SLC22A12基因多态性与吡嗪酰胺诱导高尿酸血症的易感性研究

doi:10.19982/j.issn.1000-6621.20220315

摘要/Abstract

摘要：

目的: 探讨SLC22A12基因多态性与吡嗪酰胺诱导肺结核患者高尿酸血症相关性。方法: 收集2019年1月至2021年3月昆明市第三人民医院收治的行强化期含吡嗪酰胺抗结核方案的514例肺结核患者作为研究对象,将发生高尿酸血症的294例患者作为尿酸升高组,未发生高尿酸血症的220例患者作为尿酸正常组。采用SNP Sequenom MassARRAY分型方法检测研究对象SLC22A12基因rs11602903、rs559946、rs475688和rs476037位点的多态性,并采用logistic回归模型分析各相关位点与吡嗪酰胺诱导高尿酸血症的相关性。结果: 吡嗪酰胺使用4周时,尿酸升高组的血尿酸[(648.32±109.23)μmol/L]明显高于尿酸正常组[(319.14±52.64)μmol/L],差异有统计学意义(t=-15.425,P=0.000)。logistic回归模型分析尿酸升高组和尿酸正常组各位点基因型和等位基因与发生高尿酸血症的相关性,结果显示:携带rs475688位点TC[50.3%(148/294) vs. 44.1%(97/220)]、TT基因型[21.8%(64/294) vs. 6.4%(14/220)]及T等位基因[46.9%(276/588) vs. 28.4%(125/440)]的患者发生高尿酸血症的风险均明显增加[OR(95%CI)值分别为2.028(1.381~2.978)、6.077(3.187~11.586)、2.229(1.714~2.900)],而携带rs11602903位点TA[32.3%(95/294) vs. 50.0%(110/220)]、TT基因型[4.1%(12/294) vs. 8.2%(18/220)]及T等位基因[20.2%(119/588) vs. 33.2%(146/440)]和携带rs559946位点TC[32.7%(96/294) vs. 45.5%(100/220)]及T等位基因[20.4%(120/588) vs. 26.4%(116/440)]的患者发生高尿酸血症的风险均明显降低[OR(95%CI)值分别为0.425(0.293~0.616)、0.328(0.152~0.710)及0.511(0.385~0.678);0.578(0.401~0.833)及0.716(0.535~0.959)]。结论: SLC22A12基因的rs11602903、rs559946位点多态性可能降低吡嗪酰胺诱导高尿酸血症风险,rs475688位点多态性可能增加吡嗪酰胺诱导高尿酸血症风险。

关键词: 基因型, 多态性,单核苷酸, 药物毒性, 疾病易感性, 吡嗪酰胺

Abstract:

Objective: To investigate the correlation between SLC22A12 gene polymorphism and hyperuricemia induced by pyrazinamide in patients with pulmonary tuberculosis. Methods: A total of 514 patients with pulmonary tuberculosis who had received an intensive regimen containing pyrazinamide in the Third People’s Hospital of Kunming from January 2019 to March 2021 were collected. A total of 294 patients with hyperuricemia were selected as the elevated uric acid group and 220 patients without hyperuricemia were selected as the normal uric acid group. The SNP Sequenom MassARRAY genotyping was used to detect the polymorphisms of rs11602903, rs559946, rs475688 and rs476037 in SLC22A12 gene, and logistic regression model was used to analyze the correlation between the the polymorphisms of related loci and hyperuricemia induced by pyrazinamide. Results: After 4-week treatment with pyrazinamide, the serum uric acid in the elevated uric acid group ((648.32±109.23) μmol/L) was significantly higher than that in the normal uric acid group ((319.14±52.64) μmol/L), and the difference was statistically significant (t=-15.425,P=0.000). Logistic regression model was used to analyze the correlation between the genotypes and alleles of each locus and the occurrence of hyperuricemia in the elevated uric acid group and the normal uric acid group. The results showed that the rs475688 TC (50.3% (148/294) vs. 44.1% (97/220)), TT genotype (21.8% (64/294) vs. 6.4% (14/220)) and T allele (46.9% (276/588) vs. 28.4% (125/440)) of patients in the normal group had a significantly increased risk of hyperuricemia after taking pyrazinamide (OR (95%CI) were 2.028 (1.381-2.978), 6.077 (3.187-11.586), 2.229 (1.714-2.900)). The risk of hyperuricemia was significantly reduced in patients with TA (32.3% (95/294) vs. 50.0% (110/220)), TT genotype (4.1%(12/294) vs. 8.2% (18/220)) and T allele (20.2% (119/588) vs. 33.2% (146/440)) of rs11602903 and TC (32.7% (96/294) vs. 45.5% (100/220)), T allele (20.4% (120/588) vs. 26.4% (116/440)) of rs559946 (OR (95%CI) were 0.425 (0.293-0.616), 0.328 (0.152-0.710), 0.511 (0.385-0.678); 0.578 (0.401-0.833), 0.716 (0.535-0.959), respectively). Conclusion: The rs11602903 and rs559946 polymorphisms of SLC22A12 gene may be related to the reduction of pyrazinamide-induced hyperuricemia. The rs475688 polymorphism may increase the risk of pyrazinamide-induced hyperuricemia.

Key words: Genotype, Polymorphism, single nucleotide, Drug toxicity, Disease susceptibility, Pyrazinamide

中图分类号:

彭江丽, 陈洁, 陈永刚, 王璐, 李娜, 罗季, 韩祎, 喻明丽, 朱江春. SLC22A12基因多态性与吡嗪酰胺诱导高尿酸血症的易感性研究[J]. 中国防痨杂志, 2023, 45(2): 151-158. doi: 10.19982/j.issn.1000-6621.20220315

Peng Jiangli, Chen Jie, Chen Yonggang, Wang Lu, Li Na, Luo Ji, Han Yi, Yu Mingli, Zhu Jiangchun. SLC22A12 gene polymorphism study on susceptibility to hyperuricemia induced by pyrazinamide[J]. Chinese Journal of Antituberculosis, 2023, 45(2): 151-158. doi: 10.19982/j.issn.1000-6621.20220315

图/表 6

图1

表1

表2

两组患者服用吡嗪酰胺前后血清尿酸、血尿素氮和血肌酐水平比较

组别	例数	尿酸(μmol/L, $x ˉ$ ±s)		血尿素氮(mmol/L, $x ˉ$ ±s)		血肌酐(μmol/L, $x ˉ$ ±s)
组别	例数	服用前	服用4周	服用前	服用4周	服用前	服用4周
尿酸升高组	294例	310.77±48.21	648.32±109.23	3.85±0.72	4.16±0.91	60.94±15.21	62.52±14.11
尿酸正常组	220例	312.35±47.62	319.14±52.64	3.89±0.67	3.92±0.83	58.42±16.15	59.67±15.43
t值		0.443	-15.425	0.622	-1.228	-1.640	-1.038
P值		0.658	0.000	0.534	0.265	0.102	0.304

表2

表3

表4

表5

肺结核患者SLC22A12基因多态性对吡嗪酰胺诱导高尿酸血症影响的多因素logistic回归分析

基因	β值	s $x ˉ$ 值	Wald χ²值	P值	OR(95%CI)值
rs11602903
AA	-	-	-	-	1.000
TA	0.174	0.065	5.527	0.018	0.425(0.293~0.616)
TT	-4.263	2.142	6.752	0.005	0.328(0.152~0.710)
A	-	-	-	-	1.000
T	-4.998	2.313	6.042	0.027	0.511(0.385~0.678)
rs559946
CC	-	-	-	-	1.000
TC	-0.561	0.314	3.425	0.003	0.578(0.401~0.833)
TT	-0.051	0.314	0.125	0.829	0.903(0.358~2.277)
C	-	-	-	-	1.000
T	-0.574	0.311	3.972	0.025	0.716(0.535~0.959)
rs475688
CC	-	-	-	-	1.000
TC	-5.276	2.407	5.150	0.033	2.028(1.381~2.978)
TT	-0.537	0.312	3.956	0.042	6.077(3.187~11.586)
C	-	-	-	-	1.000
T	0.667	0.307	4.698	0.029	2.229(1.714~2.900)
rs476037
GG	-	-	-	-	1.000
AG	0.407	0.423	0.912	0.345	1.191(0.829~1.712)
AA	0.439	0.472	0.725	0.389	1.367(0.670~2.790)
G	-	-	-	-	1.000
A	-0.124	0.221	1.613	0.288	1.156(0.885~1.511)

表5

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位点	正向PCR引物序列	反向PCR引物序列	UEP单碱基延伸引物序列
rs11602903	ACGTTGGATGATTGGGCACACC GAACCTG	ACGTTGGATGACTCACCTGCTGT GGTTGG	gcgaTTTGCTGTTACCCTGTCCT GAG
rs559946	ACGTTGGATGAAAACTTAGGCC TCCCCAAG	ACGTTGGATGAAAGTTTAACCC GCGTTGAG	ttCCCGCGTTGAGGCAGGC
rs475688	ACGTTGGATGGAGAGTGGAAGG TAAAGGTC	ACGTTGGATGAGCACGTCTACC AAGGAAAG	tgagcACCAGGAGGGGTGCCTTG
rs476037	ACGTTGGATGTTAAGTGGAGTC GGTCAGGG	ACGTTGGATGTTACCCAGAAGC CCTGTAAG	cagtCCTCAGCCACCTGCCC

位点	尿酸升高组 (294例)	尿酸正常组 (220例)	χ²值	P值	位点	尿酸升高组 (294例)	尿酸正常组 (220例)	χ²值	P值
rs11602903					rs475688
基因型			24.499	0.000	基因型			36.589	0.000
AA	187(63.6)	92(41.8)			CC	82(27.9)	109(49.5)
TA	95(32.3)	110(50.0)			TC	148(50.3)	97(44.1)
TT	12(4.1)	18(8.2)			TT	64(21.8)	14(6.4)
等位基因			22.038	0.000	等位基因			36.320	0.000
A	469(79.8)	294(66.8)			C	312(53.1)	315(71.6)
T	119(20.2)	146(33.2)			T	276(46.9)	125(28.4)
rs559946					rs476037
基因型			8.786	0.012	基因型			1.295	0.523
CC	186(63.3)	112(50.9)			GG	125(42.5)	104(47.3)
TC	96(32.7)	100(45.5)			AG	146(49.7)	102(46.4)
TT	12(4.0)	8(3.6)			AA	23(7.8)	14(6.3)
等位基因			5.047	0.025	等位基因			1.130	0.288
C	468(79.6)	324(73.6)			G	396(67.3)	310(70.4)
T	120(20.4)	116(26.4)			A	192(32.7)	130(29.6)