AAT/SERPINA1 Pi*Z variant linked to gestational length and preterm birth prevention via AAT in mice.

Abstract

About 10% of pregnancies end prematurely before 37 weeks, without effective prevention therapies. Previously, we identified rare damaging variants in SERPINA1 encoding alpha-1-antitrypsin (AAT) in families with recurrent spontaneous preterm births and detected decreased protein and transcript levels of AAT/SERPINA1 from placentas in spontaneous preterm births. Here, we investigate genetic associations between SERPINA1 variants and gestational duration and evaluate AAT supplementation as a therapeutic intervention in a mouse model of preterm birth. SERPINA1 Pi*Z variant (rs28929474-T) is associated with gestational duration (P < 5×10^-8) in European-ancestry mothers with spontaneous preterm and term deliveries. We detect a nine-day decrease in gestational duration and a fourfold odds for preterm birth vs. term birth in Pi*Z homozygotes (Pi*ZZ), compared to other genotypes. In transgenic mice without endogenous AAT, exogenous Prolastin^® treatment inhibits lipopolysaccharide induced preterm births (P < 0.05). Supplemented AAT is preferentially deposited in the placenta. Our findings support AAT's protective role in spontaneous preterm births and highlight its therapeutic potential, particularly in SERPINA1 Pi*ZZ genotype carriers.