Beta2 adrenoceptor genotype and preterm labor

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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.