β_2肾上腺素能受体基因Arg16Gly多态性与沙美特罗反应性的相关性研究

Association study between β_2-adrenergic receptor gene Arg16Gly polymorphisms and Sal-meterol response

目的:评价使用丙酸氟替卡松的哮喘患者,其β2-肾上腺素受体基因(ADRB2)Arg16Gly的变异对沙美特罗临床反应性的影响。方法:62例哮喘患者,给予丙酸氟替卡松/沙美特罗(FSC)(100μg/50μg),2次/天吸入,治疗12周,治疗结束后有2～4天的导出期;以DNA直接测序法,确定62例ADRB25个位点的基因型及单倍型。结果:①哮喘在沙美特罗治疗期间,无论Arg16Gly为哪一种基因型,哮喘控制指标如峰值呼气流速(PEF)、1秒钟用力呼气容积(FEV1)、沙丁胺醇的使用量以及哮喘症状评分较其基础值都有持续地明显地改善(P<0.001),Arg/Arg患者的PEF较其基础值增加了(114.4±21.5)L/min,Gly/Gly与Arg/Gly患者分别增加了(100.3±14.7)L/min和(103.3±23.7)L/min,但3种基因型的哮喘控制指标的变化的比较,差异无显著性(P>0.05);其他的3个哮喘指标也有相似的改变;②对沙美特罗的反应性不受单倍型配对的影响(P>0.05);③在导出期,所有患者的哮喘控制指标都有相似的下降,但无基因型方面的差异(P>0.05)。结论:在长期吸入糖皮质激素的情况下,Arg16Gly基因型或单倍型不会影响对沙美特罗的治疗反应性。然而,目前尚需要大规模的前瞻性的临床药物遗传学研究以及遗传流行病学研究来进一步阐明。

Objective：To evaluate the effects of variation Arg16Gly in ADRB2 on clinical response to the salmeterol administered with fluticasone propionate in subjects with asthma. Methods：Sixty-two asthma patients were administered with twice-daily therapy of fluticasone propionate/salmeterol（100 μg/50 μg） for 12 weeks, followed by a 2-to 4-day run-out period. Using direct DNA sequencing, five SNPs in the promoter and coding block regions of ADRB2 were determined in sixty-two asthma patients, and haplotypes were combined. Results ： ①There was sustained and significant improvement respectively （P 〈 0.001 ） in all measurements of asthma control （PEF, FEV1, albuterol use and asthma symptom score） in subjects receiving salmeterol, compared with baseline, regardless of Arg16Gly genotype. PEF increased with （114.4 ± 21.5）L/min,（100.3 ± 14.7）L/min and （103.3 ± 23.7）L/min in subjects with the Arg/Arg, Gly/Gly and Arg/Gly genotypes respectively, compared with baseline. While, there was no significant difference in the improvement among three genotypes. ②Responses did not be modified by haplotype pairs. ③During the run-out period, all subjects had similar decreases in measurements of asthma control, with no differences among genotypes. Conclusion：Response to salmeterol does not vary with ADRB2 genotypes after chronic dosing with an inhaled corticosteroid. However, larger prospective clinical pharmaeogenetie studies to evaluate haplotypes across different ethnic/racial groups, as well as genetic epidemiologie studies, are further needed to help elucidate this field