Associations between SLC2A9 Single Nucleotide Polymorphisms and Susceptibility to Pyrazinamide Induced Hyperuricemia
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摘要:
目的 探讨云南地区汉族人群SLC2A9基因单核苷酸多态性与吡嗪酰胺致高尿酸血症（pyrazinamide induced hyperuricemia，PIHU）的易感性关系。 方法 应用Mass ARRAY法对294例PIHU患者（试验组）和220例非PIHU患者（对照组）的SLC2A9基因单核苷酸多态性位点rs2280205、rs3733591、rs3775948、rs10939650基因型进行检测，比较基因型及等位基因频率分布，分析不同遗传模型下4个位点多态性与PIHU的易感性关系。 结果 2组间rs2280205位点基因型频率及等位基因频率分布比较，差异有统计学意义（P < 0.05），携带等位基因A的患者PIHU风险增高；rs2280205位点多态性在共显性、显性、隐性模型下与PIHU显著相关（均P < 0.05）。rs3733591位点基因型频率及等位基因频率在2组间分布比较，差异有统计学意义（P < 0.05），携带等位基因T的患者PIHU风险增高；rs3733591位点多态性在共显性、显性、隐性模型下与PIHU显著相关（均P < 0.05）。rs3775948位点基因型频率及等位基因频率在2组间分布比较，差异有统计学意义（均P < 0.001），携带等位基因C的患者PIHU风险增高；rs3775948位点多态性在共显性和显性模型下与PIHU显著相关（均P < 0.05）。rs10939650位点基因型频率及等位基因频率在2组间分布比较，差异有统计学意义（均P < 0.001），携带等位基因C的患者PIHU风险增高；rs10939650位点多态性在共显性和隐性模型下与PIHU显著相关（均P < 0.05）。 结论 SLC2A9基因rs2280205、rs3733591、rs3775948、rs10939650位点多态性可能与云南地区汉族人群PIHU的易感性相关，rs2280205位点等位基因A、rs3733591位点等位基因T、rs3775948位点等位基因C、rs10939650位点等位基因T可能是发生PIHU的风险因素。 Abstract:Objective To explore the association between gene single nucleotide polymorphisms of SLC2A9 and susceptibility to pyrazinamide induced hyperuricemia （PIHU） in Yunnan Han population. Methods The polymorphisms of SLC2A9 gene rs2280205, rs3733591, rs3775948 and rs10939650 were detected by Mass ARRAY method. Genotype and allele frequency distribution were compared between the test group （n = 294） and the control group （n = 220） and analyzing the association between the polymorphisms of SLC2A9 with susceptibility to PIHU in different genetic models. Results There were significant differences in genotype frequency and allele frequency distribution of rs2280205 between the two groups （P < 0.05）. Patients carrying allele A had an increased risk of PIHU; rs2280205 polymorphism was significantly correlated with PIHU in co-dominant, dominant and recessive models （all P < 0.05）. rs3733591 genotype frequency and allele frequency distribution between the two groups, the difference was statistically significant （P < 0.05）, the patients with allele T increased the risk of PIHU. rs3733591 polymorphism was significantly correlated with PIHU in co-dominant, dominant and recessive models （all P < 0.05）. rs3775948 genotype frequency and allele frequency distribution between the two groups, the difference was statistically significant （all P < 0.001）, the patients with allele C of PIHU increased risk; rs3775948 polymorphism was significantly associated with PIHU in both co-dominant and dominant models （P < 0.05）. rs10939650 genotype frequency and allele frequency distribution between the two groups, the difference was statistically significant （all P < 0.001）, the patients with allele C of PIHU increased risk; rs10939650 polymorphism was significantly associated with PIHU in both co-dominant and recessive models （P < 0.05）. Conclusion SLC2A9 gene polymorphisms rs2280205, rs3733591, rs3775948 and rs10939650 may be associated with the susceptibility to PIHU in Yunnan Han population, and allele A of rs2280205, allele T of rs3733591, allele C of rs3775948 and allele T of rs10939650 may be risk factors for PIHU. -
Key words:
- Pyrazinamide /
- Hyperuricemia /
- SLC2A9 gene /
- Single nucleotide polymorphisms
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图 1 rs3733591位点基因分型图
A~C：rs3733591位点野生纯合型分型图、突变纯合型分型图、突变杂合型分型图；图中第1条标线为UEP相对分子质量，第2条标线为UEP+C碱基的相对分子量，第3条标线为UEP+T碱基的相对分子量。
Figure 1. Genotypes of rs3733591 loci
表 1 SLC2A9基因SNPs引物序列
Table 1. Primer sequences of SNPs with SLC2A9 gene
SNPs 引物序列 PCR扩增产物长度（bp） rs2280205 上游引物：5’ACGTTGGATGACTGACCATTCTCTCTGCTCC-3’ 135 下游引物：5’ACGTTGGATGTACTCAAGGTGACGTATGGG-3’ UEP引物：5’-gagggGACGTATGGGATCTTTGCC-3’ rs3733591 上游引物：5’-ACGTTGGATGTTTCCCAAGAGGTAGAGGAG-3’ 147 下游引物：5’-ACGTTGGATGATGGTGACAATCACGGTGAC-3’ UEP引物：5’-ctgaGGATGCTCCTCTGCACG-3’ rs3775948 上游引物：5’-ACGTTGGATGCTTCACAACAACCCTCTGAC-3’ 131 下游引物：5’-ACGTTGGATGAAGTCTGGGCTCCGATACAC-3’ UEP引物：5’-AGCTATGTGTTTCTTAAACTCTTT-3’ rs10939650 上游引物：5’-ACGTTGGATGTGACCTCCCAAGAACCTTTC-3’ 130 下游引物：5’-ACGTTGGATGACCCAGACACTCTGACTTTG-3’ UEP引物：5’-CGGTGGACTTGTGGGGAC-3’ 
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表 2 PZA治疗4～5周后研究对象的基本情况[n（%）/
$ \bar x \pm s $ ]Table 2. The basic situation of the study subjects after 4～ 5 weeks of PZA treatment [n（%）/
$ \bar x \pm s $ ]指标 试验组（n = 294） 对照组（n = 220） χ2/t P 性别 0.065 0.573 男 155（52.7） 118（53.6） 女 139（47.3） 102（46.4） 年龄（岁） 46.80 ± 9.98 45.91 ± 10.76 0.042 0.837 血尿素氮（mmol/L） 3.92 ± 0.83 4.16 ± 0.91 −1.228 0.265 血肌酐（μmol/L） 62.52 ± 14.11 59.67 ± 15.43 −1.038 0.304 血尿酸（μmol/L） 648.32 ± 109.23 319.14 ± 52.64 −15.425 < 0.001* *P < 0.05。
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表 3 SLC2A9基因SNPs位点基因型及等位基因频率分布比较[n（%）]
Table 3. The comparison of the genotype and allele frequencies of SLC2A9 gene SNPs [n（%）]
SNPs 基因型/等位基因 试验组（n = 294） 对照组（n = 220） χ2 P OR（95%CI） rs2280205 野生GG 152（51.7） 133（60.5） 6.568 0.037* AA 20（6.8） 6（2.7） AG 122（41.5） 81（36.8） A 162（27.5） 93（21.1） 5.552 0.018* 1.419（1.060～1.900） G 426（72.5） 347（78.9） HWE平衡P值 0.9000 0.478 rs3733591 野生CC 40（13.6） 54（24.5） 12.791 0.002* TT 122（41.5） 66（30.0） CT 132（44.9） 100（45.5） C 212（36.1） 208（47.3） 13.108 < 0.001* 1.590（1.236～2.045） T 376（63.9） 232（52.7） HWE平衡P值 0.938 0.633 rs3775948 野生GG 52（17.7） 79（35.9） 26.277 < 0.001* CC 118（40.1） 53（24.1） GC 124（42.2） 88（40.0） G 228（38.8） 246（55.9） 29.732 < 0.001* 2.002（1.558～2.573） C 360（61.2） 194（44.1） HWE平衡P值 0.383 0.153 rs10939650 野生CC 82（27.9） 69（31.4） 25.157 < 0.001* TT 92（31.3） 28（12.7） TC 120（40.8） 123（55.9） T 304（51.7） 179（40.7） 12.267 < 0.001* 1.561（1.216～2.003） C 284（48.3） 261（59.3） HWE平衡P值 0.089 0.259 OR：比值比；95%CI：95%置信区间。*P < 0.05。
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表 4 SLC2A9基因SNPs与PIHU的风险相关性（经调整性别、年龄后）[n（%）]
Table 4. Association between SNPs of SLC2A9 gene and the risk for PIHU （after adjustment for gender and age） [n（%）]
SNPs 遗传模型 基因型 OR 95%CI P rs2280205 共显性 野生GG 1.000 AA 2.917 1.138～7.478 0.021* AG 1.318 0.915～1.898 0.138 显性 AA+AG vs. GG 1.428 1.002～2.035 0.048* 隐性 AA vs. GG+AG 2.603 1.028～6.596 0.037* rs3733591 共显性 野生CC 1.000 TT 2.495 1.503～4.142 0.000* CT 1.782 1.098～2.893 0.019* 显性 TT+CT vs. CC 2.066 1.313～3.250 0.002* 隐性 TT vs. CC+CT 1.655 1.143～2.396 0.007* rs3775948 共显性 野生GG 1.000 CC 3.382 2.099～5.450 <0.001* GC 2.141 1.373～3.337 0.001* 显性 CC+GC vs. GG 2.607 1.736～3.917 <0.001* 隐性 CC vs. GG+GC 1.297 0.883～1.906 0.185 rs10939650 共显性 野生CC 1.000 TT 2.765 1.627～4.700 <0.001* TC 0.821 0.546～1.233 0.342 显性 TT+TC vs. CC 1.181 0.806～1.731 0.392 隐性 TT vs. CC+TC 3.123 1.958～4.981 <0.001* *P<0.05。
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