W Bahia1,2, R R Finan3, M Al-Mutawa4, A Haddad5, A Soua6, F Janhani1, T Mahjoub1, W Y Almawi4. 1. Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), University of Monastir, Monastir, Tunisia. 2. Faculty of Science of Bizerte, University of Carthage, Tunis, Tunisia. 3. Department of Obstetrics and Gynaecology, Hôtel-Dieu de France, Beirut, Lebanon. 4. Faculty of Sciences, El Manar University, Tunis, Tunisia. 5. Department of Obstetrics and Gynaecology, Fattouma Bourguiba University Hospital, Monastir, Tunisia. 6. Department of Obstetrics and Gynaecology, Houcine Bouzaiene Regional Hospital, Gafsa, Tunisia.
Abstract
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.
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.