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43: Response to 17-α-hydroxyprogesterone is affected by progesterone receptor polymorphisms

      Objective

      Although 17-α-hydroxyprogesterone (17-OHP) reduces recurrence of preterm birth (PTB), a substantial proportion of women who receive this treatment still deliver preterm. We examined SNPs in the progesterone receptor gene in women with prior spontaneous PTB (SPTB) receiving 17-OHP and investigated the effect on recurrent PTB risk and treatment response.

      Study Design

      Women with prior SPTB treated with 17-OHP were identified from our database. DNA was extracted from stored maternal blood samples. Genotyping was performed using commercially-available TaqManreal-time PCR assays (Applied Biosystems) for ten SNPs in the progesterone receptor gene. Allele and genotype frequencies were compared using Chi Square and Fisher exact tests as appropriate.

      Results

      74 women with a history of prior SPTB treated with 17-OHP were genotyped. 14% were Caucasian, 78% African American, and 8% Hispanic. 26% (n = 19) delivered <35 wks. Women with recurrent PTB were more likely to have the minor allele at rs1042838 (78% vs 22%, p=0.001). Possession of at least one copy was associated with a 3-fold higher risk of PTB < 35 weeks gestation (RR 3.0, CI 1.5 – 6.2). All homozygotes for the minor allele delivered < 35 weeks vs only 33% of heterozygotes (p=0.02). The minor allele at rs3740753 was more frequent in women with recurrent PTB < 35 weeks than in those delivering ≥ 35 weeks (66% vs. 33%, p=0.04). No women were homozygous for the minor allele, but the heterozygous state was associated with a 3-fold higher risk of preterm birth < 35 weeks gestation (RR 3.0, CI 1.5 – 6.2). None of the other SNPs examined were significant at the allele or genotype level.

      Conclusions

      In this cohort of women at risk for recurrent preterm birth treated with 17-OHP, possession of the minor allele at rs1042838 or rs3740753 in the progesterone receptor gene was associated with an increased risk for recurrent preterm birth. Whether these SNPs are an intrinsic marker for underlying susceptibility to PTB or a pharmacogenetic variable that modulates response to treatment warrants further investigation.