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J Immunol. 2014 Jun 1;192(11):5069-73. doi: 10.4049/jimmunol.1400577. Epub 2014 Apr 28.

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

Author information

  • 1Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom;
  • 2Cancer 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;
  • 3Division of Epidemiology, Norwegian Institute of Public Health, 0403 Oslo, Norway; and.
  • 4Division of Infectious Disease Control, Norwegian Institute of Public Health, 0403 Oslo, Norway.
  • 5Department 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.

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 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.

PMID:
24778445
[PubMed - indexed for MEDLINE]
PMCID:
PMC4028203
Free PMC Article
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