The objective of the proposed investigation is to identify human major histocompatibility complex (MHC) and non-MHC genes or regions that influence reproductive outcome. we propose to continue our population-based studies in the Hutterites and, in addition, conduct a prospective cohort study of pregnancy outcome among young Hutterite couples who have not yet completed their families. The Hutterites are an anabaptist sect that lives communally and proscribes contraception. Our data continue to show longer intervals from marriage to each birth among couples sharing HLA-A, -B, or -DR antigens (Ober et. al., Fert. Steril. 44:227-232, 1985). Results of a prospective pilot study of pregnancy outcome in the Hutterites initiated in year -02 of our grant period, suggest that longer birth intervals among couples sharing antigens may result from the effects of genes in more than one MHC region (i.e., HLA- A linked and HLA-Dr linked) and that these genes may exert different effects fat different stages of gestation. Our pilot data indicate that Hutterite couples sharing HLA-Dr antigens have longer intervals to a recognized pregnancy (p<.05). Whether these differences are due to peri-implantation losses or factors that interfere with conception is unknown. On the other hand, Hutterite couples sharing HLA-A antigens experience increased recognized (>6 weeks gestation) fetal loss rates (p<.05). In addition, signification effects of Gm (immunoglobulin allotypes) mating types on Hutterite family sizes were also observed (Ober et. al., Am. J. Hum. Gen. 39:A242, 1986). In our renewal grant, we propose to better define MHC genes or regions that influence Hutterite fertility and examine their interactions with non-MHC genes (such as immunoglobulin and transferrin). In addition, we propose to elucidate the effects (reduced pregnancy rates v. increased fetal loss rates) and mechanisms (immunologic v. genetic) of these genes. Further refinement of MHC sharing will be possible using restriction fragment length polymorphim (RFLP) analysis with probes for MHC genes. RFLP studies for immunoglobulin and transferrin genes will increase the number of informative couples for analyses of fertility effects of these genes. RFLP analysis has proven to be a valuable technique for identifying MHC disease susceptibility genes. To our knowledge, this approach has not been applied to studies of genes that affect fertility, but offers a powerful tool by which such genes can be identified.
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