SCN1A基因多态性与卡马西平治疗壮族癫痫患者疗效的关系
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摘要
目的探讨SCN1A基因单核苷酸多态性(SNP)与卡马西平治疗壮族癫痫患者疗效的关系。方法利用MassARRAY-IPLEX和基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)技术检测186例广西百色地区卡马西平规范治疗的壮族癫痫患者(有效组66例,无效组120例)外周血SCN1A rs4667869和rs10497275基因型,应用反相高效液相色谱法检测卡马西平血药浓度,评估两组患者不同基因型和等位基因分布频率与卡马西平疗效的关联性,分析不同基因型患者间卡马西平血药浓度的差异性。结果rs4667869检测到GG、GC和CC 3种基因型,rs10497275检测到GG、GA和AA3种基因型。无效组与有效组相比,rs4667869等位基因分布(χ~2=11.790,P=0.001)和基因型分布(χ~2=10.655,P=0.005)差异均有统计学意义;而rs10497275等位基因分布(χ~2=3.335,P=0.068)和基因型分布(χ~2=3.046,P=0.218)差异均无统计学意义,rs4667869CC基因型与GG+GC基因型相比,CC基因型对卡马西平抗癫痫疗效更低(OR=2.800,95%CI:1.495～5.244)。在卡马西平治疗有效66例患者中,rs4667869 GG+GC基因型与CC基因型患者之间血药浓度(t=1.273,P=0.083)和rs10497275GG+GA基因型与AA基因型患者之间血药浓度(t=0.963,P=0.064)的差异均无统计学意义。结论 SCN1Ars4667869位点SNP与百色地区壮族癫痫卡马西平耐药性形成有关。
Objective To investigate the relationship between the single nucleotide polymorphisms of SCN1A genes and the therapeutic effects of carbamazepine in Zhuang population with epilepsies. Methods We used Mass ARRAY-IPLEX and matrix assisted laser desorption/ionization time of flight mass spectrometry( MALDI-TOF-MS) technology to detect the SCN1A gene rs4667869 and rs10497275 genotypes in peripheral blood of186 Zhuang individuals with epileptic(66 cases in effective group and 120 cases of ineffective group) who received the standardized treatment of carbamazepine in Baise Region. The reversed phase high-performance liquid chromatography was used to determine blood drug level of carbamazepine. The correlations between the genotypes,alleles and the carbamazepine efficacy of the two groups were evaluated, respectively. We also analyzed the difference of carbamazepine's blood concentration between different genotypes. Results Three genotypes of GG, GC and CC were detected in rs4667869 locus. There were 3 genotypes of GG, GA and AA found in rs 10497275 locus.The differences in the allele distribution(χ~2 = 11.790, P = 0.001) and genotype distribution(χ~2= 10.655, P =0.005) of the rs4667869 locus were statistically significant between the two groups(ineffective group vs. effective group). However, there was no significant difference in allele distribution( χ~2 = 3.335,P= 0.068) and genotype(χ~2= 3.046, P = 0.218) for rs 10497275 locus in these two groups. Compared with the GG + GC genotype, the CC genotype of rs4667869 locus significantly reduced the antiepileptic efficacy of carbamazepine(OR = 2.800, 95%CI : 1.495～5.244). W hile there were no significant differences in blood concentration of genotype CC(t=1.273,P = 0.083) comparing with genotypes GG + GC in rs4667869. No significant differences were found in blood concentration between genotype AA and genotypes GG + GA of rs 10497275(t= 0.963, P = 0.064). Conclusions These results suggest that the single nucleotide polymorphisms of rs4667869 in SCN1A genes could be associated with the drug resistance of carbamazepine in Zhuang population with epilepsies.
Objective To investigate the relationship between the single nucleotide polymorphisms of SCN1A genes and the therapeutic effects of carbamazepine in Zhuang population with epilepsies. Methods We used Mass ARRAY-IPLEX and matrix assisted laser desorption/ionization time of flight mass spectrometry( MALDI-TOF-MS) technology to detect the SCN1A gene rs4667869 and rs10497275 genotypes in peripheral blood of186 Zhuang individuals with epileptic(66 cases in effective group and 120 cases of ineffective group) who received the standardized treatment of carbamazepine in Baise Region. The reversed phase high-performance liquid chromatography was used to determine blood drug level of carbamazepine. The correlations between the genotypes,alleles and the carbamazepine efficacy of the two groups were evaluated, respectively. We also analyzed the difference of carbamazepine's blood concentration between different genotypes. Results Three genotypes of GG, GC and CC were detected in rs4667869 locus. There were 3 genotypes of GG, GA and AA found in rs 10497275 locus.The differences in the allele distribution(χ~2 = 11.790, P = 0.001) and genotype distribution(χ~2= 10.655, P =0.005) of the rs4667869 locus were statistically significant between the two groups(ineffective group vs. effective group). However, there was no significant difference in allele distribution( χ~2 = 3.335,P= 0.068) and genotype(χ~2= 3.046, P = 0.218) for rs 10497275 locus in these two groups. Compared with the GG + GC genotype, the CC genotype of rs4667869 locus significantly reduced the antiepileptic efficacy of carbamazepine(OR = 2.800, 95%CI : 1.495～5.244). W hile there were no significant differences in blood concentration of genotype CC(t=1.273,P = 0.083) comparing with genotypes GG + GC in rs4667869. No significant differences were found in blood concentration between genotype AA and genotypes GG + GA of rs 10497275(t= 0.963, P = 0.064). Conclusions These results suggest that the single nucleotide polymorphisms of rs4667869 in SCN1A genes could be associated with the drug resistance of carbamazepine in Zhuang population with epilepsies.
引文
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[2]FRY A E,REES E,THOMPSON R,et al.Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy[J].BMC Med Genet,2016,17(1):34.
[3]DACI A,BERETTA G,VLLASALIU D,et al.Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration,metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients[J].PLoS One,2015,10(11):1-17.
[4]ZHOU B T,ZHOU Q H,YIN J Y,et al.Comprehensive analysis of the association of SCN1A gene polymorphisms with the retention rate of carbamazepine following monotherapy for new-onset focal seizures in the Chinese Han population[J].Clin Exp Pharmacol Physiol,2012,39(4):379-384.
[5]黄瑞雅,解继胜,李雪斌,等.广西桂西壮族癫痫患者生活质量调查[J].中国医学科学院学报,2007,29(1):103-106.
[6]钱哲,陈海燕,黄清,等.基因SCN1Ars3812718多态性与桂西地区难治性癫痫相关性的研究[J].右江医学,2017,45(2):129-133.
[7]MARGARI L,LEGROTTAGLIE A R,VINCENTI A,et al.Association between SCN1A gene polymorphisms and drug resistant epilepsy in pediatric patients[J].Seizure,2018,55(2):30-35.
[8]TAKAORI T,KUMAKURA A,ISHII A,et al.Two mild cases of Dravet syndrome with truncating mutation of SCN1A[J].Brain Dev,2017,39(1):72-74.
[9]SHI X Y,TOMONOH Y,WANG W Z,et al.Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes[J].Brain Dev,2016,38(1):40-46.
[10]赵晰,何周康,张晶,等.SCNIA基因多态性与卡马西平治疗儿童癫痫疗效的关系[J].儿科药学杂志,2011,17(1):26-28.