Par´ametros f´ısicos de la regi´on molecular

Relation between genetics and Gestational hypertension

We found that women with MTHFR 677 TT versus CC genotype had almost 3 times more risk of developing gestational hypertension. Our findings were largely in line with other studies and metanalysis confirming the relationship between the variants of that polymorphism and gestational hypertension. The

MTHFR 677 C>T polymorphism has been previously associated with

hypertension and stroke outside of pregnancy (303). Our group recently reported that the TT genotype is associated with increased risk of hypertension in adults under 50 years of age (139). There are also several studies that have investigated the association between the polymorphism and gestational hypertension.

Hernández-Díaz et al (2005) studied U.S. and Canadian white women with nonmalformed infants and found that the T allele was present int 69% of women with gestational hypertension versus 57% of control women. Compared with 677CC homozygotes, the OR (95% CI) of gestational hypertension for women who were 677 TT/CT was 1.9 (0.9, 4.0) (304). Stronger associations were found in two metanalysis. Kosmas et al (2004) across 23 comparisons (3169 hypertensive women and 3044 controls) found that having the T allele (TT or CT) increased the OR (95% CI) of gestational hypertension by 1.2 (1.0, 1.4) in patients with diastolic hypertension > 110mmHg. No association was seen in patients with less severe diastolic hypertension. They conclude that the C677T polymorphism increased the risk of severe hypertension but not the risk for milder hypertension (305). More recently, Yang et al (2014) confirmed also that the C677T polymorphism was

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significantly associated with gestational hypertension with an OR (95% CI) 1.2 (1.1, 1.3) (306).

However, some results are controversial. An underestimated effect of the polymorphism may come from the variance of the polymorphism according to ethnicity. When Yang et al stratified the analysis by ethnicity they observed significant association among East Asian and Caucasian, but not among Latinos, Black Africans and Indians (306). The use of folic acid supplementation during pregnancy can also mask the effect. Hernández-Díaz et al suggest that the association between MTHFR C677T polymorphism and gestational hypertension disappeared when they restrict the analyses to women supplemented with folic acid during the first five months of gestation (304). In the case of our study, we did not observe an association between the genotype and gestational hypertension when we adjusted for folate status when it was highest during pregnancy, during the peak of folic acid supplement use during the first trimester. We were strict in excluding pregnancies affected by gestational diabetes and intrauterine growth retardation from our analysis. While these pregnancy complications and underlying conditions can occur simultaneously, with gestational hypertension, in an initial analysis, exploring potential mechanisms, we excluded them. On the other hand, an inconsistent definition of gestational hypertension or prenatal control of the same can also be bias for the results. We strictly adhered to the definition of gestational hypertension, so that we did not misclassify participants with underlying hypertension as having hypertension induced by pregnancy. We only included pregnancies that had complete prenatal control of blood pressure (consisting of a measurement before and after 20 GW), in our analysis.

On the contrary, paternal genotype was not associated with increased risk of gestational hypertension. We did not find in our literature search, any other

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study of the association between paternal MTHFR 677 C>T genotype and gestational hypertension. Nonetheless, Hernández-Díaz et al (2005) suggest a possible effect of the offspring genotype in the risk of gestational hypertension because they found an association between fetal 677TT/CT genotype and maternal risk of gestational hypertension [0R (95%CI) 2.4 (1.1, 5.0)] (304). As foetal genotype is determined 50% from father’s genotype, we propose that paternal genotype can influence maternal risk of developing gestational hypertension. Other studies have suggested that paternal imprinted genes in the fetus contribute to increase pregnant woman’s risk to develop preeclampsia (307). It makes sense if we consider that preeclampsia results from dysfunctional placentation and the placenta has the same genotype as the fetus.

We found that maternal BMI was also a risk factor for gestational hypertension. We expected this because BMI is a well known risk factor for hypertension and gestational hypertension. Previous studies have also reported the same association (308, 309, 310). In addition, is well known that have had previous pregnancies reduces the risk to develop gestational hypertension compared to nulliparous women (311).

Relation between tHcy and Gestational hypertension

We found no association between maternal and paternal tHcy levels and the risk of gestational hypertension. Some studies showed that elevated tHcy is a risk factor of developing hypertension outside of pregnancy (312, 313). Our group recently reported that elevated tHcy was only associated with increased risk of hypertension in adults older than 50 years (139) and it is unclear that homocysteine is causally involved. Furthermore, a potential association is

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harder to see between tHcy and gestational hypertension because tHcy concentration is greatly affected during pregnancy by physiological and endocrinological processes (100). There have been few studies of such an association. Studies examining maternal tHcy levels at early pregnancy, like ours, have demonstrated a relationship between elevated tHcy and preeclampsia but they did not find the same association with gestational hypertension. In addition, we did not find studies examining the contribution of paternal homocysteine levels to the risk of gestational hypertension. In a prospective cohort study, Dodds et al reported that there was no significant association between tHcy concentration before 20 GW and the risk of developing gestational hypertension (273). Sun et al (2017) in a retrospective cohort study with 147 confirmed cases of gestational hypertension failed to find a significant difference between tHcy concentrations in the gestational hypertension and control groups (240). They only found a significant association in the group of severe preeclampsia compared to controls with an OR (95% CI) of 1.1 (1.1, 1.2). Cotter et al (2003) studied 71 cases of non-severe preeclampsia and 142 controls in Dublin, taking blood samples at early pregnancy. Participants with plasma homocysteine values >7.8 µmol/L (upper third) had significantly increased risk of developing preeclampsia [OR 95%CI 4.1 (1.4, 12.6)] (85).

Prenatal tHcy may not be a good biomarker for gestational hypertension, but it is relevant for detecting preeclampsia. Normally, elevated tHcy concentrations are related with severe disease status leading to a higher damage of the structure of blood vessels. It has been suggested that low concentrations of tHcy may even affect the endothelium slightly and play a subtle role in occurrence of lowest disease stages (240) like gestational hypertension, making this relationship almost undetectable. In our study population, mothers are mostly folic acid supplemented at early pregnancy. This could be a reason why our tHcy ≥P90 group have tHcy levels too low to

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cause the endothelial dysfunction and the following rise of blood pressure. Lastly, another possibility lies in the difference between the pathological processes involved in gestational hypertension and preeclampsia, justified by the higher increase on tHcy concentrations in preeclampsia than in gestational hypertension (240).

Further investigation is needed to establish whether there is an association between paternal factors related to one carbon metabolism and gestational hypertension or preeclampsia. This knowledge would inform preventive preconception policies including fathers.

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