Mol. Hum. Reprod. Advance Access originally published online on March 19, 2008
Molecular Human Reproduction 2008 14(5):317-324; doi:10.1093/molehr/gan013
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Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies
1Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074 Singapore, Singapore 2Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074 Singapore, Singapore 3Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore 4Department of Obstetrics and Gynecology, Sultanah Aminah Hospital, Johor Bahru, Johor 80100, Malaysia 5Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119074 Singapore, Singapore 6Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center, 169610 Singapore, Singapore 7 Duke-NUS Graduate Medical School, 169547 Singapore, Singapore 8Children’s Medical Institute and Department of Laboratory Medicine, National University Hospital, 119074 Singapore, Singapore
9 Correspondence address. Tel: +65-6772-4152; Fax: +65 6779 7486; E-mail: paecs{at}nus.edu.sg
Pre-eclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity. Structural or functional alterations of human leukocyte antigen (HLA)-G present at the maternal–fetal interface may predispose women to PE. We tested the HLA-G gene for association with PE in a case–control study of 83 PE and 240 normotensive Malay women. HLA-G was amplified in a single-tube multiplex-PCR reaction and genotyped for 18 single nucleotide polymorphisms (SNPs) by multiplex-minisequencing. Case–control comparisons were performed, and associations with disease were expressed as odds ratios (ORs). Risk for PE was significantly associated with fetal allele G*0106 only in multigravid pregnancies (P = 0.002, OR = 5.0, 95% CI = 1.8–13.8). Among multigravid pregnancies, the frequency of PE babies heterozygous or homozygous for G*0106 was also significantly higher compared with normal control babies (P = 0.002, OR = 5.4, 95% CI = 1.9–15.4). Multivariate analyses with adjustment for factors associated with PE revealed similar results (P = 0.003, OR = 10.1, 95% CI = 2.2–46.8). Additionally, a significantly higher frequency of fetal–maternal G*0106 genotype mismatch was observed in PE compared with normal multigravid pregnancies (P = 0.001, OR = 9.6, 95% CI = 2.4–38.7). Thus, paternal HLA-G G*0106 contribution significantly increases risk for PE in multigravidas who do not carry this allele, potentially mediated by a gradual maternal alloimmune response to repeated exposure to the paternal HLA-G variant.
Key words: pregnancy/placenta/pre-eclampsia/HLA-G/haplotype
Both authors contributed equally to this work. Submitted on November 28, 2007; resubmitted on February 11, 2008; accepted on February 19, 2008.
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