β2-肾上腺素能受体多态性／单倍型与支气管哮喘表型的相关性

Association between beta2-adrenergic receptor haplotype/polymorphisms and asthma phenotype

目的研究β2-肾上腺素能受体基因的多态性／单倍型与支气管舒张剂的反应性及血清免疫球蛋白E的负对数（lgIgE）间的关系。方法2006年2月至2007年2月采用DNA测序法测定了201例哮喘患者（哮喘组）和276名健康对照者（健康对照组）的β2-AR基因5个位点（-47、-20、46、79、252）的基因型并确定其单倍型。统计学处理采用SPSS 11．5软件。以拟和优度的χ^2检验计算各位点基因型频率是否符合Hardy-Weinberg平衡。5个位点基因型的频率比较采用卡方检验，位点间的连锁不平衡采用确切概率法，不同基因型及单倍型与定量指标间的比较采用方差分析。如果方差分析有统计学意义，则用LSD方法对各组间的值进行两两比较。结果哮喘组中Arg16Arg16基因型患者的支气管舒张剂反应性为（13±4）L，与Arg16Gly16基因型[（7±3）L]及Gly16Gly16基因型[（7±3）L]比较差异有统计学意义（F=81．55，P〈0．01）；在哮喘组6种单倍型中，单倍型Arg16Gln27／Arg16Gln27的△FEV1最高[（13．4±3．5）L]，与其他种单倍型[Gly16Gln27／Gly16Gln27（6．4±0．6）L、Gly16Glu27／Gly16Glu27（7．6±3．1）L、Gly16Gln27／Gly16Glu27（6．9±3．5）L、Gly16Gln27／Arg16Gln27（7．2±3．3）L及Gly16Glu27／Arg16Gln27（7．9±2．7）L]比较差异有统计学意义（F=32．55，P〈0．01）；哮喘组中Gln27Gln27基因型患者的血清lgIgE为（2．51±0．33）IU／L，与Gln27Glu27基因型患者的血清lgIgE[（2．30±0．82）IU／L]比较差异有统计学意义（F=3．89，P〈0．05）；哮喘组中单倍型Gly16Glu27／Arg16Gln27的血清lgIgE最低[（2．13±0．15）IU／L]，与其他4种单倍型[Arg16Gln27／Arg16Gln27为（2．56±0．14）IU／L、Gly16Glu27／Gly16Glu27为（2．40±0．16）IU／L、Gly16Gln27／Gly16Glu27为（2．54±1．26）IU／L、Gly16Gln27／Arg16Gln27为（2．48±0．48）IU／L]比较差异有统计学意义（F=3．56，P〈0．01）。结论依据所研究的哮喘表型，无论是β2-AR基因的多态性，还是单倍型均可能影响疾病的表现。

Objective To analyze the association of single nucleotide polymorphisms （SNP）/ haplotypes of beta2-adrenergic receptor （β2-AR） gene with bronchodilator response and total serum immunoglobulin E （IgE）. Methods Five SNP （ in positions ： - 47, - 20, 46, 79, 252） genotypes of β2-AR gene in 201 asthmatic patients and 276 controls were determined by direct DNA sequencing, and the haplotypes were combined from 2006 February to 2007 February. Satistical analyses were performed with SPSS 11.5 software. The genotype frequencies for each polymorphism were tested for deviation from the Hardy-Weinberg equilibrium by χ^2 goodness-of-fit analysis. The frequencies of the five polymorphic genotypes were compared with χ^2 test, and the degree of linkage disequilibrium occurring between these polymorphic loci were analyzed by fisher＇ s exact. For the comparison of quantitative traits among different genotypes/haplotypes, ANOVA was used. Least significant difference （LSD） was used if there was statistical significant. Results The bronchodilator response in patients with Arg16Arg16 was （13 ± 4）L, significantly higher than those with Arg16Gly16 [ （7 ± 3） L and Gly16Gly16 （7 ± 3） L, F = 81.55, P 〈 0. 01 ]. When β2-AR haplotypes were analyzed, bronchodilator response was highest in patients with haplotype Arg16Gln27/Arg16Gln27 [ （ 13.4 ± 3.5 ） L], compared to that with Gly16Gln27/Gly16Gln27 [ （6.4 ± 0.6） L ], Gly16Glu27/Gly16Glu27 [ （ 7. 6 ± 3.1 ） L], Gly16Gln27/Gly16Glu27 [ （ 6. 9 ± 3.5 ） L ], Gly16Gln27/Arg16Gln27 [ （7. 2 ±3.3） L, and Gly16Glu27/Arg16Gln27 （7.9 ±2.7） L,F =32.55, P 〈 0.01 ]. The total IgE level was （2.51 ± 0. 33） IU/L in patients with genotype Gln27Gln27, significantly higher than that with Gln27Glu27 [ （ 2.30 ± 0. 82 ） IU/L, F = 3. 89, P 〈 0. 05 ]. The total IgE level was significantly lowest in patients with haplotype Gly16Gln27/Arg16Gln27 （ 2. 13 ± 0. 15 ） IU/L, compared to that with Arg16Gln27/Arg16Gln27 （2. 56 ± 0. 14） IU/L, Gly16Glu27/Gly16Glu27 （2.40±0. 16 ） IU/L, Gly16Gln27/Gly16Glu27 （ 2.54±1.26 ） IU/L, Gly16Gln27/Arg16Gln27 [ （ 2.48±0. 48 ） IU/L, F = 3. 56, P 〈 0. 01 ]. Conclusions These results indicate that depending on phenotypes studied, either an individual β2-AR SNP or haplotype might affect disease manifestations.