Association of lncRNA MALAT1 and GAS5 polymorphisms with genetic susceptibility to hepatocellular carcinoma
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摘要:
目的 探讨长链非编码RNA(long non-coding RNA, lncRNA)人肺腺癌转移相关的转录本1(metastasis-associated lung adenocarcinoma transcript 1, MALATl)及生长阻滞特异性转录本5(growth arrest specific transcript 5, GAS5)基因多态性与肝细胞癌(hepatocellular carcinoma, HCC)易感性的关联。 方法 收集225例HCC患者的癌组织及220例健康体检者外周静脉血标本，提取癌组织及血标本的DNA分别当作本病例对照研究的病例组与对照组。同时利用TaqMan MGB等位基因分型试剂盒对两组病例MALAT1 rs11227209及GAS5 rs55829688位点的单核苷酸多态性(single nucleotide olymorphism, SNP)进行检测，采用SPSS 17.0软件分析实验结果。 结果 MALAT1 rs11227209位点基因型频率(CC、CG、GG)在病例组中分布为：46.2%、42.7%、11.1%，在对照组中分布为：50.0%、42.7%、7.3%。分别进行纯合突变基因型CC与显性模型CG+GG基因型组比较，以及纯合野生基因型GG与隐性模型CG+CC基因型组的比较，发现两组基因型分布差异无统计学意义($\chi$2=0.636, P=0.425; $\chi$2=1.933, P=0.164)。GAS5 rs55829688基因型频率(TT、TC、CC)在病例组中的分布为：45.3%、43.6%、11.1%，在对照组中的分布为：57.7%、38.2%、4.1%。病例组CC基因型人群分布高于对照组(OR=3.459, 95% CI: 1.546~7.738, P=0.003)。病例组C等位基因携带频率也高于对照组(OR=1.624, 95% CI: 1.208~2.184, P=0.001)；C等位基因为风险基因，个体携带C等位基因可以增加罹患HCC的风险(OR=1.647, 95% CI: 1.132~2.395, P=0.009)。遗传易感性分层分析结果显示，女性患者携带GAS5 rs55829688 CT+TT基因型可降低HCC的发病风险(OR=0.161, 95% CI: 0.045~0.580, P＝0.005)，且≥50岁人群分组中若携带该位点CT+TT基因型，则HCC发病风险也降低(OR=0.232, 95% CI: 0.074~0.728, P＝0.012)。 结论 GAS5 rs55829688位点SNP与HCC的发病风险相关，携带CC基因型个体HCC的发病风险增高。同时年龄及性别和GAS5 rs55829688位点的SNP可能会共同影响HCC的发病风险。而MALAT1 rs11227209位点SNP与HCC发病风险无相关性。 -
关键词:
- 肝细胞癌 /
- 长链非编码RNA /
- 人肺腺癌转移相关的转录本1 /
- 生长阻滞特异性转录本5 /
- 单核苷酸多态性 /
- 易感性
Abstract:Objective This study aims to investigate the relationship between long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and growth arrest specific transcript 5 (GAS5) gene polymorphisms and hepatocellular carcinoma (HCC) susceptibility. Methods Cancer tissues from 225 HCC patients and peripheral venous blood samples from 220 healthy individuals were collected.DNA was extracted from these samples, constituting the case and control groups in this case-control study. At the same time, the single nucleotide polymorphism (SNP) of MALAT1 rs11227209 and GAS5 rs55829688 were detected using the Taq-Man MGB allele typing kit, and the results were analyzed by SPSS 17.0. Results The genotype frequencies(CC, CG, GG)of MALAT1 rs11227209 were 46.2%, 42.7%, and 11.1% in the case group and 50.0%, 42.7%, and 7.3% in the control group. Comparisons between homozygous mutant genotype CC and dominant model CG+GG genotype group, as well as homozygous wild genotype GG and recessive model CC+CG genotype group, revealed no statistically significant differences in genotype distribution ($\chi$2=0.636, P=0.425; $\chi$2=1.933, P=0.164). The genotype frequency (TT, TC, CC) of GAS5 rs55829688 were 45.3%, 43.6%, and 11.1% in the case group and 57.7%, 38.2%, and 4.1% in the control group. The distribution of CC genotype was higher in the case group (OR=3.459, 95% CI: 1.546-7.738, P=0.003). The frequency of C Allele was significantly higher in the case group compared to the control group (OR=1.624, 95% CI: 1.208-2.184, P=0.001). Allele C was a risk gene, increasing the risk of HCC in carriers (OR=1.647, 95% CI: 1.132-2.395, P=0.009). Genetic susceptibility stratification analysis showed that female patients carrying GAS5 rs55829688 CT+TT genotype could reduce the risk of HCC (OR=0.161, 95% CI: 0.045-0.580, P=0.005), as could individuals aged ≥50 years with the CT+TT genotype (OR=0.232, 95% CI: 0.074-0.728, P=0.012). Conclusions The SNP at rs55829688 of GAS5 is associated with increased HCC risk, particularly for individuals with CC genotype.Age, gender and the SNP of GAS5 rs55829688 may jointly impact the risk of HCC. No association was found between SNP at MALAT1 rs11227209 and HCC risk. -
表 1 lncRNA MALAT1与GAS5 SNP编码基因的引物序列及探针序列
Table 1. Primer sequence and probe sequence of genes encoding MALAT1 and GAS5 SNP
SNP 引物序列(5′-3′) 探针序列 MALAT1 rs11227209 F: GCGACGAGTTGTGCTGCTAT C: VIC-CTGCTATCTTAGCTGTCCTTATAGG-MGB C > G R: TCCTCCAAACCCCAAGACCA G: FAM-TGGCCATTCCAGGTGGTGGTATTTA-MGB GAS5 rs55829688 F: CATCACGTGGACGGTCATGT P1:FAM-CTGCCCACAATGG-MGB T > C R: ACCTTCTTCCCACCCCTTAAGT P2:HEX-TCTGCCCGCAATG-MGB 
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表 2 病例组和对照组人群一般资料比较结果[n(%)]
Table 2. Comparison results of the general data of the case group and the control group [n(%)]
变量 病例组(n=225) 对照组(n=220) $\chi$2值 P值 变量 病例组(n=225) 对照组(n=220) $\chi$2值 P值 年龄组(岁) 0.092 0.762 吸烟 1.023 0.312 ≥50 96(42.7) 97(44.1) 是 111(49.3) 98(44.5) < 50 129(57.3) 123(55.9) 否 114(50.7) 122(55.5) 性别 2.100 0.147 饮酒 1.555 0.212 男 139(61.8) 121(55.0) 是 80(35.6) 66(30.0) 女 86(38.2) 99(45.0) 否 145(64.4) 154(70.0)
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表 3 病例组与对照组MALAT1 rs11227209及GAS5 rs55829688基因多态性的比较
Table 3. Comparison of MALAT1 rs11227209 and GAS5 rs55829688 gene polymorphism between case and control groups
MALAT1/GAS5 SNP 等位基因型 病例组(n=225) 对照组(n=220) $\chi$2值 OR值(95% CI) P值 MALAT1 rs11227209 CC 104(46.2) 110(50.0) 1.000 C>G CG 96(42.7) 94(42.7) 0.150 1.080(0.731~1.597) 0.699 GG 25(11.1) 16(7.3) 2.082 1.653(0.835~3.270) 0.149 C 304(67.6) 314(71.4) 1.000 G 146(32.4) 126(28.6) 1.519 1.197(0.899~1.593) 0.218 CC 104(46.2) 110(50.0) 1.000 CG+GG 121(53.8) 110(50.0) 0.636 1.163(0.802~1.688) 0.425 GG 25(11.1) 16(7.3) 1.000 CG+CC 200(88.9) 204(92.7) 1.933 0.627(0.325~1.210) 0.164 GAS5 rs55829688 TT 102(45.3) 127(57.7) 1.000 T＞C TC 98(43.6) 84(38.2) 3.504 1.453(0.983~2.148) 0.061 CC 25(11.1) 9(4.1) 9.122 3.459(1.546~7.738) 0.003 T 302(67.1) 338(76.8) 1.000 C 148(32.9) 102(23.2) 10.297 1.624(1.208~2.184) 0.001 TT 102(45.3) 127(57.7) 1.000 TC+CC 123(54.7) 93(42.3) 6.805 1.647(1.132~2.395) 0.009 CC 25(11.1) 9(4.1) 1.000 TC+TT 200(88.9) 211(95.9) 7.187 0.341(0.155~0.749) 0.007
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表 4 MALAT1 rs11227209及GAS5 rs55829688 SNP与HCC易感性关系分层分析(病例组/对照组)
Table 4. Stratified analysis of the relationship between MALAT1 rs11227209 and GAS5 rs55829688 SNP and HCC susceptibility (case groups/control groups)
变量 MALAT1 rs11227209多态性 GAS5 rs55829688多态性 GG CG+CC OR值(95% CI) P值 CC CT+TT OR值(95% CI) P值 性别 男 10/16 123/111 0.693(0.302~1.589) 0.386 11/6 128/115 0.607(0.218~1.694) 0.340 女 9/6 77/93 0.552(0.188~1.619) 0.279 11/4 75/95 0.161(0.045~0.580) 0.005 年龄组(岁) ≥50 10/13 83/87 0.734(0.305~1.765) 0.489 4/15 81/93 0.232(0.074~0.728) 0.012 < 50 12/5 117/118 0.413(0.141~1.209) 0.107 10/5 119/118 0.504(0.167~1.520) 0.224 吸烟 是 10/13 98/88 0.857(0.358~2.051) 0.728 6/15 96/92 0.417(0.155~1.122) 0.083 否 12/6 100/116 0.440(0.159~1.214) 0.113 10/3 104/119 0.262(0.070~0.978) 0.046 饮酒 是 10/14 66/56 0.842(0.347~2.042) 0.703 5/15 65/61 0.355(0.122~1.036) 0.058 否 11/6 134/148 0.494(0.187~1.372) 0.176 10/4 135/150 0.360(0.110~1.175) 0.090
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