Toll-like Receptor Gene Polymorphisms and Preeclampsia Risk: A Case-Control Study and Data Synthesis

Abstract

Background. Preeclampsia is a syndrome of exaggerated innate inflammatory response. It is plausible that this innate inflammation may be mediated by Toll-like receptors (TLRs). A portion of the familial susceptibility to the development of preeclampsia may be mediated by single nucleotide polymorphisms (SNPs) in the TLR gene sequences. Published reports vary in their finding an association between TLR SNPs and preeclampsia risk. Methods. Common SNPs of the TLR2 (Arg753Gln) and co-segregating TLR4 (Asp299Gly and Thr399Ile) genes were screened in 94 women with pre-eclampsia and 176 healthy pregnancy controls. We performed a data synthesis of our findings with those in published reports to ascertain whether or not we could explain the apparent disparity in the literature. Results. The presence of TLR2 (RR 2.57 [95% CI 1.31, 5.05]) and TLR4 (RR 2.06 [1.16, 3.67]) SNPs aggregated with early-onset (<34 + 0 weeks), but not late-onset (≥34 + 0 weeks), preeclampsia. Through synthesis of these and the published data, TLR polymorphisms appear to lower thresholds for early-onset and severe preeclampsia, but not late-onset or mild disease. Conclusions. TLR2 and TLR4 SNPs appear to alter susceptibility to developing the maternal syndrome of preeclampsia. Data synthesis of these data and other studies strengthens the association for early-onset and severe disease, in particular. A definitive and fully powered cohort study is required.

• Preeclampsia
• TLR2
• TLR4
• Polymorphism
• Innate immunity

ACKNOWLEDGMENTS

The other members of the Toxaemia research group are R.C. Brunham, K.C. Choi, M. Krajden, P.C.K. Leung, D.M. Patrick, and E. Thomas.

Declaration of Interest

None of the authors have a conflict of interest. All authors participated in the design of the study. FX, GP, and YH performed the experiments. FX, LAM, and PvD performed the statistical analyses, and FX, SET, DPS, and PvD were primarily involved in the manuscript preparation. All authors approved the final version of the manuscript. The study was approved by the University of British Columbia Clinical Research Ethics Board and the Children's and Women's Health Centre Research Review Board.

Funding

Funding received from the Canadian Institutes for Health Research [Institute for Infection and Immunity Pilot Project Grant (PvD)]; and salary awards (FX, PvD); and an operating grant (DPS) and the Michael Smith Foundation for Health Research (salary awards: FX, LAM, SET, PvD).