title: A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia.
abstract: In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.
authors.affiliation: Department of Obstetrics and Gynaecology, Makerere University, Kampala, Uganda;
authors.forename: Annettee
authors.initials: A
authors.lastname: Nakimuli
authors.affiliation: Department of Pathology, Centre for Trophoblast Research, and.
authors.forename: Olympe
authors.identifier: http://orcid.org/0000-0003-0480-7808
authors.initials: O
authors.lastname: Chazara
authors.affiliation: Department of Pathology, Centre for Trophoblast Research, and.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hiby
authors.affiliation: Department of Pathology, Centre for Trophoblast Research, and.
authors.forename: Lydia
authors.initials: L
authors.lastname: Farrell
authors.affiliation: Department of Obstetrics and Gynaecology, Makerere University, Kampala, Uganda;
authors.forename: Stephen
authors.initials: S
authors.lastname: Tukwasibwe
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom;
authors.forename: Jyothi
authors.initials: J
authors.lastname: Jayaraman
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom; Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, United Kingdom;
authors.forename: James A
authors.initials: JA
authors.lastname: Traherne
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom; Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.affiliation: Department of Obstetrics and Gynaecology, Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 OWS, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge School of Clinical Medicine, Cambridge, CB2 OWS, United Kingdom;
authors.forename: Francesco
authors.initials: F
authors.lastname: Colucci
authors.affiliation: Clinical Transplantation Laboratory, Viapath, Guy's Hospital, London, SE1 9RT, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Lougee
authors.affiliation: Clinical Transplantation Laboratory, Viapath, Guy's Hospital, London, SE1 9RT, United Kingdom;
authors.forename: Robert W
authors.initials: RW
authors.lastname: Vaughan
authors.affiliation: Medical Research Council/Uganda Virus Research Institute Uganda Research Unit on AIDS, Entebbe, Uganda; Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, United Kingdom; and.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Elliott
authors.affiliation: Department of Obstetrics and Gynaecology, Makerere University, Kampala, Uganda;
authors.forename: Josaphat
authors.initials: J
authors.lastname: Byamugisha
authors.affiliation: Medical Research Council/Uganda Virus Research Institute Uganda Research Unit on AIDS, Entebbe, Uganda;
authors.forename: Pontiano
authors.initials: P
authors.lastname: Kaleebu
authors.affiliation: Department of Obstetrics and Gynaecology, Makerere University, Kampala, Uganda;
authors.forename: Florence
authors.initials: F
authors.lastname: Mirembe
authors.affiliation: Departments of Structural Biology and Microbiology and Immunology, Stanford University, Stanford, CA 94305-5126.
authors.forename: Neda
authors.initials: N
authors.lastname: Nemat-Gorgani
authors.affiliation: Departments of Structural Biology and Microbiology and Immunology, Stanford University, Stanford, CA 94305-5126.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.affiliation: Departments of Structural Biology and Microbiology and Immunology, Stanford University, Stanford, CA 94305-5126.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.affiliation: Department of Pathology, Centre for Trophoblast Research, and am485@cam.ac.uk.
authors.forename: Ashley
authors.initials: A
authors.lastname: Moffett
mesh_terms: D044383:Black People / Q000235:genetics*; D002503:Centromere; D005260:Female; D006801:Humans; D011225:Pre-Eclampsia / Q000235:genetics / Q000517:prevention & control*; D011247:Pregnancy; D054340:Receptors, KIR / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D054340:Receptors, KIR
keywords: KIR; NK cells; Uganda; maternal mortality; pre-eclampsia