Maternal KIR in Combination with Paternal HLA-C2 Regulate Human Birth Weight

Abstract

Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are ≤5th birth weight centile. Specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analysed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. 1316 mother/baby pairs were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal activating KIR2DS1 gene associated with increased birth weight, in linear or logistic regression analyses of all pregnancies >5th centile (p=0.005, n=1316). Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p=0.005, OR=2.65). Thus maternal KIR are more frequently inhibitory with small babies but activating with big babies. At both extremes of birth weight the KIR associations occur when their HLA-C2 ligand is paternally inherited by a fetus. We conclude that the two polymorphic immune gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birth weight between two extremes with a clear role for paternal HLA.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…This situation is extremely unlikely without the impact of a form of natural selection called balancing selection, which maintains genetic variation of specific loci in the population 55. Indeed, all human populations studied to date have a representation of KIR A and B haplotypes51, 56 and the prevailing hypothesis is that the A haplotypes are good for fighting infection57, 58 whereas B haplotypes are more beneficial for reproduction 17, 59…”

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

“…To summarize, at the site of placentation all the influences of HLA-C in pregnancy are mediated by paternal HLA-C2 with the maternal KIR genotype determining the outcome (high or low birthweight). In pregnancies where the fetus is homozygous for HLA-C1, then the effect of the maternal KIR is neutral and no associations are seen [3,35].…”

“…Our results show that there is a consistent relationship between particular combinations of maternal KIR and fetal HLA-C ligands and birthweight [3,35,37,38]. We compared maternal KIR and fetal HLA-C genotypes from a large number of first pregnancies selected from the Norwegian Mother -Baby cohort (MoBa) with known birthweight corrected for gestational age and fetal sex.…”

“…We compared maternal KIR and fetal HLA-C genotypes from a large number of first pregnancies selected from the Norwegian Mother -Baby cohort (MoBa) with known birthweight corrected for gestational age and fetal sex. A HLA-C2 group in the fetus is associated with pregnancies at the two extremes of birthweight especially when the HLA-C2 allele is inherited from the father rather than the mother [3]. If the mother has two KIR A haplotypes (KIR AA genotype), then she will have inherited two copies of the inhibitory KIR for HLA-C2 allotypes, namely KIR2DL1.…”

“…Although death of babies is now less frequent due to advances in neonatal medicine, there is still considerable morbidity. Our recent study in Norway shows babies were most frequently admitted to the neonatal ward when they were born at the extremes of the birthweight spectrum [3]. This suggests there is still strong selective pressure to maintain human birthweight between these two extremes.…”