**5. Genetic association studies and preeclampsia**

**Genome-wide linkage studies** of preeclampsia and pregnancy-induced hypertension have identified different loci associated with preeclampsia that segregate with different populations: on 4q (between D4S450-D4S610 markers, found in Australia), 2q23 (between D2S112-D2S151 markers, Australia, NZ), 2p13 (D2S286, Iceland), 2p25 (D2S168, Finland), 9p13 (D9S169, Finland), and 10q22 (Netherlands). Additional loci are expected to exist in preeclamptic patients with certain complications, such as the locus 12q in patients with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome [15–18].

Candidate genes studies have provided evidence for an association with preeclampsia, frequently with inconsistent results. One of the common candidate genes is endothelial nitric oxide synthase gene (eNOS) on 7q36, which is responsible for nitric oxide production in endothelial cells. The endothelial dysfunction in preeclampsia reveals a strong association with eNOS polymorphisms. However, several other genome scans could not confirm this association. Another study found an evidence of moderate association with an increased risk for preeclampsia in women having mutations in coagulation factor genes; F5 Leiden (rs6025, G1691A), and the prothrombin (F2) gene (rs1799963, G20210A). This evidence may explain the association of the disease with coagulation disorders. Several studies found associations between renin-angiotensin-aldosterone system with gestational hypertension and preeclampsia. Earlier linkage studies found an association with angiotensinogen (AGT) locus, on 1q42-43 and the risk for hypertensive disease in different sets of population. They also found an association between specific allele AGT (T235, rs699) with essential hypertension and preeclampsia. Angiotensin converting enzyme (ACE) along with AGT receptor 1 (AGTR1) were also found to have a role in the pathogenesis of the preeclampsia. Another candidate gene that link preeclampsia to the risk of hypertension is the T allele (C677T) of the methylenetetrahydrofolate reductase (MTHFR) gene [19–23].

To conclude, no single gene or chromosomal locus currently known can explain the pathogenesis of preeclampsia. This indicates that preeclampsia is a polygenic disorder, and it reflects an integrated pathophysiological process of insufficient adaptation, not only in the placenta, but also in other tissues and organs. On the other hand, the geographical distribution of candidate genes and loci in association with the pathogenesis of preeclampsia may reflect the interaction between the different environments and the gene pool of populations.
