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Certain combinations of maternal killer immunoglobulin-like receptor (\n                    <jats:italic>KIR<\/jats:italic>\n                    ) and paternally derived fetal human leuokocyte antigen-C (\n                    <jats:italic>HLA-C<\/jats:italic>\n                    ) alleles were previously associated with higher risk of high and low birth weight in a study with limited sample size (n\u2009=\u20091,316). Using recently developed methods to impute\n                    <jats:italic>HLA<\/jats:italic>\n                    and\n                    <jats:italic>KIR<\/jats:italic>\n                    haplotypes using single nucleotide polymorphism (SNP) genotype data, we tested associations of fetal\n                    <jats:italic>HLA<\/jats:italic>\n                    and maternal\n                    <jats:italic>KIR<\/jats:italic>\n                    genotypes with offspring birth weight in a large sample. We imputed\n                    <jats:italic>KIR<\/jats:italic>\n                    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\n                    <jats:italic>KIR A<\/jats:italic>\n                    vs\n                    <jats:italic>B<\/jats:italic>\n                    haplotypes (\n                    <jats:italic>AA, AB\/BA, BB<\/jats:italic>\n                    genotypes) as well as copy number of activating receptor gene\n                    <jats:italic>KIR2DS1<\/jats:italic>\n                    (0, 1, 2 copies of the gene) in the presence of fetal\n                    <jats:italic>HLA C1\/C2<\/jats:italic>\n                    alleles, and offspring birth weight. Associations were analyzed in each cohort before performing a meta-analysis to estimate the interaction effects between maternal\n                    <jats:italic>KIR<\/jats:italic>\n                    and fetal\n                    <jats:italic>HLA-C2<\/jats:italic>\n                    on birth weight across the entire sample. The\n                    <jats:italic>KIR<\/jats:italic>\n                    haplotypes achieved imputation accuracy estimated at &gt;95% in most of the cohorts. No interaction effects were observed between either the maternal\n                    <jats:italic>A<\/jats:italic>\n                    vs.\n                    <jats:italic>B<\/jats:italic>\n                    haplotype or the maternal\n                    <jats:italic>KIR2DS1<\/jats:italic>\n                    locus and fetal\n                    <jats:italic>HLA-C<\/jats:italic>\n                    . When specifically trying to replicate the previously associated combination of maternal\n                    <jats:italic>KIR2DS1<\/jats:italic>\n                    and paternally inherited fetal\n                    <jats:italic>HLA-C2<\/jats:italic>\n                    , there was a negligible change in offspring birth weight for each additional\n                    <jats:italic>KIR2DS1<\/jats:italic>\n                    allele and\n                    <jats:italic>HLA-C2<\/jats:italic>\n                    of paternal origin (7g lower birth weight per allele [95% CI: -54, 40],\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.78). We found little evidence of association between birth weight and maternal\n                    <jats:italic>KIR<\/jats:italic>\n                    haplotypes or fetal\n                    <jats:italic>HLA-C2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012102","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T17:44:54Z","timestamp":1776707094000},"page":"e1012102","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Examining the association between fetal HLA-C, maternal KIR haplotypes and birth weight"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1106-0519","authenticated-orcid":true,"given":"Caitlin Stephanie","family":"Decina","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole M.","family":"Warrington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin 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Jr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6738-8271","authenticated-orcid":true,"given":"David","family":"Squire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7780-9586","authenticated-orcid":true,"given":"Damjan","family":"Vukcevic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4152-2238","authenticated-orcid":true,"given":"Rachel M.","family":"Freathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David 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