Preeclampsia and the C282Y Mutation in the Hemochromatosis (HFE) Gene

Abstract

The hemochromatosis (HFE) gene encodes the HFE protein, a transmembrane glycoprotein that is implicated in the modulation of iron uptake from the diet (1). The C282Y mutation in this gene is known to be associated with moderately increased serum iron indices. Recently, several studies have described an association between increased maternal iron status and an unfavorable pregnancy outcome (2)(3). Preeclampsia is one of the most common pregnancy-related syndromes as well as a major cause of fetal and maternal morbidity and mortality. Preeclampsia is defined by de novo hypertension and proteinuria in pregnancy. The etiology of preeclampsia is complex and not fully understood, but abnormal placentation and endothelial dysfunction may play an important role in its pathogenesis. Abnormal placentation may lead to a malperfused placenta with release of toxic iron through hemoglobin or heme, which finally may contribute to generalized endothelial dysfunction (2). In the present study, we analyzed the association between the C282Y allele and the presence of preeclampsia in a case–control study described previously (4). The analysis was restricted to those patients and their controls who fulfilled recent criteria for preeclampsia (157 women in each group). The HFE C282Y genotype was determined by an automated method using minor-groove-binding DNA oligonucleotides (MGB probes) as described previously (5). The presence of a C282Y allele was confirmed by conventional PCR with restriction fragment length polymorphism analysis. A Fisher exact test with a 0.050 one-sided significance level showed 90% power to detect the difference between a C282Y allele frequency of 10% (estimated population frequency) and a case frequency of 22.5% (odds ratio = 2.8) when the sample size in each group was 157. The observed frequency for the HFE C282Y allele was similar for women with preeclampsia and controls (0.070). In addition, there was no significant difference between cases and controls in the frequency of the three genotypes [wild type (wt)/wt, wt/C282Y, and C282Y/C282Y] or the presence of the C282Y allele (wt/C282Y and C282Y/C282Y; Table 1 ). Furthermore, we found that adjustment for clinical indices previously positively (familial hypertension and body mass index) and negatively (smoking) associated with preeclampsia in a logistic model had no significant effect on the distribution of the various C282Y genotypes among women who developed preeclampsia and controls. Genotype frequencies in women with preeclampsia and control women. Odds ratios were determined by multiple logistic regression analysis. Frequency of the C282Y allele. For women with preeclampsia and controls, the observed vs expected allele frequencies are 1.27% (95% confidence interval, 0.15–4.5%) and 1.91% (0.4–5.5%), respectively. Genotype frequencies in women with preeclampsia and control women. Odds ratios were determined by multiple logistic regression analysis. Frequency of the C282Y allele. For women with preeclampsia and controls, the observed vs expected allele frequencies are 1.27% (95% confidence interval, 0.15–4.5%) and 1.91% (0.4–5.5%), respectively. The finding of no differences in the C282Y allele distribution or the frequency of the C282Y allele between women with pregnancies complicated by preeclampsia and controls with uncomplicated pregnancies suggests that the C282Y polymorphism is not predominantly involved in the development of endothelial cell dysfunction as a result of increased iron caused by this mutation in women with preeclampsia. In the total group of cases and controls we found a high frequency (1 of 63) of women who were homozygous for the C282Y allele, whereas 1 in 9 were heterozygous for this allele. The proportion of pregnant women in the present study who had the C282Y/C282Y genotype (1.6%), however, did not differ significantly from the frequency of 0.3–0.5% reported previously for individuals of Northern European descent (1). In conclusion, our data do not support the hypothesis that the C282Y allele of the hemochromatosis (HFE) gene is a clinically important marker of an increased risk for the development of preeclampsia.