6%) 115 (14.7%)
    rs10766197 GG 302 (38.4%) 318 (40.6%) 3.094 0.213
    AG 396 (50.4%) 364 (46.2%)
    AA 88 (11.2%) 104 (13.2%)
    Note. HWE: Hardy-Weinberg equilibrium.

    Serum 25(OH)D concentrations were based on natural log transformed to approximate normality. When the serum 25(OH)D levels were seen as a continuous variable, all the analysis used the geometric mean to calculate the data and used the median to describe the distribution. We compared the baseline characteristics of the males and females using the t test or Chi-square test for continuous and categorical data, respectively. Multivariable adjusted linear regression was applied to investigate the association of individual SNP genotype with serum 25(OH)D levels. The odds ratio (OR) and 95% confidence intervals (CIs) were calculated to examine the association of individual SNP genotype with VDD by binary logistic regression adjusted for covariates. Covariates included gender (male and female), age, body mass index (BMI = weight in kilograms divided by height in meters squared, kg/m2), alcohol status (drinking was defined as having consumed alcohol ≥ 12 times in the last year, or not drinking), smoking status (smoked defined as currently smoked, or not smoked) and physical activity (mild, moderate or severe physical activity). The genetic risk scores (GRS) were calculated by counting the number of CYP2R1-rs1279414 and rs10766197 risk alleles. Logistic regression was used to calculate the OR of vitamin D deficiency according to the GRS. All analyses were performed using SPSS software (22.0, SPSS, Chicago, IL, USA). Statistical significance was defined at P value < 0.05.

    The complete data set included 1, 559 individuals (728 males and 831 females), the demographic and clinical characteristics were described in Table 1. The distribution of serum 25(OH)D, insulin and triacylglycerol (TG) concentrations were skewed, so natural log-transformations were performed before analysis. Male and female had similar characteristics, except (P < 0.05) that female had a higher glucose and high-density lipoprotein cholesterol (HDL-C).

    Table 1.  Demographic and Clinical Characteristics of the Study Participants

    Characteristics Total (n = 1, 559) Males (n = 728) Females (n = 831) t/χ2 P
    Age, year 50.85 ± 14.92 51.52 ± 15.46 50.26 ± 14.42 1.659 0.099
    BMI, kg/m2 24.99 ± 3.76 25.10 ± 3.66 24.89 ± 3.85 1.105 0.269
    25(OH)D3, ng/mL 20.1 (15.5-30.1) 20.6 (15.7-31.9) 19.3 (15.5-28.1) 0.944 0.345
    GLU, mmol/L 4.73 ± 0.79 4.67 ± 0.80 4.77 ± 0.79 2.490 0.013
    INS, mIUL 10.95 (8.19-14.09) 10.80 (7.85-14.27) 11.05 (8.39-13.84) 1.207 0.224
    TC, mmol/L 4.46 ± 0.99 4.50 ± 1.03 4.43 ± 0.97 1.546 0.122
    TG, mmol/L 1.26 (0.82-1.95) 1.35 (0.86-2.11) 1.17 (0.78-1.84) 4.351 < 0.001
    HDL-C, mmol/L 1.25 ± 0.31 1.22 ± 0.31 1.27 ± 0.31 3.316 0.001
    LDL-C, mmol/L 2.51 ± 0.78 2.50 ± 0.77 2.52 ± 0.79 0.349 0.728
    Vitamin D deficiency 773 (49.6%) 343 (47.1%) 430 (51.7%) 3.327 0.068
    Note.The data are presented as the means ± SD, median (interquartile range), or n (%). BMI: body mass index; GLU: glucose; INS: insulin; TC: total cholesterol; TG: triacylglycerol; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol.

    Of the 1, 559 subjects, approximately half of them (49.6%) were vitamin D deficient with 25(OH)D concentration < 20 ng/mL. VDD is a global public health problem. It has been estimated that approximately 45%-98% of general population are VDD in Asia. In China, it was reported that 64.6% of healthy adults in Gansu province had a blood level of 25(OH)D less than 20 ng/mL[7]. Recently, Lee and colleagues showed that the prevalence of VDD in healthy individuals in Taiwan of China was 22.4%[8]. These differences may be partially explained by geographical latitude, sun exposure and dietary habit. The additional explaination for the high prevalence of VDD in Henan rural area may include: 1) with the development of agricultural technology, local residents have reduced labor hours under sun exposure; 2) lifestyle of personal habits, such as whose diet is rich in pickles[6].

    The associations of individual SNP genotype with serum 25(OH)D levels and vitamin D status (VDD or not) were presented in Table 2. All four SNPs near the CYP2R1 gene (rs1279414, rs1993116, rs1076197, and rs10741657) were significantly associated with serum levels of 25(OH)D. These results are similar with other studies[3, 9]. Interestingly, stratified analysis by gender and age (cutting point of 50 years old) showed that this association could be detected only in females and in the less than 50 years old subgroups. To demonstrate this specific age and gender difference, we further compared the serum vitamin D level at two age groups (cutting point as 50 years old). The serum vitamin D levels were significantly lower in the subjects aged > 50 years old than those aged ≤ 50 years old (t = 6.62, P < 0.001). This suggested that differences in vitamin D levels among different genotypes might be caused by age rather than genotype. However, in the stratified analysis by gender, the differences of vitamin D level in gender were not detected (t = 0.944, P = 0.345). Almesri also reported that VDR (rs12721377) gene polymorphism was associated with vitamin D levels in females, but not in males[10]. Effects of gender dimorphism on T2DM and obesity have been previously reported[11, 12]. This specific-gender association may be related to the interaction between vitamin D and circulating sex hormone concentrations.

    Table 2.  Associations of Individual CYP2R1 Polymorphism with Serum Levels of 25(OH)D and Vitamin D Deficiency

    SNPs Risk/No-risk Allele Serum 25(OH)D Concentration Mean (n) Pa Vitamin D Deficiency Pb
    AA Aa aa OR (95% CI)
    rs1279414 G/A
      Whole 19.8 (591) 20.7 (749) 18.0 (219) 0.003 1.139 (1.014-1.315) 0.037
      Male 20.7 (256) 20.7 (374) 18.7 (98) 0.419 1.118 (0.903-1.385) 0.305
      Female 19.1 (335) 20.7 (375) 17.7 (121) 0.003 1.169 (0.952-1.435) 0.135
      Age ≤ 50 20.2 (296) 21.7 (386) 18.4 (112) 0.006 1.042 (0.848-1.281) 0.695
      Age > 50 19.3 (295) 19.7 (363) 17.9 (107) 0.366 1.224 (0.992-1.511) 0.059
    rs1993116 G/A
      Whole 19.3 (612) 20.7 (724) 19.6 (223) 0.003 0.921 (0.796-1.067) 0.273
      Male 19.8 (287) 21.3 (345) 20.6 (96) 0.094 0.886 (0.714-1.100) 0.272
      Female 19.0 (325) 20.2 (379) 18.4 (127) 0.010 0.919 (0.750-1.126) 0.415
      Age ≤ 50 20.3 (315) 22.6 (328) 19.3 (111) 0.004 1.012 (0.822-1.245) 0.912
      Age > 50 18.6 (297) 19.6 (356) 20.3 (112) 0.402 0.841 (0.682-1.036) 0.104
    rs10741657 G/A
      Whole 19.3 (613) 20.9 (724) 19.3 (222) 0.002 0.959 (0.699-1.280) 0.350
      Male 19.7 (286) 21.4 (346) 20.4 (96) 0.084 0.924 (0.743-1.149) 0.477
      Female 19.0 (327) 20.3 (378) 18.4 (126) 0.010 0.908 (0.739-1.115) 0.356
      Age ≤ 50 20.3 (315) 22.6 (368) 19.3 (111) 0.004 1.037 (0.840-1.281) 0.732
      Age > 50 18.6 (298) 19.9 (356) 20.2 (111) 0.320 0.830 (0.673-1.023) 0.080
    rs10766197 A/G
      Whole 20.2 (595) 20.7 (743) 18.0 (221) 0.018 1.164 (1.006-1.348) 0.041
      Male 20.9 (260) 20.7 (365) 18.8 (103) 0.525 1.188 (0.960-1.471) 0.113
      Female 19.2 (335) 20.6 (378) 17.7 (118) 0.007 1.513 (1.081-2.117) 0.016
      Age ≤ 50 20.3 (302) 21.7 (383) 19.0 (109) 0.049 1.041 (0.847-1.280) 0.702
      Age > 50 20.1 (293) 19.6 (360) 17.8 (112) 0.238 1.149 (0.937-1.410) 0.183
    Note. aThe analyses were performed under multi-linear regression adjusted for age, gender, BMI, alcohol status, smoking status and physical activity. bThe analyses were performed under logistic regression adjusted for age, gender, BMI, alcohol status, smoking status and physical activity in the allele genetic models. AA was selected to be the most common homozygous genotype; Aa refers to the heterozygous genotype; aa refers to the homozygous genotype; n: number of genotype in individual SNP; OR: odds ratio; CI: confidence interval.

    The multivariable adjusted logistic regression for VDD confirmed the association of CYP2R1 SNPs (rs1279414 and rs10766197) with VDD (OR = 1.39, 95% CI: 1.014-1.315, P = 0.037; OR = 1.164, 95% CI: 1.006-1.348, P = 0.041) (Table 2). This conclusion was supported by previous studies[13]. The GRS is used for evaluating the effects of genetic susceptible factors in risk prediction models. The contribution of multiple SNPs may be aggregated by GRS in order to evaluate the additive genetic effects on the risk of disease and improve the prediction of disease incidence from hereditary factors[14]. In our study, the GRS ranged from zero to four (Table 3). As the GRS increased, the individual's risk and proportion of VDD were increased. The results of the present study indicate that the GRS of CYP2R1 variants are significantly associated with VDD. Carriers with two or more risk alleles could increase the association of VDD by 1.6 to 1.77-fold compared to non-risk alleles and which needs to be confirmed in other independent studies.

    Table 3.  Association and Percentage of Genetic Variants and Vitamin D Deficiency

    Variants OR (95% CI) N VDD (%) P
    Individual variants
      CYP2R1-rs1279414(G) 1.139 (1.014-1.315) 0.037
      CYP2R1-rs10766197(A) 1.164 (1.006-1.348) 0.041
    Number of risk alleles from
    rs1279414 and rs10766197
      0 1.0 (reference) 188 46.1%
      1 1.02 (0.56-1.85) 60 49.1% 0.961
      2 1.60 (1.15-2.23) 668 60% 0.006
      3 + 4 1.77 (1.27-2.47) 643 61% 0.001
    Note. The analysis were performed under logistic regression adjusted for age, gender, BMI, alcohol status, smoking status and physical activity. OR: odds ration; CI: confidence interval, VDD: vitamin D deficiency.

    We report here that VDD is highly prevalent in rural population of Henan province in China. Our results support the current evidence that the CYP2R1 variants are significantly associated with serum 25(OH)D levels and VDD. In conclusion, due to single geographical limitations, further well-designed and large scale studies are needed to reveal the association of CYP2R1 gene variants with vitamin D levels in people situated in diverse rural areas in China.

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