Correlation between KRAS Gene Polymorphism and Non-small Cell Lung Cancer in Yunnan Han Population
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摘要:
目的 探讨KRAS基因多态性与云南汉族人群非小细胞肺癌发生发展及病理类型的相关性。 方法 选取455例非小细胞肺癌患者,391例健康对照作为研究对象。采用Taqman探针基因分型法对KRAS基因3’UTR区域3个单核苷酸多态性(single nucleotide polymorphism,SNP)位点rs12587(G > T) 、rs12245(A > C)、 rs1137282(A > G)进行基因分型。根据分型结果,分析等位基因、基因型及单倍型与非小细胞肺癌发生、病理类型(鳞癌、腺癌)和临床分期(I+II期、III+IV期)的相关性。 结果 rs12587(G > T)位点等位基因G在非小细胞肺癌组的分布频率显著高于对照组(P = 0.008,OR = 1.365,95%CI 1.086~1.716);在显性模式下携带T等位基因的个体(G/T+T/T)患非小细胞肺癌的风险显著降低(P = 0.011,OR = 0.70 ,95%CI 0.53~0.92)。病例分层分析发现,鳞癌组与对照组的rs12587(G > T)位点等位基因和基因型频率,差异有统计学意义(P < 0.001、P = 0.001);在显性模式下携带T等位基因的个体(G/T+T/T)患肺鳞癌的风险显著降低(P < 0.001,OR = 0.45 ,95%CI 0.30~0.68)。非小细胞肺癌病例组与对照组rs12245(A > C)位点等位基因分布频率及基因型,差异无统计学意义(P > 0.05);在显性模式下携带A等位基因的个体(A/T+A/A)患非小细胞肺癌的风险显著降低(P = 0.028,OR = 0.73 ,95%CI 0.55~0.97)。病例分层分析发现鳞癌组与对照组的rs12245(A > C)位点等位基因和基因型频率,差异有统计学意义(P = 0.003、P = 0.001);在超显性模式下,基因型为A/T的个体患肺鳞癌的风险显著降低(P<0.001,OR = 0.43 ,95%CI 0.28~0.67)。 结论 KRAS基因3’UTR区域SNP位点rs12587(G > T)等位基因G可能是云南汉族人群非小细胞肺癌及鳞癌发生的风险因素。SNP位点rs12245(A > C)等位基因A可能是云南汉族人群非小细胞肺癌发生的保护性因素。 Abstract:Objective To investigate the correlation between KRAS gene polymorphism and the occurrence and development of non-small cell lung cancer in Yunnan Han population. Methods In this study, 455 patients with non-small cell lung cancer and 391 healthy controls were selected as the research objects. Three single nucleotide polymorphism (SNP) sites rs12587 (G > T), rs12245 (A > C), rs1137282 (A > G) in the 3′UTR region of KRAS gene were identified by Taqman probe genotyping. According to the typing results, the correlations of alleles, genotypes and haplotypes with the occurrence, pathological types (squamous cell carcinoma, adenocarcinoma) and clinical stages (I+II, III+IV) of non-small cell lung cancer were analyzed. Results The distribution frequency of rs12587 (G > T) allele G in the non-small cell lung cancer group was significantly higher than that in the control group (P = 0.008, OR = 1.365, 95%CI 1.086~1.716). It was carried in the dominant mode Individuals with the T allele (G/T+T/T) had a significantly lower risk of developing non-small cell lung cancer (P = 0.011, OR = 0.70, 95%CI 0.53~0.92). Case stratification analysis found that the allele and genotype frequencies of the rs12587 (G > T) locus were significantly different between the squamous cell carcinoma group and the control group (P < 0.001, P = 0.001); Individuals with the T allele (G/T+T/T) had a significantly lower risk of lung squamous cell carcinoma (P < 0.001, OR = 0.45, 95%CI 0.30~0.68). There was no significant difference in the distribution frequency of the rs12245 (A > C) locus allele and genotype between the non-small cell lung cancer case group and the control group (P > 0.05); Individuals (A/T+A/A) had a significantly lower risk of developing non-small cell lung cancer (P = 0.028, OR = 0.73, 95%CI 0.55~0.97). Case stratification analysis found that the allele and genotype frequencies of the rs12245 (A > C) locus were significantly different between the squamous cell carcinoma group and the control group (P = 0.003, P = 0.001); Individuals with genotype A/T had a significantly lower risk of lung squamous cell carcinoma (P < 0.001, OR = 0.43, 95%CI 0.28~0.67). Conclusions The G allele of the SNP site rs12587 (G > T) in the 3′UTR region of KRAS gene may be a risk factor for the occurrence of non-small cell lung cancer and squamous cell carcinoma in Yunnan Han population. SNP rs12245 (A > C) allele A may be a protective factor for the occurrence of non-small cell lung cancer in Yunnan Han population. -
Key words:
- Non-small cell lung cancer /
- KRAS /
- SNPs /
- Correlation /
- Yunnan Han population
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龋病的发生是由于口腔细菌失衡引起牙体硬组织慢性破坏的感染性疾病。目前最有效的防龋药物是氟制剂[1],但长期使用会导致抗酸耐氟菌株的产生,且容易引起氟中毒[2]。防龋疫苗也在飞速发展,其安全性和临床运用还有差距。因此,天然药物的防龋备受关注。
近年来,关于苏木(Caesalpinia sappan L.)活性研究主要集中在抗肿瘤[3-4]和免疫抑制[5]方面,尤其在抗器官移植排斥反应方面的报道较多[6],同时,苏木还具有良好的抑菌、杀菌效果[7-10]。课题组前期实验证实苏木对口腔致龋菌有抑制效果,但对牙齿硬组织生物矿化的研究还未见报道,本实验将研究苏木对釉质龋的再矿化作用,为开发天然防龋药物奠定理论和实验基础。
1. 材料与方法
1.1 主要材料及试剂
苏木药材2018年购于大理市中药材批发市场,产地:广西,分装日期:20180409。经大理大学药学院张德全教授鉴定为豆科云实属苏木植物。
冰乙酸、氯化钾(天津市风船化学试剂科技有限公司);二水氯化钙(国药集团化学试剂有限公司);磷酸二氢钾(天津市化学试剂研究所);75%乙醇、石油醚、正丁醇、乙酸乙酯(上海申博化工有限公司)。以上试剂均为分析纯。
变形链球菌菌种(S.m)(广东微生物菌种保藏中心);TPY液体培养基(青岛高科技工业园海博生物技术有限公司);氯己定(国药集团);人工唾液(上海源叶生物科技有限公司)。
1.2 主要仪器
高速多功能粉碎机(上海塞耐机械有限公司);隔水式恒温培养箱(上海-恒科技有限公司);自动转塔数显显微维氏硬度计(依工测试测量仪器仪器上海有限公司);YMP-2B金相试样磨抛机(苏州欧卡精密光学仪器有限公司);ZQX-1全自动金相试样镶嵌机(苏州欧卡精密光学仪器有限公司);日立S-3400N扫描电子显微镜。
1.3 方法
1.3.1 药材的萃取
药材粉碎,75% 乙醇加热回流提取3 次,2 h/次,提取液合并,减压浓缩至无醇味。将部分浓缩液加适量的水,依次使用石油醚、乙酸乙酯、正丁醇、水萃取,得到乙酸乙酯、正丁醇和水3个萃取部位,减压浓缩并冷冻干燥得各萃取部位冻干粉备用,石油醚萃取部位量太少弃去。
1.3.2 菌液的制备
菌种在TPY固体培养基中复苏48 h,体视显微镜观察无杂菌后在TPY液体培养基中增菌18 h,离心,沉积菌用无菌生理盐水稀释,得到大约1.5×108 cfu/mL菌液备用[11]。
1.3.3 最低抑菌浓度(MIC)值的测定
将苏木乙醇提取物及各萃取物分别溶于TPY液体培养基中,二倍稀释法配制浓度为10.0 0 ,5.00 0,2.50 0,1.25 0,0.625 0,0. 312 5,0.156 2 mg/mL,取配好的菌液20 μL和不同浓度药液2 mL于12孔板中培养48 h,体视显微镜观察没有菌落生长的含药液浓度为MIC[11-12]。阳性对照为0.05%的氯己定,阴性对照为TPY培养基。以上实验重复3次,见表1。
表 1 不同溶剂萃取物对变形链球菌的MIC值(mg/mL,n = 3)Table 1. MIC values of different solvent extracts against Streptococcus mutans (mg/mL,n = 3)项目 10.00 5.000 2.500 1.250 0.6250 0.3215 0.1562 阴性对照 阳性
对照乙醇萃取物 − − − + + + + + − 乙酸乙酯萃取物 − − − + + + + + − 正丁醇萃取物 − − − + + + + + − 水萃取物 − − − + + + + + − 注:+:表示有菌生长;−:表示无菌生长。阴性对照:TPY培养基;阳性对照:0.05% 洗必泰。 1.3.4 牙釉质硬度的测量 [13-15] 试液的配制
脱矿液:0.15 mol/L KCl,调 pH 至 4.50,定容至1000 mL。酸性缓冲液:50 mmol/L HAc,1.35 mmol/L KH2PO4,2.25 mmol/L CaCl2,130 mmol/L KCl,调pH至5.50,定容至1000 mL。牙釉质样本的准备 : 新鲜牛牙齿,剔除软组织,分离牙冠和牙根,牙冠用超声清洗器超声30 min,选取无裂痕、龋损、氟斑的牙冠去离子水冲洗、晾干。开窗(5 mm×5 mm),用磨抛机将牙冠表面打磨成光滑平面,用自动转塔数显显微维氏硬度计测牙釉质硬度,筛选硬度值(330±10) kg/mm2(P > 0.05)的样本,得到初始硬度值SMH0。
牙釉质的脱矿 : 样本随机分为8个组(有1组不脱矿),每组10颗牙齿(6颗用于硬度测试,4颗用于扫描电镜观察),分别浸泡在等量的脱矿溶液中,37℃恒温,每天更换新配脱矿液,连续脱矿10 d。按2.4.2的方法测牙釉质脱矿后的硬度值,得到SMH1。牙釉质的再矿化 : 脱矿后的样本取出编号, A组是脱矿前,B组脱矿后,C组是阴性组(去离子水),D组是阳性组(NaF 20 mg/mL),E组是乙醇提取物,F组是乙酸乙酯萃取部位,G组是正丁醇萃取部位,H组是水萃取部位,以上4个实验组用药浓度为变形链球菌的MIC值,开窗脱矿面按间隔3 h的时间节点用药,用药时间10 min/次,去离子水冲样本后,酸性缓冲液中浸泡30 min,再放入人工唾液30 min,每天循环3次,共14 d。各组随机取出6颗牛切牙测牙釉质再矿化后的硬度值,得到SMH2。
SMH0为初始硬度值,SMH1为脱矿后硬度值,SMH2为再矿化后硬度值。∆SMH1 = SMH2-SMH1,是初步评估苏木的再矿化能力。硬度恢复率SMHR%表示牙齿再矿化后硬度的恢复情况。SMHR% = [(SMH2-SMH1)÷(SMH0-SMH1)]×100%。
1.4 扫描电镜(SEM)观察脱矿釉质表面[16-17]
釉质样本4颗,干燥,2次喷铂后置扫描电镜(SEM)15.0 KV,放大5000倍下观察釉质样本表面形态变化,见图1。
1.5 统计学处理
采用SPSS 20.0统计软件对样本显微硬度值进行统计处理,计量资料以(
$\bar x \pm s $ )表示,组间比较采用SNK-q检验,组内比较采用配对t检验(α = 0.05),P < 0.05为差异有统计学意义。2. 结果
2.1 苏木萃取物MIC值
苏木4种萃取物对变形链球菌的MIC均为2.500 mg/mL。以下实验的药物浓度为此浓度,见图1。
2.2 牙釉质脱矿及再矿化后硬度测量
脱矿前选取硬度值在(330±10) kg/mm2左右的样本,各组样本显微硬度值无显著性差异(P > 0.05);脱矿后各组间显微硬度值也无显著性差异(P > 0.05)。各实验组的 ∆SMH1与阴性组相比有统计学意义(P < 0.05),效果最好的是水萃取部位组。各实验组对釉质龋都有提高硬度恢复率的作用,与阴性组相比均有统计学意义(P < 0.05),其中水萃取部位组硬度恢复率高于其它实验组(P < 0.05),达到66.9%,但低于阳性组(P < 0.05),见表2。
表 2 各实验组对牙釉质硬度的影响 ($\bar x \pm s $ ,n = 6 )Table 2. Effects of different experimental groups on enamel hardness ($\bar x \pm s $ ,n = 6 )组别 SMH0 SMH1 SMH2 ∆SMH1 SMHR(%) 乙醇组 332.9 ± 4.89 168.8 ± 5.64 269.3 ± 7.44*#& 95.3 ± 8.69*#& 58..2 ± 0.05*#& 乙酸乙酯组 335.0 ± 3.65 167.9 ± 3.95 200.1 ± 7.27*#& 32.1 ± 10.33*#& 19.1 ± 0.06*#& 正丁醇组 333.2 ± 3.84 169.2 ± 4.46 244.2 ± 5.28*#& 74.9 ± 7.37*#& 45.7 ± 0.04*#& 水组 335.1 ± 3.89 169.1 ± 4.29 281.6 ± 5.14*#& 111.0 ± 7.84*#& 66.9 ± 0.04*#& 阳性组 335.3 ± 4.28 171.4 ± 7.06 303.8 ± 5.60#& 132.3 ± 9.61#& 80.8 ± 0.05#& 阴性组 333.9 ± 5.75 167.6 ± 6.96 170.5 ± 4.15*& 0.85 ± 8.63*& 0.3 ± 0.05*& 与阳性组比较,*P < 0.05;与阴性组比较,#P < 0.05;任意两实验组比较,&P < 0.05。 2.3 牙釉质脱矿及再矿化SEM观察
脱矿前牙体表面平整光滑无异物。经过10 d脱矿处理后釉质表面出现凹坑,釉质被溶解,表面呈现较大间隙。阳性对照组可见釉质表面有球形矿物质沉积,相对光滑。阴性对照组牙体表面出现规则凹坑,有少量沉积物。乙醇提取物组釉质表面有矿物质沉积,鳞片状凹陷变浅,沉积物疏松;乙酸乙酯萃取部位组、正丁醇萃取部位组和水萃取部位组表面均有不同程度的颗粒状沉积物,覆盖脱矿缝隙,凹陷不同程度变浅,见图1。
3. 讨论
龋病是一种常见的口腔疾病,疾病的发生与发展和致龋菌过度生长有关[18]。致龋菌利用碳水化合物无氧条件下产生乳酸,同时使口腔环境 pH下降,导致牙釉质脱矿继而发生龋病[19]。正常情况下,釉质脱矿和再矿化过程不是独立过程,而是相互交替的动态平衡过程。
有研究证实从中药苏木中分离得到了包括苏木素类、原苏木素类、高异黄酮类、黄酮类、查耳酮类等多种成分[20-21]。本研究发现苏木乙醇提取物和各萃取部位均有良好的抑菌效果。在生物矿化实验中,各实验组对牙釉质都有良好的修复作用,其中水萃取部位硬度恢复率可达66.9%。SEM观察发现,脱矿牙釉质表面呈现典型早期釉质龋,牙体表面出现凹陷及不规则鳞状突起。经苏木各提取部位再矿化处理后的釉质表面均有颗粒状沉积物,牙体表面的凹陷减少且变浅,从形态学上证明苏木乙醇提取物和各萃取部位能够促进脱矿牙釉质的再矿化。
综上所述,中药苏木对口腔致龋菌有明显的抑制作用同时对龋齿有明显的修复作用,具有的潜在防龋效果,从而可以抑制龋病的发生和发展。
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表 1 病例的临床特征(n)
Table 1. The clinical characteristics of the subjects enrolled in this study (n)
人数/病理分型/
临床分期非小细胞肺癌 对照 t/χ2 P 人数 455 391 − − 年龄(岁) 55.84 ± 10.53 54.58 ± 9.92 −1.781 0.075 性别(男/女) 314/141 245/146 3.784 0.052 病理分型 鳞癌(SCC) 164 − − − 腺癌(AC) 265 − − − 鳞癌合并腺癌 8 − − − 其他类型 18 − − − 临床分期 I 期+ II期 148 − − − III期 + IV期 307 − − − 表 2 KRAS基因SNP位点等位基因和基因型在NSCLC和对照组的分布频率[n(%)]
Table 2. The allelic and genotypic frequencies of SNPs in KRAS gene between NSCLC case and control groups [n(%)]
SNPs 等位基因/ 基因型 对照组 非小细胞癌组 OR(95%CI) P rs12587 G 583(74.6) 728(80.0) 1.37(1.09~1.72) 0.008* T 199(25.4) 182(20.0) G/G 223(57.0) 298(65.6) 0.035* G/T 137(35.0) 132(29.0) T/T 31(7.9) 25(5.5) rs12245 T 595(76.1) 727(79.9) 0.80 (0.64~1.01) 0.059 A 187(23.9) 183(20.1) T/T 227(58.1) 297(65.3) 0.088 T/A 141(36.1) 133(29.2) A/A 23(5.9) 25(5.5) rs1137282 A 712(91.0) 838(92.1) 1.14 (0.81~1.61) 0.442 G 70(9.0) 72(7.9) A/A 323(82.6) 387(85.1) 0.442 A/G 66(16.9) 64(14.1) G/G 2(0.5) 4(0.9) *P < 0.05。 表 3 KRAS基因3个SNP位点与NSCLC相关性的遗传模式分析[n(%)]
Table 3. The inheritance analysis of three SNPs between NSCLC and control groups [n(%)]
SNPs 遗传模式 基因型 对照组 NSCLC OR (95%CI) P AIC BIC rs12587 共显性模式 G/G 223 (57.0) 298 (65.5) 1 0.034* 1165.1 1188.8 G/T 137 (35.0) 132 (29.0) 0.71 (0.53~0.96) T/T 31 (7.9.0) 25 (5.5) 0.61 (0.35~1.07) 显性模式 G/G 223 (57.0) 298 (65.5) 1 0.011* 1163.4 1182.3 G/T-T/T 168 (43.0) 157 (34.5) 0.70 (0.53~0.92) 隐性模式 G/G-G/T 360 (92.1) 430 (94.5) 1 0.180 1168 1187 T/T 31 (7.9) 25 (5.5%) 0.69 (0.40~1.19) 超显性模式 G/G-T/T 254 (65.0) 323 (71.0) 1 0.052 1166.1 1185 G/T 137 (35.0) 132 (29.0) 0.75 (0.56~1.00) 逻辑累加模式 --- --- --- 0.75 (0.60~0.94) 0.011* 1163.3 1182.3 rs12245 共显性模式 T/T 227 (58.1) 297 (65.3) 1 0.080 1166.8 1190.5 A/T 141 (36.1) 133 (29.2) 0.72 (0.53~0.96) A/A 23 (5.9) 25 (5.5) 0.82 (0.45~1.49) 显性模式 T/T 227 (58.1) 297 (65.3) 1 0.028* 1165 1184 A/T-A/A 164 (41.9) 158 (34.7) 0.73 (0.55~0.97) 隐性模式 T/T-A/T 368 (94.1) 430 (94.5) 1 0.790 1169.8 1188.7 A/A 23 (5.9) 25 (5.5) 0.92 (0.51~1.66) 超显性模式 T/T-A/A 250 (63.9) 322 (70.8) 1 0.031* 1165.2 1184.2 A/T 141 (36.1) 133 (29.2) 0.73 (0.54~0.97) 逻辑累加模式 --- --- --- 0.80 (0.64~1.01) 0.059 1166.3 1185.3 rs1137282 共显性模式 A/A 323 (82.6) 387 (85) 1 0.460 1170.3 1194 A/G 66 (16.9) 64 (14.1) 0.81 (0.55~1.17) G/G 2 (0.5) 4 (0.9) 1.53 (0.28~8.45) 显性模式 A/A 323 (82.6) 387 (85.0) 1 0.320 1168.9 1187.8 A/G-G/G 68 (17.4) 68 (14.9) 0.83 (0.57~1.20) 隐性模式 A/A-A/G 389 (99.5) 451 (99.1) 1 0.590 1169.6 1188.5 G/G 2 (0.5) 4 (0.9) 1.58 (0.29~8.73) 超显性模式 A/A-G/G 325 (83.1) 391 (85.9) 1 0.250 1168.6 1187.5 A/G 66 (16.9) 64 (14.1) 0.80 (0.55~1.17) 逻辑累加模式 --- --- --- 0.87 (0.61~1.22) 0.410 1169.2 1188.1 *P < 0.05。 表 4 NSCLC组和对照组的单倍型分布差异[n(%)]
Table 4. The haplotype analysis between CC and control group [n(%)]
单倍型 对照组 NSCLC OR(95%CI) P G-T-A 578.48(74.0) 720.12(79.1) 1.272(1.009~1.604) 0.041* T-A-A 119.49(15.3) 116.88(12.8) 0.803(0.610~1.058) 0.119 T-A-G 66.49(8.5) 65.12(7.2) 0.817(0.572~1.166) 0.265 *P < 0.05。 表 5 KRAS基因中SNP位点的等位基因和基因型在鳞癌病例组、腺癌病例组和对照组的分布频率[n(%)]
Table 5. The allelic and genotypic frequencies of SNPs in KRAS gene between SCC,AC and control groups [n(%)]
SNPs 等位基因/
基因型对照组 鳞癌组 腺癌组 鳞癌组vs对照组 腺癌组vs对照组 OR(95%CI) P OR(95%CI) P rs12587 G 583(74.6) 276(84.1) 410(77.4) 0.55(0.39-0.77) <0.001* 1.17 (0.90~1.51) 0.245 T 199(25.4) 52(15.9) 120(22.6) G/G 223(57.0) 121(73.8) 160(60.4) 0.001* 0.865 G/T 137(35.0) 34(20.7) 90(34.0) T/T 31(7.9) 9(5.5) 15(5.7) rs12245 T 595(76.1) 276(84.1) 409(77.2) 0.60 (0.43~0.84) 0.003* 1.06 (0.82~1.38) 0.650 A 187(23.9) 52(15.9) 121(22.8) T/T 227(58.1) 121(73.8) 159(60.0) 0.001* 0.884 T/A 141(36.1) 34(20.7) 91(34.3) A/A 23(5.9) 9(5.5) 15(5.7) rs1137282 A 712(91.0) 304(92.7) 484(91.3) 0.80 [0.50-130] 0.372 1.03(0.70~1.53) 0.865 G 70(9.0) 24(7.3) 46(8.7) A/A 323(82.6) 142(86.6) 221(83.4) 0.265 0.875 A/G 66(16.9) 20 (12.2) 42 (15.8) G/G 2(0.5) 2 (1.2) 2 (0.8) *P < 0.05。 表 6 SNP位点在NSCLC不同病理类型与对照组的遗传模式分析[n(%)]
Table 6. The inheritance analysis of the SNP sites between SCC,AC group and control group [n(%)]
SNPs 遗传模式 基因型 对照组[n(%)] 鳞癌组[n(%)] 腺癌组[n(%)] 鳞癌组vs对照组 腺癌组vs对照组 OR (95%CI) P AIC BIC OR (95%CI) P AIC BIC rs12587 共显性
模式G/G 223 (57.0) 121 (73.8) 160 (60.4) 1 < 0.001* 631.9 653.5 1 0.4 891.6 914 G/T 137 (35.0) 34 (20.7) 90 (34.0) 0.42 (0.27~0.66) 0.91 (0.65~1.28) T/T 31 (7.9) 9 (5.5) 15 (5.7) 0.59 (0.26~1.31) 0.65 (0.34~1.25) 显性模式 G/G 223 (57.0) 121 (73.8) 160 (60.4) 1 < 0.001* 630.5 647.8 1 0.36 890.6 908.5 G/T-T/T 168 (43.0) 43 (26.2) 105 (39.6) 0.45 (0.30~0.68) 0.86 (0.63~1.19) 隐性模式 G/G-G/T 360 (92.1) 155 (94.5) 250 (94.3) 1 0.49 645.5 662.7 1 0.22 889.9 907.8 T/T 31 (7.9) 9 (5.5) 15 (5.7) 0.76 (0.35~1.68) 0.67 (0.35~1.28) 超显性
模式G/G-T/T 254 (65.0) 130 (79.3) 175 (66.0) 1 < 0.001* 631.7 649 1 0.78 891.3 909.3 G/T 137 (35.0) 34 (20.7) 90 (34.0) 0.44 (0.28~0.68) 0.95 (0.69~1.33) 逻辑累加
模式--- --- --- --- 0.57 (0.41~0.80) < 0.001* 634.3 651.6 0.85 (0.66~1.10) 0.22 889.9 907.9 rs12245 共显性
模式T/T 227 (58.1) 121 (73.8) 159 (60.0) 1 < 0.001* 632.3 653.9 1 0.86 893.1 915.6 A/T 141 (36.1) 34 (20.7) 91 (34.3) 0.42 (0.27~0.66) 0.92 (0.66~1.28) A/A 23 (5.9) 9 (5.5) 15 (5.7) 0.71 (0.31~1.62) 0.91 (0.46~1.80) 显性模式 T/T 227 (58.1) 121 (73.8) 159 (60.0) 1 < 0.001* 631.6 648.9 1 0.59 891.1 909.1 A/T-A/A 164 (41.9) 43 (26.2) 106 (40.0) 0.46 (0.30~0.69) 0.92 (0.67~1.26) 隐性模式 T/T-A/T 368 (94.1) 155 (94.5) 250 (94.3) 1 0.84 645.9 663.2 1 0.85 891.4 909.3 A/A 23 (5.9) 9 (5.5) 15 (5.7) 0.92 (0.41~2.08) 0.94 (0.48~1.84) 超显性
模式T/T-A/A 250 (63.9) 130 (79.3) 174 (65.7) 1 < 0.001* 631 648.3 1 0.64 891.2 909.2 A/T 141 (36.1) 34 (20.7) 91 (34.3) 0.43 (0.28~0.67) 0.93 (0.67~1.28) 逻辑累加
模式--- --- --- --- 0.59 (0.42~0.83) 0.0016 636 653.2 0.93 (0.72~1.21) 0.61 891.2 909.1 rs1137282 共显性
模式A/A 323 (82.6) 142 (86.6) 221 (83.4) 1 0.24 645 666.6 1 0.86 893.1 915.5 A/G 66 (16.9) 20 (12.2) 42 (15.8) 0.65 (0.37~1.13) 0.93 (0.61~1.42) G/G 2 (0.5) 2 (1.2) 2 (0.8) 1.78 (0.25~12.88) 1.54 (0.21~11.11) 显性模式 A/A 323 (82.6) 142 (86.6) 221 (83.4) 1 0.16 644 661.2 1 0.8 891.4 909.3 A/G-G/G 68 (17.4) 22 (13.4) 44 (16.6) 0.69 (0.40~1.17) 0.95 (0.62~1.44) 隐性模式 A/A-A/G 389 (99.5) 162 (98.8) 263 (99.2) 1 0.53 645.5 662.8 1 0.66 891.2 909.2 G/G 2 (0.5) 2 (1.2) 2 (0.8) 1.91 (0.26~13.78) 1.56 (0.22~11.23) 超显性模式 A/A-G/G 325 (83.1) 144 (87.8) 223 (84.2) 1 0.11 643.4 660.6 1 0.72 891.3 909.2 A/G 66 (16.9) 20 (12.2) 42 (15.8) 0.64 (0.37~1.12) 0.93 (0.61~1.42) 逻辑累加
模式--- --- --- --- 0.75 (0.46~1.23) 0.25 644.6 661.9 0.97 (0.65~1.44) 0.88 891.4 909.3 *P < 0.05。 -
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