Association of Single Nucleotide Polymorphisms of Calcium Sensitive Receptor Gene with Calcium Nephrolithiasis and Hypercalciuria in Chinese Dai Population
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摘要:
目的 研究云南德宏州傣族人群CaSR基因多态性与含钙肾结石和高钙尿的相关性。 方法 云南德宏州的傣族含钙肾结石患者为实验组,云南德宏州的体检健康傣族人群为对照组,抽静脉血进行CaSR基因3个SNP位点rs7652589、rs1801725、rs1042636测定,结石组研究对象行24 h尿钙值测定,进行基因相关对比分析。 结果 rs7652589位点纯合AA型基因者与AA+GG基因者在含钙肾结石的发生对比分析,差异具有统计学意义(P < 0.05)。rs1042636位点的GG型基因者的24 h尿钙值与AA和AG基因型者对比,差异具有统计学意义(P < 0.05)。rs7652589位点GG型基因者24 h尿钙与AA和AG型基因者对比,差异具有统计学意义(P < 0.05)。 结论 云南德宏州傣族人群中CaSR基因上的rs7652589位点多态性与含钙肾结石和高钙尿的发生有关,rs1042636位点的GG型基因与傣族高钙尿发生相关,rs7652589位点GG型基因可能是该民族发生高钙尿和含钙肾结石的候选基因。 Abstract:Objective To study the association of CaSR gene polymorphism with calcium nephrolithiasis and hypercalciuria in Chinese Dai population. Methods The Dai patients with calcium containing renal calculi in Dehong Prefecture, Yunnan Province, China were selected as the experimental group, and the healthy Dai people in Dehong Prefecture, Yunnan Province were taken as the control group. The venous blood was drawn for the determination of the three SNP loci rs7652589, rs1801725, and rs1042636 of the CaSR gene. The subjects in the stone group were tested for 24-hour urine calcium value, and the gene correlation was analyzed. Results There was a statistical difference between the homozygous AA gene and AA+GG gene at rs7652589 locus in the occurrence of calcium nephrolithiasis (P < 0.05). The 24 h urine calcium value of the GG genotype with rs1042636 locus was significantly different from that of the AA based and AG genotype (P < 0.05). There was a significant difference in 24 h urine calcium between those with GG genotype at rs7652589 locus and those with AA and AG genotype (P < 0.05) Conclusion The rs7652589 polymorphism on the CaSR gene in the Dai population in China is related to the occurrence of calcium nephrolithiasis and hypercalciuria. The GG gene at rs1042636 is related to the occurrence of hypercalciuria in the Dai population. The GG gene at rs7652589 may be a candidate gene for the occurrence of hypercalciuria leading to calcium nephrolithiasis in this ethnic group. -
盆腔器官脱垂是因妊娠、年龄等原因导致的盆底支持薄弱,进而盆腔脏器移位,连锁引发其他器官位置及功能异常的一类疾病[1]。其中子宫脱垂、阴道前后壁脱垂较为多见。子宫脱垂在发展中国家女性的平均发病率为 19.7%,在中国,随着年龄增长,60岁以上盆腔器官脱垂发病率近25%[2-4]。目前盆腔器官脱垂分期(POP-Q分期法)Ⅱ期及以下子宫脱垂女性以康复治疗为主,多为盆底生物反馈电刺激、行为治疗,结合针灸推拿等[5]。生物反馈电刺激仅能改善盆底肌肉的健康状态,对盆底筋膜、韧带的作用有限,妇科射频治疗作为一项较新的技术,正好可以弥补传统治疗方式的不足。本研究进行妇科射频联合盆底生物反馈电刺激与传统方式治疗子宫脱垂的疗效进行比较,诣找寻更优化的治疗方案,现报道如下。
1. 资料与方法
1.1 一般资料
选取2021年1月1日至2021年12月31日就诊于昆明市妇幼保健院健康管理中心符合相关要求患者150名。随机分成对照组和观察组,每组各75人,由于样本脱落最终收集符合相关患者140名,对照组68人,观察组72人。年龄21~57岁,平均( 34.55±7.70)岁;产次0~3次,平均(1.39±0.61)次;阴道分娩0~3次,平均(1.14±0.81)次;剖宫产0~2次,平均(0.27±0.55)次;末次妊娠时间0.12~30 a,平均6.20±8.94 a。
纳入标准:(1)符合盆腔器官脱垂分期(POP-Q分期)诊断为Ⅰ、Ⅱ期者[3];(2)在近1 a内未对本病接受系统治疗者;(3)精神、认知正常,能配合完成观察者。排除标准:(1)子宫脱垂Ⅲ期及以上者;(2)身体不健康,有其他疾病史不能完成妇科射频治疗者;(3)不能积极配合完成观察,病例脱落者。
1.2 方法
对照组:予盆底生物反馈电刺激(型号:麦澜德MLD B4)治疗。方案选择神经肌肉电刺激、肌电触发电刺激、生物反馈训练。根据每次治疗的情况适当进行调整,隔天治疗1次,每次30 min,10次为1个疗程,连续治疗2个疗程,月经期停止治疗。2个疗程结束后立即进行评估。
观察组:予盆底生物反馈电刺激+妇科射频治疗。在对照组基础上,前2周均进行盆底生物反馈电刺激,后续治疗中间隔加用妇科射频治疗仪(武汉半边天BBT-RF-C280)进行治疗。射频全过程50~60 min,7 d 1次,5次为一个疗程,连续治疗一疗程,月经前后3 d及月经期停止治疗。妇科射频一个疗程联合盆底生物反馈电刺激治疗两个疗程结束后立即进行评估。
1.3 疗效观察
1.3.1 疗效评价
根据患者的治疗情况将治疗效果分为治愈、好转、无效3个级别,其中治愈是指患者的子宫脱垂症状消失,体征指标恢复正常;好转是指患者的子宫脱垂症状减轻,体征指标明显改善; 无效是指患者的子宫脱垂症状无变化甚至更加严重,临床体征无任何改善。
1.3.2 POP-Q评分
取膀胱截石位,Valsalva动作下观察Aa、Ba、Ap、Bp、C、D点,TVL长度。治疗前后都进行POP-Q评分,且手检均位为同一医生。采用POP-Q评分进行子宫脱垂分期,共分为5期,0期为正常,C点距离在-TVL-(TVL-2);Ⅰ期为脱垂最远端围产过处女膜缘,且距离大于1 cm;Ⅱ期为脱垂最远端超过处女膜缘距离小于1 cm;Ⅲ期为脱垂最远端超过处女膜缘,距离大于1 cm,但小于TVL-2;Ⅳ期为完全脱出,且最远端距离大于TVL-2 cm[3]。
1.3.3 盆底肌功能评估
通过生物反馈电刺激评估仪(型号:MLD B4)进行盆底肌肉功能评估,记录肌电图,测量治疗前后盆底肌慢肌阶段平均值和耐力测试阶段平均值。
1.4 统计学处理
采用 SPSS20.0 软件进行分析, 其中计量资料以(
$\bar x \pm s $ )表示,行t检验,计数资料行χ2检验,P < 0.05为差异有统计学意义。2. 结果
2.1 基线资料
2组年龄、产次、阴道分娩次数、剖宫产分娩次数比较差异无统计学意义(P > 0.05),见表1。
表 1 2组基本情况比较($\bar x \pm s $ )Table 1. Basic information comparison between the two groups ($\bar x \pm s $ )组别 n 年龄(岁) 产次(次) 阴道分娩次数(次) 剖宫产分娩次数(次) 观察组 72 34.11 ± 5.68 1.53 ± 0.581 1.33 ± 0.77 0.22 ± 0.54 对照组 68 32.22 ± 6.94 1.25 ± 0.61 0.94 ± 0.81 0.32 ± 0.56 P 0.14 0.735 0.633 0.902 2.2 子宫脱垂情况比较
进行2组疗效,观察组治愈率为69.4%,对照组治愈率44.1%,观察组高于对照组(P < 0.05),见表2。根据POP-Q评分,观察组治疗后阴道前壁Aa点恢复程度优于对照组(P < 0.05),观察组治疗后阴道后壁Ap点恢复程度优于对照组(P < 0.05),见表3。以C点为参照点,观察组治疗后子宫脱垂程度平均值显著高于对照组(P < 0.05),见表4。
表 2 2组治疗疗效比较[n(%)]Table 2. Comparison of curative effect between two groups [n(%)]组别 n 治愈 有效 无效 观察组 72 50(69.4) 14(19.4) 8(11.1) 对照组 68 30(44.1) 23(33.8) 15(22.1) 表 3 2组阴道前后壁情况比较[($\bar x \pm s $ ),cm]Table 3. Comparison of the anterior and posterior vaginal walls between the two groups [($\bar x \pm s $ ),cm]组别 n 阴道前壁 阴道后壁 治疗前Aa(cm) 治疗后Aa(cm) 治疗前Ap(cm) 治疗后Ap(cm) 观察组 72 −1.12 ± 1.07 −2.51 ± 0.56* −2.17 ± 0.96 −2.73 ± 0.51* 对照组 68 −0.96 ± 1.35 −1.49 ± 1.19* −1.68 ± 1.39 −2.09 ± 1.05* 与治疗前比较,*P < 0.05。 表 4 2组治疗前后子宫脱垂情况比较[($\bar x \pm s $ ),cm]Table 4. Comparison of uterine prolapse before and after treatment in two groups [($\bar x \pm s $ ),cm]组别 n 治疗前C点 治疗后C点 治疗前后子宫脱垂疗效程度 观察组 72 −3.06 ± 0.97* −5.59 ± 1.34* 2.51 ± 0.122* 对照组 68 −3.48 ± 0.62 −4.31 ± 1.03 0.85 ± 0.89 P 0.017 0 0 与对照组比较,*P < 0.05。 2.3 慢肌阶段平均值情况比较
观察组治疗后慢肌阶段平均值高于对照组(P < 0.05),说明Ⅱ类肌纤维收缩程度改善情况优于对照组,见表5。
表 5 2组治疗前后慢肌阶段平均值情况对比较($\bar x \pm s $ )Table 5. Comparison of the mean value of the slow muscle stage before and after treatment between the two groups ($\bar x \pm s $ )组别 n 治疗前慢肌阶段平均值 治疗后慢肌阶段平均值 P 观察组 72 22.02 ± 9.49 30.655 ± 8.15 0 对照组 68 23.28 ± 9.47 27.38 ± 1.40 0.004 P 0.363 0.018 2.4 耐力测试阶段平均值情况比较
观察组治疗后耐力测试阶段平均值高于对照组(P < 0.05),说明肌肉耐力改善程度优于对照组,见表6,见图1,表7。
表 6 2组治疗前后耐力测试阶段平均值情况比较($\bar x \pm s $ )Table 6. Comparison of the mean value of endurance test before and after treatment in two groups ($\bar x \pm s $ )组别 n 治疗前耐力测试阶段平均值 治疗后耐力测试阶段平均值 P 观察组 72 19.82 ± 8.33 27.81 ± 7.56 0 对照组 68 21.07 ± 8.78 26.39 ± 5.34 0 P 0.366 0.004 表 7 盆底肌电评估Table 7. Glazer evaluation chart阶段 指标 测试值 参考值 前静息阶段 平均值 6.44↑ 2~4 μV 变异性 0.10 < 0.2 快肌(Ⅱ 类肌)测试阶段 快速收缩时间 0.26 < 0.5 s 最大值 25.21↓ 35~45 μV 快速放松时间 12.80↓ 30~40 μV 慢肌(Ⅰ类肌)测试阶段 平均值 10.13↓ 25~35 μV 变异性 0.67↑ < 0.5 s 耐心测试 平均值 0.28↑ < 0.2 变异性 0.18 < 0.2 后 10 s/前 10 s比值 0.75↓ 0.8~1.0 后静息阶段 平均值 3.90 2~4 μV 变异性 0.06 < 0.2 3. 讨论
本研究中,子宫脱垂患者Glazer评估大部分有异常,主要表现为慢肌数值、耐力测试降低,常伴有阴道前后壁的膨出。联合治疗组对于阴道前后壁膨出程度、子宫脱垂程度、肌力改善程度优于传统生物反馈电刺激组。子宫脱垂的原因主要是由于支持结构疏松薄弱、筋膜韧带等结缔组织松弛[6]。依据“干船坞”理论得知,子宫脱垂不仅需解决肌肉松弛问题,还需改善盆底筋膜、韧带。筋膜、韧带是一种纤维肌性组织,由平滑肌、胶原蛋白、弹性蛋白等组成,支撑盆腔器官的稳定性和可塑性。胶原蛋白、弹性蛋白的丢失、成纤维细胞弹性或胶原蛋白代谢紊乱被认为是子宫脱垂发病重要病因[7-10]。生物反馈电刺激主要针对盆底的慢肌训练,进而对肌肉耐力有一定的疗效。但是电流刺激强度在人体组织中存在衰减,治疗深度有限,对于伴随深层肌肉松弛的子宫脱垂患者疗效欠佳[11-12]。
射频技术最早用于皮肤领域,是目前非侵入方式治疗皮肤松弛的首选方式 [13],改良后的射频治疗仪器也被用于外阴和阴道治疗[14]。射频治疗能使现有胶原立即收缩,并随后激活成纤维细胞,使新生胶原生成,提升盆底受损的筋膜、韧带等结缔组织的弹性、强度,此外,局部温度升高,使血管扩张、毛细血管开放、氧气增加和引流得到改善,可这种现象可以改善静脉丛的循环,从而改善整个盆腔血液循环[15-18],因此对于盆底结缔组织可起到修复作用。在本研究中,前期使用生物反馈电刺激着重进行盆底肌肉锻炼,增强肌肉稳定性,后期进行妇科射频治疗修复子宫筋膜韧带等以达到巩固、延长治疗效果的目的。其治疗探头能精细控制能量,最大限度地减少组织损伤和患者不适,结合本研究中无不良反应发生,故射频治疗应用于女性盆底康复是安全、有效的[19]。
综上所述,正常盆底依赖完整的肌肉、结缔组织的相互作用,维持动态平衡,传统盆底生物反馈电刺激的治疗仅针对盆底肌进行锻炼,疗效是有限的,联合射频治疗之后,对于改善子宫脱垂的症状更有优势。妇科射频治疗的引进使治疗方案更优化,增加临床疗效,且无创、安全,值得推广。
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表 1 研究对象一般信息对比分析
Table 1. Comparative analysis of general information of research subjects
项目 结石组 对照组 χ2/t P 性别 男 87(54.4) 55(63.2) 1.803 0.179 女 73(45.6) 32(36.8) 年龄(岁) 50.63 ± 14.08 51.93 ± 17.58 0.597 0.552 BMI(kg/m2) 24.38 ± 3.33 24.26 ± 3.93 −0.271 0.787 尿pH 5.8 ± 0.6 5.7 ± 0.5 1.3242 0.1867 表 2 引物设计
Table 2. Primer design
引物编号 引物序列 碱基数(bp) Tm值(℃) 扩增产物片段大小(bp) rs7652589-F ATGTGGAAGAAGAAGAGA 18 56 593 rs7652589-R ACGAGAAGAGATAAGTCA 18 56 593 rs1801725-rs1042636-F* CAGCAACGTCTCCCGCAA 18 60 599 rs1801725-rs1042636-R* TGCATTCTCCCTAGCCCAGT 20 60 599 *2个基因位点位置临近,1个引物可以涵盖2个位点。 表 3 哈迪-温伯格平衡检验结果
Table 3. Hardy-Weinberg test
SNP位点 基因型 基因型频数 基因型频率 期望基因型频率 期望基因型频数 χ2 P rs1042636 AA 66 0.268 0.273 67.123 0.082 0.960 AG 125 0.508 0.499 122.754 GG 55 0.224 0.228 56.1123 rs1801725 GG 221 0.898 0.901 221.635 0.705 0.703 GT 25 0.102 0.096 23.730 TT 0 0.000 0.003 0.635 rs7652589 AA 109 0.441 0.444 109.556 0.025 0.987 AG 111 0.449 0.445 109.889 GG 27 0.109 0.112 27.556 表 4 等位基因型频数分析
Table 4. Allelic frequency analysis
基因位点 等位碱基 结石组 对照组 χ2 P rs1042636 A 163 94 0.345 0.557 G 155 80 AA 39 27 1.531 0.465 AG 85 40 GG 35 20 rs1801725 G 302 165 0.005 0.946 T 16 9 GG 143 78 0.005 0.944 GT 16 9 TT 0 0 rs7652589 A 221 108 2.478 0.115 G 99 66 AA 79 30 6.004 0.0497* AG 63 48 GG 18 9 *P < 0.05。 表 5 纯合型与其他基因型频数分析
Table 5. Homozygous and other genotypes frequency analysis
基因位点 基因型 结石组 对照组 χ2 P rs1042636 AA 39 27 1.761 0.415 AG+GG 120 60 AA+AG 124 67 0.013 0.861 GG 35 20 rs1801725 GG 143 78 0.551 0.759 GT+TT 16 9 GG+GT 159 87 N N TT 0 0 rs7652589 AA 79 30 5.069 0.024* AG+GG 81 57 AA+AG 142 78 0.047 0.828 GG 18 9 *P < 0.05。 表 6 单体型分析对应基因位点及位置
Table 6. Haploid analysis corresponding loci and positions
对应基因 SNP位点 位点的位置(GRCh38,3:) CaSR rs1042636 122284922 rs1801725 122284910 rs7652589 122170241 表 7 SNP位点连锁不平衡分析结果(D')
Table 7. Analysis results of linkage disequilibrium at SNP loci (D')
SNP位点 rs7652589 rs1801725 rs1801725 0.082 - rs1042636 0.456 1 表 8 SNP位点连锁不平衡分析结果(r^2)
Table 8. Analysis results of linkage disequilibrium at SNP loci (r^2)
SNP位点 rs7652589 rs1801725 rs1801725 0.001 - rs1042636 0.096 0.049 表 9 2组CaSR基因SNP位点的单倍型分析结果[n(%)]
Table 9. Haploid analysis results of two sets of CaSR gene SNP loci [n(%)]
单体型 结石组(频率) 对照组(频率) χ2 P OR 95%CI AGA 114(35.8) 59(33.9) 0.075 0.785 0.776 0.126~4.775 AGG 39(12.2) 29(16.6) 0.013 0.908 1.115 0.175~7.112 GGA 98(30.8) 46(26.4) 0.142 0.706 0.704 0.114~4.359 GGG 51(16.0) 31(17.8) 0.010 0.922 0.912 0.144~5.764 表 10 2组实验对象高钙尿平均值、高钙尿发病率对比分析表[n(%)/
$\bar x \pm s $ ]Table 10. Comparative analysis of average hypercalciuria and incidence rate of hypercalciuria between two groups [n(%)/
$\bar x \pm s $ ]项目 结石组 对照组 χ2/t P 正常尿钙 97(39) 79(32) 25.061 < 0.001* 高钙尿 63(26) 8(3) 尿钙值(mg) 353 ± 52 196 ± 76 12.84 < 0.001* 草酸钙结石 131(82) - - - 磷酸钙结石 29(18) - - - *P < 0.05。 表 11 结石组各基因型与24 h尿钙值对比分析(
$\bar x \pm s $ )Table 11. Comparative analysis of different genotypes and 24-hour urinary calcium levels in the stone group (
$ \bar x \pm s$ )基因位点 基因型 基因
例数24 h尿钙值
(mg/24 h)t P rs1042636 AA 39 294 ± 44 3.7927 0.0003* AG 85 311 ± 57 2.18 0.0312 GG 35 335 ± 49 rs1801725 GG 143 317 ± 72 0.6355 0.526 GT 16 305 ± 68 TT 0 0 rs7652589 AA 79 207 ± 48 11.5477 < 0.0001* AG 63 342 ± 61 0.7587 0.4503 GG 18 354 ± 52 *P < 0.05。 -
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