Examining the association between fetal HLA-C, maternal KIR haplotypes and birth weight

Human birth weight is under stabilizing selection, seeking balance between extremes of high and low, thereby reducing fetal and maternal perinatal mortality risk. Certain combinations of maternal killer immunoglobulin-like receptor (KIR) and paternally derived fetal human leuokocyte antigen-C (HLA-C) alleles were previously associated with higher risk of high and low birth weight in a study with limited sample size (n=1,316). Using recently developed methods to impute HLA and KIR haplotypes using single nucleotide polymorphism (SNP) genotype data, we tested associations of fetal HLA and maternal KIR genotypes with offspring birth weight in a large sample. We imputed KIR haplotypes using the KIR*IMP imputation software in 10,602 mother-offspring pairs of European descent from singleton pregnancies from five studies. Using mixed linear regression models to account for mothers with multiple children, we tested associations between maternal KIR A vs B haplotypes (AA, AB/BA, BB genotypes) as well as copy number of activating receptor gene KIR2DS1 (0, 1, 2 copies of the gene) in the presence of fetal HLA C1/C2 alleles, and offspring birth weight. Associations were analyzed in each cohort before performing a meta-analysis to estimate the interaction effects between maternal KIR and fetal HLA-C2 on birth weight across the entire sample. The KIR haplotypes achieved imputation accuracy estimated at >95% in most of the cohorts. No interaction effects were observed between either the maternal A vs. B haplotype or the maternal KIR2DS1 locus and fetal HLA-C. When specifically trying to replicate the previously associated combination of maternal KIR2DS1 and paternally inherited fetal HLA-C2, there was a negligible change in offspring birth weight for each additional KIR2DS1 allele and HLA-C2 of paternal origin (7g lower birth weight per allele [95% CI: -54, 40], P = 0.78). We found little evidence of association between birth weight and maternal KIR haplotypes or fetal HLA-C2 and were unable to replicate previously reported findings. Our observations reinforce the importance of replication and the use of large sample sizes in the validation of genetic associations. Author SummaryBabies born with very high or low birth weights and their mothers are at a higher risk of illness and death than babies with weights close to average. Genes involved in the maternal immune system, called "KIR", and the fetal immune system, called "HLA-C", are important for early development of the placenta. Previously published research using a small sample has provided evidence for the role of interacting combinations of these genes in driving the spectrum of birth weight and maintaining the balancing selection of mother-child physiology that results in healthy birth outcomes. Here we harness recently developed methods to impute these genetic data to test associations of maternal KIR and fetal HLA with childs birth weight in a larger sample. By examining >10,000 European ancestry mother-child pairs, we found no relationship between childs birth weight and any of the genetic combinations we tested of KIR in the mother and HLA-C in the fetus. We show that despite biological plausibility, it is important to validate genetic associations through replication and using the largest sample sizes possible. Future research could benefit from including birth weights in the true extremes of the spectrum, using methods such as high throughput genome sequencing technologies which could provide more accurate data for these gene regions on a larger scale, and investigation in ancestrally diverse populations.