Beta2 adrenoceptor genotype and preterm labor

描述（由申请人提供）：早产是美国的一个主要公共卫生问题，发生在大约11%的妊娠中，并导致70-85%的围产期发病率和死亡率。早产（PTL）发生率的个体、种族和民族差异可能至少部分基于人群间的遗传差异。β 2-肾上腺素能受体长期以来一直是治疗（PTL）的治疗靶点，因为β 2 AR刺激促进子宫舒张。由于药物代谢的遗传变异和治疗靶点的结构或功能，药物的治疗反应和副作用特征在个体和群体之间存在显著差异。已经描述了β 2 AR的单核苷酸多态性（遗传变异），其在功能和对激动剂刺激的反应方面不同。我们的初步数据表明，β 2 AR的Arg 16基因型与早产保护和发生早产时对β 2激动剂安胎反应显著更好相关。精氨酸基因型与受体对刺激的脱敏反应降低有关，表明这种形式的受体可能在面对环境条件时更好地维持子宫静止（例如，感染、炎症、多胎妊娠），这可能导致早产。本项目的目的是在一项前瞻性、治疗标准化队列研究中，在来自多个种族的妇女中确定B2 AR遗传变异性在早产发生率中的作用，并确定B2 AR基因型在对保胎β-肾上腺素受体激动剂治疗反应中的作用。将研究来自三个不同种族群体（高加索人，非洲裔美国人和西班牙裔）的女性。将在每个种族人群中比较早产妇女与足月分娩妇女的B2 AR基因型分布，以确定β 2 AR基因型对早产发生率的影响。早产妇女将接受包括B2 AR激动剂特布他林在内的方案治疗，并确定β 2 AR基因型对治疗成功、失败和副作用的影响。我们的研究结果将有助于了解导致早产的个体遗传因素和种族/种族流行病学，并将有助于在现代遗传知识的基础上针对特定人群进行适当的治疗。

DESCRIPTION (provided by applicant): Preterm birth is a major public health problem in the United States, occurring in approximately 11% of pregnancies, and contributing to 70-85% of perinatal morbidity and mortality. Individual, racial, and ethnic differences in incidence at outcome from preterm labor (PTL) are likely based, at least in part, on genetic differences between populations. The beta2-adrenergic receptor has long been a therapeutic target in the treatment of (PTL) since Beta2AR stimulation promotes uterine relaxation. The therapeutic response to and side-effect profile of drugs differs significantly between individuals and groups due to genetic variation in drug metabolism and the structure or function of the therapeutic target. Single nucleotide polymorphisms (genetic variations) of the Beta2AR have been described which differ in function and response to stimulation with agonists. Our preliminary data demonstrate that the Arg 16 genotype of the Beta2AR is associated with protection from preterm delivery and a significantly better response to Beta2-agonist tocolysis when preterm labor occurs. The arginine genotype is associated with decreased desensitization of the receptor in response to stimulation, suggesting that this form of the receptor might better maintain uterine quiescence in the face of environmental conditions (e.g., infection, inflammation, multiple gestation) which can predispose to preterm labor. It is the goal of this project to define the role of genetic variability in the B2AR in the incidence of preterm labor in a prospective, treatment-standardized cohort study, in women from several ethnic groups, and to define the role of B2AR genotype in the response to tocolytic b-adrenoceptor agonist treatment. Women from three different ethnic groups (Caucasian, African-American, and Hispanic) will be studied. The B2AR genotype distribution in women with preterm labor will be compared to women delivering at term within each ethnic population to determine the effect of Beta2AR genotype on the incidence of preterm labor. Women with preterm labor will be treated with a protocol including the B2AR agonist terbutaline and the effect of Beta2AR genotype on the success, failure, and side effects of treatment will be defined. Our findings will contribute to understanding of the individual genetic factors and ethnic/racial epidemiology contributing to preterm delivery and will help to target appropriate therapy to defined populations on the basis of modern genetic knowledge.