Natural selection of FLT1 alleles and their association with malaria resistance in utero

doi:10.1073/pnas.0803657105

Natural selection of FLT1 alleles and their association with malaria resistance in utero

*Mother–Offspring Malaria Studies Project, Seattle Biomedical Research Institute, Seattle, WA 98109;
Departments of ^†Pathology and
^‡Global Health, University of Washington, Seattle, WA 98195; and
^§National Institute of Medical Research, Dar es Salaam, Tanzania

Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved July 17, 2008 (received for review April 15, 2008)

Abstract

Placental malaria (PM) caused by Plasmodium falciparum contributes significantly to infant mortality in sub-Saharan Africa and is associated with pregnancy loss. We hypothesized that fetal genes that modify PM would be associated with fetal fitness. During PM, placental trophoblasts produce soluble fms-like tyrosine kinase 1 (sFlt1), also known as soluble VEGF receptor 1, an angiogenesis inhibitor associated with preeclampsia. Here we present a study examining the genotype of the fms-related tyrosine kinase 1 (FLT1) 3′ UTR in Tanzanian mother–infant pairs. First-time mothers suffer the most PM, and newborn FLT1 genotype distribution differed by birth order, with newborns of first-time mothers outside of Hardy–Weinberg equilibrium (HWE) during peak PM season. Among first-time but not other mothers, maternal FLT1 genotype was associated with a history of prior pregnancy loss. During PM, newborn FLT1 genotype was associated with low birth weight and placental inflammatory gene expression. FLT1 genotype was also associated with Flt1 levels among study subjects and in vitro. Thus, FLT1 variants confer fetal fitness in utero and are associated with the maternal immune response during PM. This indicates that FLT1 is under natural selection in a malaria endemic area and that human exposure to malaria can influence the evolutionary genetics of the maternal-fetal relationship.

Footnotes

^¶To whom correspondence should be addressed. E-mail: pduffy{at}sbri.org
Author contributions: A.M., M.F., T.K.M., and P.E.D. designed research; A.M., M.F., J.L., T.K.M., and P.E.D. performed research; A.M. and P.E.D. analyzed data; and A.M. and P.E.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.