PROJECT IIIHLA-G is a nonclassical HLA gene that is expressed primarily in fetal tissues at the maternal-fetalinterface, where it plays a significant role in the establishment of implantation. Although the exons ofthis gene have few polymorphisms, the 5'-upstream region, containing all of the known regulatoryelements, is extraordinarily polymorphic. Recently, we reported associations between variants in thisgene and miscarriage, and suggested that variation in expression levels of HLA-G mRNA and proteininfluences pregnancy success. In this application, we propose to directly study the relationshipbetween HLA-G polymorphisms, mRNA expression level, and adverse pregnancy outcomesassociated with shallow placental invasion (preeclampsia, preterm labor, and preterm delivery).
In Aim 1, we will compare by quantitative SNaPshot differences in mRNA levels in primarycytotrophoblast cells from placentas that are heterozygote for different HLA-G polymorphisms.
In Aim2, we will measure the relative abundance of the differentially spliced transcripts (called G1, G2, G3,G4, G5, and G6) by real time RT-PCR in primary cytotrophoblast cells from placentas with differentHLA-G genotypes.
In Aim 3, we will assess the effects of polymorphisms on risk for preeclampsia,preterm labor, and preterm delivery in African American and Caucasian patients who deliver at theChicago Lying-in Hospital and their neonates. Further, we will examine the relationship between HLAGpolymorphisms and preterm labor/delivery with and without maternal and fetal infection in thesepatients. Identifying genetic variants in the HLA-G gene that are associated with adverse pregnancyoutcome would implicate this gene and aberrations in its expression in the pathophysiology of themost common disorders in pregnancy. This study has the potential to identify unsuspectedmechanisms that influence pregnancy success and may suggest novel therapeutic strategies forwomen with these disorders.
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