Maternal KIR in Combination with Paternal HLA-C2 Regulate Human Birth Weight Susan E. Hiby, Richard Apps, Olympe Chazara, Lydia E. Farrell, Per Magnus, Lill Trogstad, Håkon K. Gjessing, This information is current as Mary Carrington and Ashley Moffett of September 23, 2021. J Immunol 2014; 192:5069-5073; Prepublished online 28 April 2014; doi: 10.4049/jimmunol.1400577 http://www.jimmunol.org/content/192/11/5069 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/04/27/jimmunol.140057 Material 7.DCSupplemental http://www.jimmunol.org/ References This article cites 28 articles, 5 of which you can access for free at: http://www.jimmunol.org/content/192/11/5069.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Maternal KIR in Combination with Paternal HLA-C2 Regulate Human Birth Weight Susan E. Hiby,*,†,1 Richard Apps,‡,x,1 Olympe Chazara,*,† Lydia E. Farrell,*,† Per Magnus,{ Lill Trogstad,‖ Ha˚kon K. Gjessing,{ Mary Carrington,‡,x and Ashley Moffett*,† Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combi- nations 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 Downloaded from 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. The Journal of Immunology, 2014, 192: 5069–5073. http://www.jimmunol.org/ irth weight has been considered “perhaps the most clear placental perfusion, or from prolonged obstructed labor with the cut example of a human character that is subject to sta- risk of postpartum hemorrhage and sepsis. Although genetic fac- B bilizing selection” and is pertinent for those studying tors are known to be important, there is no consensus on what is genetic variants influencing human evolution, disease, and natural the differential contribution of maternal and paternal genes to selection (1). The size of a human infant at the end of gestation birth weight or which genes are responsible (6–8). Fetal growth in determines both the risk of obstetric complications as well as the utero partly depends on the development of a maternal blood supply chances of survival of the baby in the neonatal period (2, 3). High to the placenta that requires structural modifications of the uterine maternal and fetal perinatal mortality rates are strongly associated spiral arteries. Arterial transformation is mediated by infiltration of by guest on September 23, 2021 with being too small or too large at birth, with the lowest perinatal placental trophoblast cells into the maternal decidua and arterial mortality occurring very close to the mean of birth weight dis- walls (9). A growing body of evidence indicates that this process, tribution (1, 4, 5). Mothers are also at risk at these two extremes: which must be carefully balanced between under and over tropho- either from pre-eclampsia, a systemic syndrome triggered by poor blast invasion, is controlled by the maternal uterine NK cells (uNK) that are a distinctive feature of the decidua during placentation (10). *Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United uNK express killer Ig–like receptors (KIR) that can bind to Kingdom; †Centre for Trophoblast Research, University of Cambridge, Cambridge HLA-C, the only classical HLA molecule expressed by tropho- ‡ CB2 1QP, United Kingdom; Cancer and Inflammation Program, Laboratory of blast (11, 12). Both KIR and HLA-C genes are polymorphic, Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD 21702; xRagon Institute of Massachusetts General Hos- meaning that in each pregnancy maternal KIR and fetal HLA-C pital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA genetic combinations can differ. KIR are highly variable both in the 02139; {Division of Epidemiology, Norwegian Institute of Public Health, 0403 Oslo, Norway; and ‖Division of Infectious Disease Control, Norwegian Institute of Public number of genes on a haplotype as well as allelic polymorphism at Health, 0403 Oslo, Norway individual KIR loci (13). Two main KIR haplotypes are found in all 1S.E.H. and R.A. contributed equally to this work. human populations, A and B. KIR A haplotypes carry fewer genes, Received for publication March 5, 2014. Accepted for publication March 19, 2014. most of which encode inhibitory receptors, including KIR2DL1 This work was supported by Wellcome Trust Grants 090108/Z/09/Z and 085992/Z/ and KIR2DL3, which bind HLA-C. KIR B haplotypes have varying 08/Z, British Heart Foundation Grant PG/09/077/27964, and the Centre for Tropho- numbers of additional, mainly activating receptors but only one, blast Research. This work was also supported by Frederick National Laboratory for KIR2DS1, can bind to trophoblast HLA-C molecules (12). KIR Cancer Research Contract HHSN261200800001E and by the Intramural Research Program of National Institutes of Health, Frederick National Laboratory, Center for distinguish between all HLA-C allotypes as two mutually exclusive Cancer Research. The content of this publication does not necessarily reflect the epitopes, HLA-C1 or HLA-C2 (C1 or C2), defined by a dimorphism views or policies of the Department of Health and Human Services, nor does mention at position 80 of the a1 domain of the a helix (14). All C2 allotypes of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and are bound specifically by KIR2DL1 and KIR2DS1. In white British analysis, decision to publish, or preparation of the manuscript. the KIR A and KIR2DS1 haplotype frequencies are 60% and 20%, Address correspondence and reprint requests to Prof. Ashley Moffett, Department of respectively, and the HLA-C2 allele frequency is nearly 30%. Pathology and Centre for Trophoblast Research, University of Cambridge, Tennis Court Immunogenetic studies provide evidence for a co-operative in- Road, Cambridge CB2 1QP, U.K. E-mail address: [email protected] teraction of uNK and trophoblast to regulate placentation. Three The online version of this article contains supplemental material. disorders of pregnancy, pre-eclampsia, fetal growth restriction Abbreviations used in this article: f, fetus; FGR, fetal growth restriction; KIR, killer Ig–like receptor; m, mother; MoBa, Norwegian Mother and Child Cohort Study; OR, (FGR), and recurrent miscarriage, share a common primary path- odds ratio; uNK, uterine NK cell. ogenesis of defective arterial transformation by trophoblast (12, 15, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400577 5070 KIR AND HLA REGULATE HUMAN BIRTH WEIGHT with pre-eclampsia (defined by new hypertension .140/90 mmHg after week 20 together with new protein urea .300 mg/24 h), 118 pregnancies with fetal growth restriction (birth weight #5th centile), and 404 normal pregnancies of primiparous women. From the MoBa cohort 995 normal pregnancies were analyzed. These were primigravida who had a single live born, normally formed infant with a gestation length of .259 d and ,300 d determined from last menstrual period and confirmed by ultra- sonogram. The mothers had no medical conditions, including hyperten- sion, renal disease, pre-eclampsia, thyroid disease, gestational diabetes, or fetal hydrops. An additional 141 pregnancies with pre-eclampsia from the MoBa cohort were analyzed. These were defined by new hypertension .140/90 after 20 wk gestation combined with proteinuria .+1 dipstick on at least two occasions. Ethical approval for analysis of United Kingdom subjects was obtained from the Cambridge Research Ethics Committee (reference nos. 01/197 and 05/Q0108/367; Cambridgeshire, U.K.). The Regional Committee for Ethics in Medical Research and the Data In- spectorate have approved the MoBa study. In both cohorts informed written consent was obtained from all participants. FIGURE 1. Distribution of birth weights in the Norwegian population Genotyping with percentage of babies transferred to the special care baby unit for the Typing of 12 KIR genes in the mothers and HLA-C groups C1 and C2 in n years 1999–2008 ( = 795,068). both mothers and babies was carried out using PCR with sequence-specific primers as previously described (17, 18). Downloaded from 16).