COL۱۲A۱-rs۹۷۰۵۴۷, Mutant Allele Advantage by Being Protective against Recurrent Spontaneous Abortion

Recurrent spontaneous abortion (RSA) is one of the causes of infertility following fetus creation. This can lead to the reduction of the fertility rate in various populations. Collagens’ structure, their ratios to each other, and their connections to various receptors are some of the key players in successful fetus implantation. Among them, COL۱۲A۱ has a special role because of its very high expression in the uterus. Also, the CD۴۴ protein as a cell adhesion molecule which is a receptor for some of the collagens plays a significant role in RSA. The aim of the study is to investigate the association of CD۴۴-rs۱۳۳۴۷ and CoL۱۲A۱-rs۹۷۰۵۴۷ with RSA in a case-control base, and the impacts of COL۱۲A۱-rs۹۷۰۵۴۷ on protein structure. To genotype single nucleotide polymorphisms (SNPs) of the genes, the PCR-RFLP method was performed on the ۱۲۴ RSA and ۱۲۴ control samples. The results were analyzed by the binary-logistic regression method (p-value≤۰.۰۵). The SNPs’ effect on the proteins’ structure was analyzed by PSIPRED, HOPE, LOMET, and chimera-USF. Proteins signaling pathway and physical interaction between COL۱۲A۱ and CD۴۴ were investigated by KEGG-pathway and GeneMANIA, respectively. Results showed that TT (P= ۰.۰۳۲) genotype of CD۴۴-rs۱۳۳۴۷ increased the risk of RSA while the CT (P= ۰.۰۲۷) genotype of CD۴۴-rs۱۳۳۴۷, TT (P= ۰.۰۴۴) genotype, and T (P= ۰.۰۱۹) mutant allele of COL۱۲A۱-rs۹۷۰۵۴۷ decreased the risk of RSA. Moreover, ۳D structures investigation indicated that COL۱۲A۱-rs۹۷۰۵۴۷ may affect the structure of COL۱۲A۱ and its interaction with Integrins. The analysis of the signaling pathway and proteins’ physical interaction network also revealed the interaction of COL۱۲A۱ and CD۴۴ with MMP۲ and MMP۹. On this base, we recommend that T allele of COL۱۲A۱-rs۹۷۰۵۴۷ has a protective feature against RSA, especially in homozygous form by improving their interaction with Integrins and probably MMPs, too. On the other hand, the CD۴۴-rs۱۳۳۴۷ probably has an indirect influence on the attachment of the fetus to the extracellular matrix by affecting the MMPs and finally leading to a greater risk of RSA.

Keywords:

CD۴۴ , COL۱۲A۱ , MMPs , Physical interaction network , RSA