Genetic variation in the progesterone receptor gene and susceptibility to recurrent pregnancy loss: a case-control study.

OBJECTIVE

To investigate the association of progesterone receptor (PGR) gene variants with susceptibility to recurrent pregnancy loss (RPL).

DESIGN

Retrospective case-control study.

SETTING

Outpatient obstetrics and gynaecology clinics.

POPULATION

Women with RPL (396), defined as three or more consecutive miscarriages of unknown aetiology, and 361 women used as controls.

METHODS

PGR genotyping was performed by the allelic exclusion method (real-time polymerase chain reaction).

MAIN OUTCOME MEASURES

PGR single nucleotide polymorphisms (SNPs) and the distribution of their alleles, genotypes and haplotypes.

RESULTS

Higher minor allele frequencies (MAFs) for rs590688, rs10895068, and rs1942836 were seen in RPL cases than in controls, which remained significant after controlling for multiple comparisons. Significantly higher frequencies of heterozygous (1/2) rs608995, along with heterozygous (1/2) and homozygous (2/2) rs590688, rs10895068, and rs1942836 genotype carriers, were seen between RPL cases versus controls, respectively, which persisted after controlling for age, body mass index (BMI), and menarche. The increased risk of RPL associated with rs590688 and rs1942836 was dependent on the number of minor alleles, thus suggesting a 'dose-dependent' effect associated with both variants. Varied linkage disequilibrium (LD) was noted between rs590688, rs10895068, rs608995, and rs1942836 PGR variants associated with RPL. Haplotypes with an increased frequency of CGTC and reduced frequency of GGAT were noted in women with RPL, compared with controls, thereby indicating these haplotypes as RPL-susceptible and RPL-protective, respectively. This association persisted after controlling for multiple comparisons, and after adjusting for covariates.

CONCLUSIONS

We have confirmed a positive association of specific PGR variants (rs590688, rs10895068, and rs1942836) and PGR haplotypes (ATGCCGTC and ATTCGGTC) with an increased risk of RPL, thereby supporting a role for PGR as an RPL candidate locus.

TWEETABLE ABSTRACT

Genetic variants in progesterone receptor gene are associated with increased risk of recurrent pregnancy loss.