| 摘要: |
| 目的 探讨绝经后2型糖尿病患者护骨因子（OPG）基因rs4355801、rs6993813位点多态性及突变与骨代谢的关系。方法 选取2020年10月至2021年10月就诊于石河子大学第一附属医院的绝经后女性200例，根据病情分为糖耐量及骨量正常组（A组，52例）、糖耐量正常但骨量异常组（B组，43例)、骨量正常的2型糖尿病组（C组，47例）、2型糖尿病合并骨量异常组（D组，58例）。收集患者年龄、身高、体重、绝经年限等基线资料，计算BMI、腰臀比。用罗氏全自动生化分析仪测定甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、血钙、血磷、碱性磷酸酶（ALP）、空腹血糖（FPG）等生物化学指标，HPLC测量糖化血红蛋白（HbA1c），双能X线测量L1～4椎体及股骨颈骨密度，飞行时间质谱测定OPG基因rs4355801、rs6993813位点多态性及基因型分型。采用多元线性回归分析筛选骨密度的影响因素。使用SHEsis软件进行单核苷酸多态性位点的连锁不平衡分析及单体型分析。结果 4组间年龄、BMI、腰臀比存在差异（P＜0.05）。与A组、B组相比，C组、D组的FPG、HbA1c水平均升高（均P＜0.05）；与B组相比，C组HDL-C水平升高、ALP水平降低（均P＜0.05）；与C组相比，D组ALP水平升高（P＜0.05）；与A组、C组相比，B组、D组的L1～4椎体骨密度及股骨颈骨密度水平均降低（均P＜0.05）。OPG基因rs4355801、rs6993813位点均符合Hardy-Weinberg平衡。rs4355801位点基因型及等位基因频率分布组间差异均无统计学意义（均P＞0.05）；与A组相比，C组、D组rs6993813位点基因型分布均存在差异（均P＜0.05），而等位基因频率分布在各组间差异均无统计学意义（均P＞0.05）。 C组rs4355801位点突变型患者FPG、HbA1c水平均低于野生型患者（均P＜0.05），D组rs4355801位点突变型患者L1～4 椎体骨密度水平高于野生型患者（P＜0.05），D组rs6993813位点突变型患者血磷水平低于野生型患者、股骨颈骨密度水平高于野生型患者（均P＜0.05）。多元线性回归分析显示，绝经年限增加及BMI、TG、LDL-C、HDL-C降低是绝经后女性L1～4椎体骨密度降低的危险因素，绝经年限增加、HDL-C降低、血磷降低是股骨颈骨密度降低的危险因素；rs4355801位点AG基因型是绝经后女性L1～4椎体骨密度、股骨颈骨密度增加的保护因素（均P＜0.05）。rs4355801、rs6993813位点野生型与突变型绝经后女性骨密度的差异均无统计学意义（均P＞0.05）。OPG基因rs4355801、rs6993813位点之间存在明显连锁不平衡关系（D’＞0.9，r2＞0.3）；携带GT单体型的绝经后女性骨量异常风险增高（P＜0.05），携带AT单体型的绝经后女性骨量异常风险降低（P＜0.05）。OPG基因rs4355801、rs6993813位点的交互作用未对绝经后女性骨密度产生影响（均P＞0.05）。结论 rs4355801位点突变可能参与了绝经后女性的骨代谢、糖代谢，rs6993813位点突变及多态性参与了绝经后女性的骨代谢。OPG基因rs4355801、rs6993813位点的明显连锁关系可能影响绝经后女性的骨密度。 |
| 关键词: 绝经后女性 2型糖尿病 护骨因子 骨质疏松症 基因多态性 基因突变 |
| DOI：10.16781/j.CN31-2187/R.20220683 |
| 投稿时间：2022-08-22修订日期：2023-03-06 |
| 基金项目:2018年度兵团科技发展专项（2018BB040），石河子大学成果转化与技术推广项目（CGZH201911）． |
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| Correlations of polymorphisms and mutations of osteoprotegerin gene rs4355801 and rs6993813 loci with bone metabolism in postmenopausal women with type 2 diabetes mellitus |
| WANG Lizhen1,LI Jun1*,LI Siyuan2,XIANG Qinglin3,REN Yanxia1,WANG Yaning1 |
(1. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shihezi University, Shihezi 832000, Xinjiang Uygur Autonomous Region, China;
2. Department of Histology and Embryology, Shihezi University School of Medicine, Shihezi 832000, Xinjiang Uygur Autonomous Region, China;
3. Department of Critical Care Medicine, Dazhou Central Hospital, Dazhou 635000, Sichuan, China
*Corresponding author) |
| Abstract: |
| Objective To investigate the correlations of polymorphisms and mutations of osteoprotegerin (OPG) gene rs4355801 and rs6993813 loci with bone metabolism in postmenopausal women with type 2 diabetes mellitus (T2DM). Methods From Oct. 2020 to Oct. 2021, 200 postmenopausal women who visited The First Affiliated Hospital of Shihezi University were enrolled and divided into normal glucose tolerance and bone mass group (group A, n=52), normal glucose tolerance but abnormal bone mass group (group B, n=43), T2DM with normal bone mass group (group C, n=47), and T2DM with abnormal bone mass group (group D, n=58). The baseline data such as age, height, weight, and years since menopause (YSM) were collected, and body mass index (BMI) and waist-hip ratio (WHR) were calculated. Biochemical indicators such as triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), blood calcium, blood phosphorus, alkaline phosphatase (ALP), and fasting blood glucose (FBG) were measured by Roche automatic biochemical analyzer. Glycosylated hemoglobin (HbA1c) was measured by high-performance liquid chromatography. Bone mineral densities (BMDs) of the lumbar spine (L1-4) and neck of femur (NOF) were measured by dual energy X-rays. Polymorphism and genotyping of OPG gene rs4355801 and rs6993813 loci were determined by time-of-flight mass spectrometry. Multiple linear regression analysis was used to analyze the influencing factors of BMD. Linkage disequilibrium analysis and haplotype analysis of single nucleotide polymorphism loci were performed using SHEsis software. Results There were significant differences in age, BMI, and WHR among the 4 groups (P＜0.05). Compared with groups A and B, the levels of FPG and HbA1c in groups C and D were significantly increased (all P＜0.05). Compared with group B, the level of HDL-C in group C was significantly increased, while the level of ALP was significantly decreased (P＜0.05). Compared with group C, the level of ALP in group D was significantly increased (P＜0.05). The BMD (L1-4) and BMD (NOF) in groups B and D were significantly decreased compared with groups A and C (all P＜0.05). The OPG gene rs4355801 and rs6993813 loci were in line with Hardy-Weinberg equilibrium. There were no significant differences between groups in rs4355801 genotype or allele frequency distribution (all P＞0.05). Compared with group A, there was a difference in rs6993813 genotype distribution in groups C and D (both P＜0.05), and there was no significant difference in allele frequency distribution among groups (all P＞0.05). The FPG and HbA1c levels of the patients with rs4355801 mutant type were both significantly lower than those with the wild type in group C (both P＜0.05). In group D, the BMD (L1-4) of rs4355801 mutant type was significantly higher than that with the wild type (P＜0.05). The patients with rs6993813 mutant type in group D had significantly lower blood phosphorus levels and higher BMD (NOF) compared to the wild type (both P＜0.05). Multiple linear regression analysis showed that the increase of YSM and the decreases of BMI, TG, LDL-C, and HDL-C were the risk factors for the decrease of BMD (L1-4); the increase of YSM and the decreases of HDL-C and blood phosphorus were the risk factors for the decrease of BMD (NOF); and rs4355801 AG genotype was a protective factor for the increases of BMD (L1-4) and BMD (NOF) in postmenopausal women (both P＜0.05). There was no significant difference in BMD between wild-type and mutant rs4355801 or rs6993813 loci in postmenopausal women (both P＞0.05). There was a significant linkage disequilibrium relationship between the OPG gene rs4355801 and rs6993813 loci (D’＞0.9, r2＞0.3), and the risk of abnormal bone mass in postmenopausal women with GT haplotype was significantly higher (P＜0.05) and the risk of abnormal bone mass in postmenopausal women with AT haplotype was significantly lower (P＜0.05). The interactions of the OPG gene rs4355801 and rs6993813 loci had no effect on BMD in postmenopausal women (both P＞0.05). Conclusion OPG gene rs4355801 mutation may be involved in bone metabolism and glucose metabolism of postmenopausal women, and rs6993813 mutation and polymorphism are involved in bone metabolism of postmenopausal women. The significant linkage relationship of the OPG gene rs4355801 and rs6993813 loci may affect the BMD of postmenopausal women. |
| Key words: postmenopausal women type 2 diabetes mellitus osteoprotegerin osteoporosis gene polymorphism gene mutation |
