Maternal KIR in combination with paternal HLA-C2 regulate human birth weight

• Published in: The Journal of immunology (1950) 2014-06, Vol.192 (11), p.5069-5073
• Main Authors: Hiby, Susan E, Apps, Richard, Chazara, Olympe, Farrell, Lydia E, Magnus, Per, Trogstad, Lill, Gjessing, Håkon K, Carrington, Mary, Moffett, Ashley
• Format: Article
• Language: English
• Subjects: Birth Weight - genetics; Birth Weight - immunology; Female; HLA-C Antigens - genetics; HLA-C Antigens - immunology; Humans; Infant, Newborn; Male; Pregnancy; Receptors, KIR - genetics; Receptors, KIR - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1400577

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 analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 1316) were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal-activating KIR2DS1 gene was 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, odds ratio = 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.