Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.
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.
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom;
Susan E
SE
Hiby
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139;
Richard
R
Apps
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom;
Olympe
O
Chazara
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom;
Lydia E
LE
Farrell
Division of Epidemiology, Norwegian Institute of Public Health, 0403 Oslo, Norway; and.
Per
P
Magnus
Division of Infectious Disease Control, Norwegian Institute of Public Health, 0403 Oslo, Norway.
Lill
L
Trogstad
Division of Epidemiology, Norwegian Institute of Public Health, 0403 Oslo, Norway; and.
Håkon K
HK
Gjessing
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139;
Mary
M
Carrington
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; am485@cam.ac.uk.
Ashley
A
Moffett
D001724:Birth Weight / Q000235:genetics / Q000276:immunology*; D005260:Female; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology*
D015236:HLA-C Antigens; C496212:KIR2DS1 protein, human; D054340:Receptors, KIR