Association between trefoil factor 3 gene variants and idiopathic recurrent spontaneous abortion.

Trefoil factor 3 (TFF3) gene is an inflammatory mediator expressed in human endometrium during the window of implantation. The aim of this study was to evaluate the possible genetic association of TFF3 variants in recurrent spontaneous abortion. Women with a history of recurrent spontaneous abortion (n = 164) and healthy pregnant women (n = 143) were genotyped for five TFF3 polymorphisms (rs225439 G/A, rs533093 C/T, rs225361 A/G, rs11701143 T/C and rs77436142 G/C). In addition, haplotypes formed within the gene were analysed. Within the recurrent spontaneous abortion group, women who at some point had given birth and childless women had 4.19 ± 1.75 and 5.34 ± 3.42 consecutive spontaneous abortions, respectively. Women who had experience recurrent spontaneous abortions had a lower allele frequency of the rs11701143 promoter region minor C allele compared with fertile women (0.02 versus 0.05, P = 0.015). Patients with rs225361 AG genotype had significantly more successful pregnancies before spontaneous abortion than those with homozygous AA and GG genotypes (P = 0.014). No significant differences in haplotype frequencies between patients and controls were detected. Possible genetic risk factors identified that might contribute to the pathogenesis of idiopathic recurrent spontaneous abortion were TFF3 gene variants.

The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study.

BACKGROUND: Histidine-rich glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage. METHODS: The study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP. RESULTS: The results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p<0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p<0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p<0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p<0.05). CONCLUSIONS: Women who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

Histidine-rich glycoprotein gene polymorphism in patients with recurrent miscarriage.

Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage.

Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: a retrospective case control study.

BACKGROUND: Recurrent miscarriage affects approximately 1% of all couples. There is a known relation between hypothyroidism and recurrent miscarriage. Phosphodiesterase 8B (PDE8B) is a regulator of cyclic adenosine monophosphate (cAMP) with important influence on human thyroid metabolism. Single nucleotide polymorphism (SNP) rs 4704397 in the PDE8B gene has been shown to be associated with variations in serum Thyroid Stimulating Hormone (TSH) and thyroxine (T4) levels. The aim of this study was to investigate whether there is an association between the SNP rs 4704397 in the PDE8B gene and recurrent miscarriage. METHODS: The study was designed as a retrospective case control study. 188 cases with recurrent miscarriage were included and compared with 391 controls who had delivered at least once and with no history of miscarriage or assisted reproduction. RESULTS: No difference between cases and controls concerning age was found. Bivariate associations between homozygous A/A (OR 1.57, 95% CI 0.98-2.52) as well as G/G carriers (OR 1.52, 95% CI 1.02-2.25) of SNP rs 4704397 in PDE8B and recurrent miscarriage were verified (test for trend across all 3 genotypes, p=0.059). After adjustment for known confounders such as age, BMI and smoking the association between homozygous A/A (AOR 1.63, 95% CI 1.01-2.64, p=0.045) and G/G (AOR 1.52, 95% CI 1.02-2.27, p=0.039) carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage remained. CONCLUSIONS: Our findings suggest that there is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage.

Basal and Regulatory Promoter Studies of the AKR1C3 Gene in Relation to Prostate Cancer.

BACKGROUND: Human 17ß-hydroxysteroid dehydrogenase type 5 (17ß-HSD5) formally known as aldo-keto reductase 1C3 (AKR1C3) play a major role in the formation and metabolism of androgens. The enzyme is highly expressed in the prostate gland and previous studies indicate that genetic variation in the AKR1C3 gene may influence the prostate volume and risk of prostate cancer. AIM: Here we aimed to further study the genetic regulation of AKR1C3 and its putative role in prostate cancer. EXPERIMENTS: A previously identified promoter polymorphism (A>G, rs3763676) localized at -138 from the translational start site were studied in relation to prostate cancer in a Swedish population based case-control study including 176 patients diagnosed with prostate cancer and 161 controls. Moreover, we have studied the basal and androgen induced promoter activity of the AKR1C3 gene. Expression studies with AKR1C3 promoter reporter constructs were performed in HepG2 and DSL2 cells. RESULTS: We found that carriers of the promoter A-allele had a borderline significant decreased risk of prostate cancer (OR = 0.59; 95% CI = 0.32-1.08). We also show that dihydrotestosterone (DHT) induced the promoter activity of the A-allele 2.2-fold (p = 0.048). Sp3 seem to play an important role in regulating the transcription activity of AKR1C3 and site-directed mutagenesis of a GC-box 78 base-pair upstream the ATG-site significantly inhibited the basal AKR1C3 promoter activity by 70%. CONCLUSION: These results further supports previous findings that the A>G promoter polymorphism may be functional and that AKR1C3 plays a critical role in prostate carcinogenesis. Our findings also show that the members of Sp family of transcription factors are important for the constitutive expression of AKR1C3 gene.