**6. Adaptive polymorphisms of hypoxia genes**

Here, we discuss some of the known genetic polymorphisms that influence maternal vascular adaptation in normal pregnancy and preeclampsia, high-altitude adaptation, and adaptive variants in healthy exercise. These genetic changes affect the protein activity and production, and can be set as early predictive markers for adaptation.

#### **6.1 Endothelial nitric oxide synthase (eNOS): (rs1799983, G894T, Glu298Asp)**

Healthy pregnancy is associated with enhanced endothelium-dependent vasodilation in the brachial artery, a response mediated by NO. These changes are thought to be an important physiological adaptation that accommodates the increased circulating blood volume and cardiac output during pregnancy. A common polymorphism of the eNOS gene is G894T in the mature protein that has been associated with the differences in endothelium-dependent dilation at 12-week gestation. There are several reports on the association between eNOS 894T allele polymorphism and PE susceptibility. They also provide a potential mechanism linking eNOS polymorphism with the prediction of cardiovascular disorders and pulmonary edema in which NO bioactivity is impaired [24–26].

In high-altitude adaptation, previous studies showed that the eNOS G894T polymorphism contributed to physiology and pathophysiology of humans at high altitude by regulating the production of NO. The 894G allele carriers and GG genotype might be a beneficial factor for HA adaptation through enhancing the level of NO, and 894T allele and heterozygous G/T of the 894G/T variant are associated with the susceptibility to high-altitude pulmonary edema (HAPE) at Qinghai-Tibet. In acclimatization to high altitude, NO levels increase dramatically above the baseline levels, while visitors ill with high-altitude pulmonary edema at the time of the study or in the past, have NO levels were lower than those of their healthy counterparts. Highland indigenous populations like Tibetans have high NO levels in the lung, plasma, and red blood cells that were at least double the levels that can be found in other populations regardless of altitude. With respect to NOS3 G894T and its relation to athletic performance or status, the over-representation of the GG genotype and G allele in all athletes suggests that the G894 allele may favor many types of sports [27, 28]. This supports the adaptive function of 894G allele and genotype.

*Probably adaptive: 894G allele; less adaptive: 894 T allele*

#### **6.2 Angiotensin converting enzyme (ACE): (rs4646994, ACEI/D)**

Circulating angiotensin I-converting enzyme (ACE) exerts a tonic regulatory function in circulatory homeostasis, through the synthesis of vasoconstrictor angiotensin II. ACE I/D (insertion/deletion) polymorphism is associated with ACE level. The presence (insertion, I allele) rather than the absence (deletion, D allele) of a287 bp Alu sequence insertion fragment is associated with lower serum and tissue ACE activity and thus lower angiotensin II production. The D allele of the ACE I/D polymorphism along with higher ACE levels were over-represented in Han Chinese who was afflicted with AMS. On ascent to extreme altitudes, the I allele of the ACEI/D polymorphism may tend to have more sufficient/efficient acclimatization and consequently have less risk of developing AMS. It was hypothesized that the pioneer lowlanders who migrated to high altitude might have the I-related

**45**

*Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia*

*Probably adaptive: ACE I allele; less adaptive: ACE D allele*

**6.3 Vascular endothelial growth factor (VEGFA): (rs3025039, C 936T)**

Vascular endothelial growth factor (VEGF) is a major angiogenic factor that acts as a regulator of endothelial cell proliferation and vascular permeability. VEGF has been shown to be markedly up-regulated in hypoxic conditions. A common polymorphism of VEGFA is 936 C>T (rs3025039). The carriers of the 936T allele have lower VEGF plasma level by one-third of non-carriers. In a comparison between two groups of lowlanders on ascent to high altitude; those with 936T allele have a decreased risk of acute mountain sickness. In acute exercise, VEGF levels increases in sedentary individuals "less adaptive," whereas exercise adaptation attenuates VEGF gene expression in human skeletal muscle in trained "well adaptive" individuals. Both findings appear to be related in preeclamptic women, where the increased VEGF level is accompanied by the C allele of VEGFA. Thus, it is possible that the T allele associates with the maintenance of normal pregnancy and may confer a protective effect against the development of preeclampsia and is consistent with the concept of having the T allele and low VEGF levels among women with

It was recently shown that the gene encoding HIF-2α/EPAS-1 represents a key mutated gene in the adaptation of Tibetan populations at high altitudes. Although it is highly similar to HIF-1 and has the potential to bind and mediate many of the same genes as HIF-1, its biological actions in response to hypoxia are distinct from those of HIF-1. By now, several of these HIF-2 mediated processes have been implicated in the human response to high-altitude exposure including erythropoiesis, iron homeostasis, metabolism, and vascular permeability, which are perturbed in preeclampsia. HGB-decreasing allele of EPAS1 is under very strong positive selection in Tibetans and is strongly associated with Hb, red cell count, and hematocrit. Although there is no association between HIF-2α/EPAS-1 polymorphisms and preeclampsia in the literature, few studies found up-regulated expression of HIF-2α in preeclampsia. In earlier work, we discussed the association between EPAS1 polymorphisms and preeclampsia. Based on the strong positive association signal of adaptation in Tibetans, I emphasized on the role of EPAS1 in preeclampsia, and suggest and for the first time that the mutated EPAS1, has to be considered as a major player for placental adaptation in normal pregnancy and preeclampsia.

genotypes (the II or ID genotype) as an "inner predisposition" to overcome altitude illnesses during migration and adaptation and finally was able to settle at high altitude permanently. However, some evidence shows that they may gain their adaptation through the long period of settlement. Along with elite mountaineers, the I allele has been associated with some aspects of endurance performance in Marathon runners, rowers, cyclists, handball players, and others in different population. In the prediction of the disease, it was shown that the ACE D allele leads to increased expression of plasminogen activator inhibitor-1 (PAI-1), which can increase the risk of preeclampsia and thrombotic events and enhances the production of angiotensin

*DOI: http://dx.doi.org/10.5772/intechopen.86612*

II from angiotensin I [29, 30].

normal, uncomplicated pregnancies [31].

**6.4 HIF-2α/EPAS-1: high-altitude adaptive gene**

*Probably adaptive: 936T allele; less adaptive: 936 C allele*

#### *Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86612*

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

**6. Adaptive polymorphisms of hypoxia genes**

which NO bioactivity is impaired [24–26].

adaptation.

Here, we discuss some of the known genetic polymorphisms that influence maternal vascular adaptation in normal pregnancy and preeclampsia, high-altitude adaptation, and adaptive variants in healthy exercise. These genetic changes affect the protein activity and production, and can be set as early predictive markers for

**6.1 Endothelial nitric oxide synthase (eNOS): (rs1799983, G894T, Glu298Asp)**

In high-altitude adaptation, previous studies showed that the eNOS G894T polymorphism contributed to physiology and pathophysiology of humans at high altitude by regulating the production of NO. The 894G allele carriers and GG genotype might be a beneficial factor for HA adaptation through enhancing the level of NO, and 894T allele and heterozygous G/T of the 894G/T variant are associated with the susceptibility to high-altitude pulmonary edema (HAPE) at Qinghai-Tibet. In acclimatization to high altitude, NO levels increase dramatically above the baseline levels, while visitors ill with high-altitude pulmonary edema at the time of the study or in the past, have NO levels were lower than those of their healthy counterparts. Highland indigenous populations like Tibetans have high NO levels in the lung, plasma, and red blood cells that were at least double the levels that can be found in other populations regardless of altitude. With respect to NOS3 G894T and its relation to athletic performance or status, the over-representation of the GG genotype and G allele in all athletes suggests that the G894 allele may favor many types of sports [27, 28]. This supports the adaptive function of 894G allele

*Probably adaptive: 894G allele; less adaptive: 894 T allele*

**6.2 Angiotensin converting enzyme (ACE): (rs4646994, ACEI/D)**

Circulating angiotensin I-converting enzyme (ACE) exerts a tonic regulatory function in circulatory homeostasis, through the synthesis of vasoconstrictor angiotensin II. ACE I/D (insertion/deletion) polymorphism is associated with ACE level. The presence (insertion, I allele) rather than the absence (deletion, D allele) of a287 bp Alu sequence insertion fragment is associated with lower serum and tissue ACE activity and thus lower angiotensin II production. The D allele of the ACE I/D polymorphism along with higher ACE levels were over-represented in Han Chinese who was afflicted with AMS. On ascent to extreme altitudes, the I allele of the ACEI/D polymorphism may tend to have more sufficient/efficient acclimatization and consequently have less risk of developing AMS. It was hypothesized that the pioneer lowlanders who migrated to high altitude might have the I-related

Healthy pregnancy is associated with enhanced endothelium-dependent vasodilation in the brachial artery, a response mediated by NO. These changes are thought to be an important physiological adaptation that accommodates the increased circulating blood volume and cardiac output during pregnancy. A common polymorphism of the eNOS gene is G894T in the mature protein that has been associated with the differences in endothelium-dependent dilation at 12-week gestation. There are several reports on the association between eNOS 894T allele polymorphism and PE susceptibility. They also provide a potential mechanism linking eNOS polymorphism with the prediction of cardiovascular disorders and pulmonary edema in

**44**

and genotype.

genotypes (the II or ID genotype) as an "inner predisposition" to overcome altitude illnesses during migration and adaptation and finally was able to settle at high altitude permanently. However, some evidence shows that they may gain their adaptation through the long period of settlement. Along with elite mountaineers, the I allele has been associated with some aspects of endurance performance in Marathon runners, rowers, cyclists, handball players, and others in different population. In the prediction of the disease, it was shown that the ACE D allele leads to increased expression of plasminogen activator inhibitor-1 (PAI-1), which can increase the risk of preeclampsia and thrombotic events and enhances the production of angiotensin II from angiotensin I [29, 30].

*Probably adaptive: ACE I allele; less adaptive: ACE D allele*

## **6.3 Vascular endothelial growth factor (VEGFA): (rs3025039, C 936T)**

Vascular endothelial growth factor (VEGF) is a major angiogenic factor that acts as a regulator of endothelial cell proliferation and vascular permeability. VEGF has been shown to be markedly up-regulated in hypoxic conditions. A common polymorphism of VEGFA is 936 C>T (rs3025039). The carriers of the 936T allele have lower VEGF plasma level by one-third of non-carriers. In a comparison between two groups of lowlanders on ascent to high altitude; those with 936T allele have a decreased risk of acute mountain sickness. In acute exercise, VEGF levels increases in sedentary individuals "less adaptive," whereas exercise adaptation attenuates VEGF gene expression in human skeletal muscle in trained "well adaptive" individuals. Both findings appear to be related in preeclamptic women, where the increased VEGF level is accompanied by the C allele of VEGFA. Thus, it is possible that the T allele associates with the maintenance of normal pregnancy and may confer a protective effect against the development of preeclampsia and is consistent with the concept of having the T allele and low VEGF levels among women with normal, uncomplicated pregnancies [31].

*Probably adaptive: 936T allele; less adaptive: 936 C allele*

#### **6.4 HIF-2α/EPAS-1: high-altitude adaptive gene**

It was recently shown that the gene encoding HIF-2α/EPAS-1 represents a key mutated gene in the adaptation of Tibetan populations at high altitudes. Although it is highly similar to HIF-1 and has the potential to bind and mediate many of the same genes as HIF-1, its biological actions in response to hypoxia are distinct from those of HIF-1. By now, several of these HIF-2 mediated processes have been implicated in the human response to high-altitude exposure including erythropoiesis, iron homeostasis, metabolism, and vascular permeability, which are perturbed in preeclampsia. HGB-decreasing allele of EPAS1 is under very strong positive selection in Tibetans and is strongly associated with Hb, red cell count, and hematocrit. Although there is no association between HIF-2α/EPAS-1 polymorphisms and preeclampsia in the literature, few studies found up-regulated expression of HIF-2α in preeclampsia. In earlier work, we discussed the association between EPAS1 polymorphisms and preeclampsia. Based on the strong positive association signal of adaptation in Tibetans, I emphasized on the role of EPAS1 in preeclampsia, and suggest and for the first time that the mutated EPAS1, has to be considered as a major player for placental adaptation in normal pregnancy and preeclampsia.

Further experimental studies are needed to confirm the biological function of EPAS-1 in normal pregnancy [3, 32–34].

## **6.5 Methylenetetrahydrofolate reductase (MTHFR) (rs1801133, A222 V, C677T)**

The effects of MTHFR on preeclampsia are of great interest to researchers in the field. MTHFR plays a key role in homocysteine metabolism. Tibetans have an increased frequency of the homocysteine-decreasing allele of rs1801133 at the MTHFR locus more than other individuals from Eastern Asian ancestry. The homocysteine level in Tibetans is even lower than in Han, who lives at the same highlands of Tibet's but for shorter period. This renders them to be less adaptive compared to Tibetans. On the other hand, several studies found significant association at this locus with PE. The gene promoter of MTHFR is found to be hypermethylated in preeclamptic women, and this results in a high level of homocysteine. The same can be found in high-altitude sickness as a result of mal adaptation [35, 36].
