Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success

Abstract

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.

Figure 1.

AA genotype and activating KIR frequencies in control and preeclampsia mothers. (A) There was a significant difference in the AA genotype frequencies between controls (white bar, n = 201) and preeclampsia patients (black bar, n = 200). *, P = 0.038. (B) The AA genotype frequencies in subsets of patients with preeclampsia categorized depending on the HLA-C groups 1 and 2 of mother (M) and fetus (F) (see Table III for details and patient numbers). (a) M 1 + 1/F 1 + 2. *, P 5 0.005. OR = 3.22; CI = 95%; 1.49–6.98. (b) M 2 + 2/F 1 + 2. *, P = 0.034. (c) M 1 + 2/F 1 + 1. (d) M 1 + 2/F 2 + 2. (e) M 1 + 1/F 1 + 1. (f) M 1 + 2/F 1 + 2. *, P = 0.011. (g) M 2 + 2/F 2 + 2. The subsets in which the fetus had a C2 allotype were a, b, d, f, and g. The subsets in which the fetus only had a C1 allotype were c and e. The subset in which C2 was absent from the mother, but present in the fetus, was a. The subsets with both mother and fetus having C2 were b, d, f, and g. Subset g is an exception to the increase in frequency of maternal AA genotype when the fetus had a C2 allotype but the numbers were small (n = 6). (C) The patients from Fig. 1 A have been divided into two subsets as follows: those in which the fetus presents a C2 allotype (n = 109; *, P = 0.001; OR = 2.38; 95% CI = 1.45 − 3.90) and those in which the fetus only had a C1 allotype (n = 91; NS).

Figure 2.

(A) The addition of each activating receptor is associated with a 1.2-fold reduction in prevalence. A linear logistic model was used to relate the prevalence of preeclampsia to the numbers of activating receptors possessed by the mother (KIR2DS1, 2DS2, 2DS3, 2DS4wt, and 2DS5). Control pregnancies were compared with affected mothers presented with fetal C2 as before. The model suggests an approximate 1.2-fold reduction in prevalence with each additional activating receptor. The sample size for the mothers with five activating receptors was very small (n = 6 for control and preeclampsia mothers combined). (B) A multiplicative model is a good fit to the data. A plot of the expected versus observed numbers of affected mothers with increasing numbers of activating receptors shows that the logistic model provides a good fit.

Figure 3.

KIR genotype AA and HLA-C group 2 frequencies in different populations. Most of the HLA-C and KIR data have been taken from different cohorts within each population (references –35). The correlation coefficient (r) was −0.82.