Racial Differences in the Genetics of Preeclampsia

• Main Author: Hill, Lori
• Format: Others
• Published: VCU Scholars Compass 2011
• Subjects: Preeclampsia; Genetics; Catechol-O-methyltransferease; Endoplasmic reticulum aminopeptidase 2; Racial disparities; children of twins; Methylenetetrahydrofolate reductase; Medical Genetics; Medical Sciences; Medicine and Health Sciences
• Online Access: http://scholarscompass.vcu.edu/etd/2643; http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=3642&context=etd

Preeclampsia (PE), characterized by hypertension and proteinuria after 20 weeks of gestation, affects 5-8% of pregnancies worldwide. Although preeclampsia is a significant cause of maternal and perinatal mortality and morbidity, its etiology remains to be elucidated. Racial differences have been observed for preeclampsia, with U.S. Blacks having higher rates and more severe disease, compared to U.S. Whites and Hispanics. One potential source of racial differences in preeclampsia is genetic variation between populations. Genetic susceptibility to preeclampsia is well established, but the specific contributions of maternal vs. fetal genes, and how these vary among racial groups is poorly understood. This dissertation addressed racial differences in the genetics of preeclampsia in Chileans, U.S. Blacks, and U.S. Whites through candidate gene studies and variance components modeling. First, we determined whether three genes, which are relevant to the pathophysiology of preeclampsia, Catechol-O-methyltransferase (COMT), Methylenetetrahydrofolate reductase (MTHFR), and Endoplasmic reticulum aminopeptidase 2 (ERAP2), were associated with the risk for preeclampsia in Chilean and U.S. Black mothers and fetuses. We found that the maternal COMT and an interaction between the fetal COMT and MTHFR were associated with the risk for preeclampsia in Chileans. We also found that the fetal ERAP2 was associated with the risk for preeclampsia in U.S. Blacks. We next used structural equation modeling of a unique Children of Twins (COT), supplemented with full and half-siblings, study design to investigate the fetal genetic, maternal genetic, shared environmental, and unique environmental contributions to preeclampsia in U.S. Whites and Blacks. Through this modeling we uncovered a unique source of racial differences in preeclampsia. We found that U.S. Whites and Blacks showed a similar prevalence of preeclampsia in first births, but across the next three births, the prevalence in Whites declined to a greater degree than in Blacks. In conclusion we have identified specific maternal and fetal genes that contribute to the risk for preeclampsia. Furthermore, we have identified sources of racial differences in preeclampsia, which include differences in associations between COMT, MTHFR, and ERAP2 and the risk for preeclampsia among populations and differences in the prevalence of preeclampsia across subsequent births between U.S. Whites and U.S. Blacks.