Association Of Killer Cell Immunoglobulin-Like Receptors Gene Polymorphisms With Unexplained Early Recurrent Spontaneous Abortion

OBJECTIVES Killer cell immunoglobulin-like receptors(KIR) are expressed on the surface of natural killer(NK) cells and some of T Lymphocytes.NK cell receptors have been suggested have a high-level infiltration with stromal cells and more importantly with invading trophoblast.But their function at the fetomaternal interface remain unknown. To investigate whether the outcome of pregnancy depends on women' s KIRs, we studied the KIR gene polymorphisms in women with unexplained early recurrent spontaneous abortions (RSA).METHODS We chose 100 childless women which with two or more early abortions characterized as unexplained after extended evaluation (exclusion of anatomical,chromosomal, hormonal, metabolic, infectious, autoimmune and thrombophilic etiologies)as study group,and devided them into group A and group B(Group A are characterized as abortion with empty gestational sac and Group B are characterized as having seen heart beating at least once). We chose 112 healthy women as control. Genomic DNA from patients and controls were genotyped for presence or absence of the following KIR genes: 2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1,2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1,and KIRZ.Genotyping was performed using polymerase chain reaction of sequence specific primers(PCR-SSP).The genotypic frequencies of each KIRs were calculated as the percentage of positive numbers among all specimens. KIR genotypic frequency differences significance between patients and control subjects were tested by the two-tailed Fisher's exact test(the SAS system).The different significance of average activating KIR numbers between RSA patients and control subjects were tested by t-test.RESULTS 1. The results showed increased numbers of activating KIR genes in patients compared with control subjects (p=0.002).2. Genotypic frequencies of KIR2DL5 ( p=0.003), KIR2DS2 ( p=0.008) and KIR2DS1 (p=0.003) were much higher in patients with RSA compared to that in control subjects.3. Individuals who possessed three or less than three activating KIR gene were more frequently control subjects than patients. In contrast, individuals with more than three activating KIR genes were more frequently patients than control subjects(60.0% vs. 41.9%, respectively, p=0.009).4. In study group B the frequency of KIR2DS3 was higher than that in study group A(P=0.036).5. Genotypic frequencies of KIR2DL5 (p=0.006), KIR2DS2 (P=0.038), KIR2DS1 (P=0.044) were significantly higher in study group A than those in control group. Genotypic frequencies of KIR2DS3 (P=0.036), KIR2DS2 (P=0.017), KIR2DS1 (P=0.018) were much higher in study group B compared to those in control group.6.There are 27 genotypes founded in study group.CONCLUSIONS 1. A genetic imbalance between activating and inhibitory KIR genes especially the increased activating KIR genes may influence the pathogenesis of RSA.2.The increased frequences of KIR2DL5 , KIR2DS2 and KIR2DS1 may be one of the reasons of unexplained early recurrent spontaneous abortions.3. The increased frequency of KIR2DS3 may be one of the reasons of those patients having seen heart beating before abortion.4. KIR2DL5 gene may have more relativity to abortions characterized as empty gestational sac.5.There may be new haplotype in study group.