Killer cell immunoglobulin-like receptor (KIR) genes and their HLA-C ligands in a Ugandan population

Abstract

Killer cell immunoglobulin-like receptor (KIR) genes are expressed by natural killer cells and encoded by a family of genes exhibiting considerable haplotypic and allelic variation. HLA-C molecules, the dominant ligands for KIR, are present in all individuals and are discriminated by two KIR epitopes, C1 and C2. We studied the frequencies of KIR genes and HLA-C1 and C2 groups in a large cohort (n = 492) from Kampala, Uganda, East Africa and compared our findings with published data from other populations in sub-Saharan Africa (SSA) and several European populations. We find considerably more KIR diversity and weaker linkage disequilibrium in SSA compared to the European populations and describe several novel KIR genotypes. C1 and C2 frequencies were similar to other SSA populations with a higher frequency of the C2 epitope (54.9 %) compared to Europe (average 39.7 %). Analysis of this large cohort from Uganda in the context of other African populations reveals variations in KIR and HLA-C1 and C2 that are consistent with migrations within Africa and potential selection pressures on these genes. Our results will help understand how KIR/HLA-C interactions contribute to resistance to pathogens and reproductive success.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-013-0724-7) contains supplementary material, which is available to authorized users.

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

“…In contrast, we now show that, in Ugandans, KIR cB regions characterized by KIR2DS5, KIR2DP1, and KIR2DL1 (cB01 and cB03) are protective. The low carrier frequency of KIR2DS1 in SSA (1.4-27.8%) compared with Europe (42.5%) also suggests that KIR2DS1 does not play an important role in pregnancy success in Africans (14). One explanation for the different protective effect is that KIR2DS5, an activating KIR that likely evolved from a KIR specific for C2, does function like KIR2DS1, although there is no evidence to date that the C2 epitope is a KIR2DS5 ligand (22).…”

“…Future analysis of larger cohorts including more women with recurrent pre-eclampsia should identify if there are particular KIR2DL1 alleles responsible. One clear difference that might partially explain the increased risk of pre-eclampsia in Africans is the higher frequency of C2-bearing HLA-C allotypes across SSA compared with elsewhere in the world (14). The probability of African women having a C2-positive partner or fetus is 80% compared with 64% for European women.…”

“…Introgression of KIR2DS1 from archaic humans is also a possibility (35). Our previous findings do indicate that KIR2DS1 and KIR3DS1 (both on tB) are selected against in SSA (14,16). Studying disorders of pregnancy in an African setting is important and informative; the high rates of pre-eclampsia as well as other major disorders of pregnancy, including obstructed labor and stillbirth, and the greater genetic diversity of KIR in SSA mean that unraveling the role of the complex KIR and HLA systems will provide valuable genetic information to predict women who are at risk for a range of pregnancy disorders.…”

“…They exhibit less linkage disequilibrium (LD) between the KIR genes than other populations (14)(15)(16), and the KIR genes have greater allelic diversity (15,16). A variety of diseases and clinical conditions has been associated with combinations of HLA-C and KIR genes.…”

The role of the maternal immune system in the regulation of human birthweight

“…Indeed, it appears that the Obstetric Dilemma is more of a problem for African women. Although there are no reliable records from Africa itself, studies of women of recent African ancestry in Europe and the Americas all indicate that all the GOS ( pre-eclampsia, stillbirth, FGR and prematurity) occur more commonly as would be predicted by the high prevalence of HLA-C2 combined with KIR AA genotypes in these African populations [51]. One explanation for maintenance of these 'reproductively risky' genotypes is the observation that an individual's resistance to infections such as hepatitis C virus is correlated with a KIR AA genotype and HLA-C1 [52].…”