Early European populations are likely to have suffered from iron deficiency and consequently an increase in premature delivery and hence low birth-weight offspring (44,45). It has been demonstrated that hemochromatosis, a genetic disease associated with progressive iron overload, is associated with a C282Y mutation in the HLA-H gene. This gene has reached a high frequency in a short time (it arose around 60 generations ago (46,47)). This positive selection may well have improved the reproductive fitness of C282Y heterozygote carriers; 32% of females of reproductive age who were normal homozygotes for a hemochromatosis mutation had iron deficiency compared with only 21% of heterozygote females of reproductive age. A similar trend in iron deficiency exists for males (45). The deleterious effects of this condition are of late-onset (in the fifth or sixth decade of life), so it seems that C282Y, which represents 85% of all hemochromatosis mutations, may exert a selective advantage during the reproductive phase of the human lifecycle by lowering the complications of premature birth associated with low iron status.
Iron may play another important role in achieving a normal term pregnancy. Hypoxia inducible factor 1a (HIF-1a) is a component of the master transcription regulator (HIF) for genes that respond to hypoxia or iron deficiency. In the presence of oxygen and iron, proline residues in two degradation domains are altered by HIF-1-prolyl hydroxylases leading to ubiquitination and degradation of HIF-1a. HIF-1a is thus stable in conditions lacking oxygen or iron (49). Pre-eclampsia (pregnancy induced hypertension) is the leading cause of fetal and maternal mortality worldwide. Vascular endothelial growth factor (VEGF) may be compromised in pre-eclamptic mothers. The pre-eclamptic placenta produces elevated levels of a soluble tyrosine kinase 1 receptor that catches free VEGF. This capture of VEGF compromises the vasculature of the kidney, brain lungs and other organs which are deprived of essential survival and maintenance signals, and hence dysfunction. This has been shown to lead on to hypertension and kidney disease in rodents, which mirrors human pre-eclampsia. Mice that lack one VEGF allele also develop the same pathology shown by pregnant women with pre-eclampsia (50). It is now thought that HIF-1a may have a protective role in regulating VEGF in pre-eclampsia. Degradation of HIF-1a during nor-moxia involves binding to von Hippel-Lindau (VHL) protein via the oxygen/iron-sensitive degradation domain mentioned above. It has been suggested that homozygosity for a C598T-VHL polymorphism originated from a single founder no more than 62,000 years ago, and it may have a survival advantage. Such an advantage may involve improvements in iron metabolism, erythropoiesis, embryonic development, energy metabolism, or modulation of risk for pre-eclampsia (51).
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