The association of trefoil factor 3 gene polymorphisms and haplotypes with unexplained female infertility: Molecular insights into TFF3 regulation in receptive phase endometrium

Abstract

This study examined the genetic variation within the gene trefoil factor 3 (TFF3) in relation to unexplained female infertility in a group of women where aberrant endometrial maturation was suspected. The study consisted of 113 women with a diagnosis of unexplained infertility and 289 healthy fertile volunteers. Five single nucleotide polymorphisms rs225439, rs533093, rs225361, rs11701143, and rs77436142 within TFF3 gene were analyzed using real-time PCR. The formed haplotype pattern within the TFF3 gene in relation to infertility was also assessed. TFF3 protein localization and expression in receptive stage endometrium at the time of implantation was measured in a subset of fertile (n = 7) and infertile (n = 12) women. Allele and genotype frequencies did not differ significantly between fertile and infertile women, nor did the formed haplotypes. TFF3 protein was expressed in all cell types in receptive stage endometria in fertile and infertile women. No significant association was observed between protein expression and analyzed genotypes. A significantly higher TFF3 expression in luminal epithelial cells was detected in women with unexplained infertility (p = 0.003).

Keywords::

• Gene expression
• female infertility
• implantation
• intestinal trefoil factor
• TFF3

Acknowledgments

We thank Theodora Kunovac Kallak at the Department of Women's and Children's Health, Uppsala University for participating in evaluating the staining intensities of the samples and for providing images. We are grateful to all participants in the study and to the staff who collected the study material at the Department of Obstetrics and Gynecology, Karolinska University Hospital Huddinge; at the Fertility Center Scandinavia, Stockholm; and at the Department of Women's and Children's Health, Uppsala University. Special thanks go to Tiina Murto for helping to collect the study material, and to Dr. Inger Britt Carlsson for the language revision.

Funding

This work was supported by grants from Uppsala University; the Family planning foundation, Uppsala; Karolinska Institutet; Enterprise Estonia (Grant No. EU30200); the Estonian Ministry of Education and Science (core Grant No. SF0180044s09); and the Spanish Ministry of Education (Grant No. SB2010-0025).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.