General Internal Medicine Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Geriatric Medicine Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Lipids Health Dis. 2018 Aug 17;17(1):193. doi: 10.1186/s12944-018-0819-0.
The goal of this study was to determine if vitamin D receptor (VDR) gene polymorphisms underlie susceptibility to dyslipidemia in a Chinese Han population.
Three tag single nucleotide polymorphisms (SNPs) (rs11574129, rs2228570, and rs739837) were genotyped using TaqMan assays to determine VDR SNP associations with dyslipidemia. We genotyped 877 cases of dyslipidemia from a normotensive, non-diabetes mellitus population and 1822 non-dyslipidemia subjects in a stage I study. In a follow-up stage II study, we included a larger sample of 3124 controls and 1679 cases with dyslipidemia. Finally, we explored the potential molecular mechanism for the SNP associations using molecular modeling analysis.
We found a significant association between SNP rs2228570 and dyslipidemia in the additive (adjusted odds ratio (OR) = 1.255, 95% Confidence Interval (CI) = (1.118-1.409), P < 0.001), dominant (OR = 1.384, 95% CI = 1.384 (1.136-1.6), P = 0.001) and recessive models (OR = 1.356, 95%CI = 1.1-1.671, P = 0.004) in stage I. We further established that the rs2228570 variant was significantly associated with dyslipidemia in the additive (adjusted OR = 1.146, 95% CI = 1.053-1247, P = 0.002), dominant (OR = 1.184, 95%CI =1.018-1.376, P = 0.028) and recessive models (OR = 1.209, 95%CI = 1.064-1.374, P = 0.004) in stage II. The TT genotype was significantly higher (4.93 ± 0.75 mmol/L) compared to the TC (4.67 ± 0.47 mmol/L) or CC (4.66 ± 0.44 mmol/L) genotype (P = 0.01) in cases with elevated low-density lipoprotein cholesterol (LDL-C) levels. In contrast, the cases with the TT genotype had significantly lower serum 25(OH)D levels (18.43 ± 5.04 ng/ mL) compared to the TC (26.24 ± 4.16 ng/mL) and CC (36.76 ± 8.10 ng/ mL) genotypes (P < 0.001). Multivariable linear regression analysis indicated that the rs2228750 genotype significantly correlated with serum low-density lipoprotein-C (LDL-C) levels in cases with dyslipidemia. Using molecular modeling analysis, we further found that the rs2228570 variant changed the structure and the stability of VDR and altered the binding energy of its ligand.
The VDR rs2228570 variant may increase susceptibility to dyslipidemia in the Chinese Han population.
本研究旨在确定维生素 D 受体（VDR）基因多态性是否是中国汉族人群血脂异常易感性的基础。
使用 TaqMan 分析对三个标签单核苷酸多态性（SNP）（rs11574129、rs2228570 和 rs739837）进行基因分型，以确定 VDR SNP 与血脂异常的关联。我们在一项 I 期研究中对来自血压正常、非糖尿病人群的 877 例血脂异常病例和 1822 例非血脂异常对照进行基因分型。在后续的 II 期研究中，我们纳入了更大的样本量，包括 3124 名对照和 1679 名血脂异常病例。最后，我们使用分子建模分析探索了 SNP 关联的潜在分子机制。
我们发现 SNP rs2228570 与血脂异常在加性（调整后的优势比（OR）=1.255，95%置信区间（CI）=（1.118-1.409），P<0.001）、显性（OR=1.384，95%CI=1.384（1.136-1.6），P=0.001）和隐性模型（OR=1.356，95%CI=1.1-1.671，P=0.004）中存在显著关联。我们进一步确定，rs2228570 变异与血脂异常在加性（调整后的 OR=1.146，95%CI=1.053-1247，P=0.002）、显性（OR=1.184，95%CI=1.018-1.376，P=0.028）和隐性模型（OR=1.209，95%CI=1.064-1.374，P=0.004）中存在显著关联。在 II 期研究中，携带 TT 基因型的病例 LDL-C 水平升高（4.93±0.75mmol/L）明显高于 TC（4.67±0.47mmol/L）或 CC（4.66±0.44mmol/L）基因型（P=0.01）。相比之下，携带 TT 基因型的病例血清 25（OH）D 水平明显较低（18.43±5.04ng/mL），与 TC（26.24±4.16ng/mL）和 CC（36.76±8.10ng/mL）基因型相比（P<0.001）。多变量线性回归分析表明，rs2228750 基因型与血脂异常病例的血清 LDL-C 水平显著相关。使用分子建模分析，我们进一步发现 rs2228570 变异改变了 VDR 的结构和稳定性，并改变了其配体的结合能。
VDR rs2228570 变异可能增加中国汉族人群血脂异常的易感性。
