An accumulating body of epidemiological evidence points coherently toward an immune-based etiology for preeclampsia. Several recent studies, as well as a collection of other studies conducted over the past 25 years, suggest that exposure to paternal, fetal; or foreign antigens is protective against subsequent risk preeclampsia; and that paternal/fetal factors may be as important as maternal factors in the etiology of preeclampsia. Consistent this evidence, HLA-sharing between mother and fetus has been positively associated with risk of preeclampsia. We hypothesize that histocompatibility between mother and fetus may have a detrimental effect on pregnancy by impairing maternal recognition of the fetal allograft as a gestation, thereby compromising development of maternal immune tolerance and effective implantation of the placenta. To evaluate this hypothesis, we propose to conduct a case-control study to determine if nulliparous women who develop preeclampsia are more likely to share HLA antigens with their infants than women who have normotensive gestations. Specifically, we will examine sharing at each of five HLA loci (A, B, C, DR, and DQ), as well as generalized sharing across loci. In addition, we will evaluate selected epidemiologic factors indicative of exposure to paternal/fetal antigens (e.g., duration of sexual cohabitation, coital frequency, and use of barrier contraception with baby's father prior to conception). We will also test for the presence of gene-environment interactions to determine if effects of maternal-fetal HLA sharing are modified by the primary epidemiologic exposures under study. The study population (N=250 cases; N=250 controls), identified from Iowa and Connecticut live birth files, will include residents of four Iowa and two Connecticut counties who deliver between November l, 2001 and October 31, 2003. All participants will be asked to provide buccal cell samples from their babies and themselves for HLA genotyping (N=1,000 samples), and to respond to a 25 minute telephone interview. Medical chart abstractions will be conducted to validate case definition and control criteria. The study was powered to detect a two-fold increased risk of preeclampsia associated with the presence of only one maternal- fetal HLA mismatch across the three loci (HLA-A, B, and DRbeta1) loci, with at least 80 percent power, and an alpha of.05. The proposed study may be the first to examine the effects of maternal-fetal HLA sharing in an adequately powered epidemiological framework.
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