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Possible Gene-Gene Interaction of KIR2DL4 With its Cognate Ligand HLA-G in Modulating Risk for Preeclampsia

Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Yap Seng Chong, MD

Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Annamalai Loganath, PhD

Department of Obstetrics & Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Yiong Huak Chan, PhD

Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Jeganathan Ravichandran, MD

Department of Obstetrics & Gynecology, Sultanah Aminah Hospital, Johor Bahru, Johor, Malaysia

Caroline G. Lee, PhD

Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center, Singapore, Duke-NUS Graduate Medical School, Singapore, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Samuel S. Chong, PhD

and Children's Medical Institute and Department of Laboratory Medicine, National University Hospital, Singapore, Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, paecs{at}nus.edu.sg

Preeclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity that occurs only during pregnancy. Pregnancy is the only physiological situation where killer-cell immunoglobulin-like receptors (KIRs) may meet cognate nonself variants of human leukocyte antigen (HLA) allotypes. We previously reported that presence of fetal HLA-G*0106 was significantly associated with risk for PE in multigravid pregnancies. We have now tested the KIR2DL4 receptor gene for association with PE, as well as for its interaction with HLA-G in modulating disease risk, in a case-control study of 83 PE and 240 normotensive pregnancies. No significant association was observed between alleles of KIR2DL4 and PE in both maternal and fetal groups, either among primigravid or multigravid pregnancies. Alleles of KIR2DL4 and HLA-G were then analyzed together to determine whether particular variant ligand—receptor combinations were associated with an increased risk for PE. Gene-gene interaction analyses suggest that the presence of fetal HLA-G*0106 in combination with maternal KIR2DL4*006 is significantly associated with PE risk in multigravid pregnancies (P < .001). These data provide the first preliminary evidence suggesting that although KIR2DL4 itself is not associated with PE, it may modulate the effect of HLA-G*0106 on risk for PE.

Key Words: Haplotype • HLA-G • KIR2DL4 • placenta • preeclampsia.

This version was published on December 1, 2009

Reproductive Sciences, Vol. 16, No. 12, 1135-1143 (2009)
DOI: 10.1177/1933719109342280


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