Association of Aquaporin-3, Aquaporin-7, NOS3 and CYBA polymorphisms with hypertensive disorders in women.

Preeclampsia (PE), a pregnancy disorder influenced by oxidative stress and hypoxia, affects the health of the mother and baby and is associated with an increased risk of future hypertension (HT). Aquaporins are a family of water channels, comprising members that also transport glycerol (aquaglyceroporins) and hydrogen peroxide (peroxiporins), key molecules for metabolic homeostasis and redox signaling. Here, we investigated the association of Aquaporin-3 (AQP3; rs2231231), Aquaporin-7 (AQP7; rs2989924), NOS3 (4B/A intron) and CYBA (rs4673) genetic polymorphisms with the development of hypertensive disorders by qPCR/PCR in a cohort of 150 normotensive (NT) women (N = 90) or with previous PE (N = 60) during pregnancy. Prospectively, women were reclassified 2-16 years after pregnancy as NT (N = 98) or hypertensive (N = 48) and the genetic associations were reevaluated. In addition, genetic associations were reevaluated and compared between normotensive and hypertensive (HT) subjects. We found that AQP3 rs2231231, an aquaglyceroporin/peroxiporin, is associated with the development of HT, whereas AQP7, NOS3 and CYBA polymorphism did not correlate with PE or future HT. Because AQP3 was associated with hypertension only after pregnancy, its role might be related to later risk factors of hypertension such as metabolic syndrome or oxidative stress.

Impact on Longevity of Genetic Cardiovascular Risk and Lifestyle including Red Meat Consumption.

BACKGROUND: Cardiovascular risk (CVR) underlies aging process and longevity. Previous work points to genetic and environmental factors associated with this risk. OBJECTIVES: The aim of this research is to look for any CVR gene-gene and gene-multifactorial/lifestyle interactions that may impact health and disease and underlie exceptional longevity. METHODS: A case-control study involving 521 both gender individuals, 253 centenarians (100.26 ± 1.98 years), and 268 controls (67.51 ± 3.25 years), low (LCR, n = 107) and high (HCR, n = 161) CVR. Hypertension, diabetes, obesity (BMI, kg·m-2), and impaired kidney function were defined according to standard criteria. CVR was calculated using Q risk®. DNA was genotyping (ACE-rs4646994, AGT-rs4762, AGR1-rs5182, GRK4-rs2960306, GRK4-rs1024323, NOS3-rs1799983, and SLC12A3-rs13306673) through iPlex-MassARRAY®, read by MALDI-TOF mass spectrometry, and analyzed by EARTDECODE®. RESULTS: Antilongevity factors consisted (OR 95% CI, p < 0.05) BMI 1.558 (1.445-1.680), hypertension 2.358 (1.565-3.553), smoking habits 4.528 (2.579-7.949), diabetes 5.553 (2.889-10.675), hypercholesterolemia 1.016 (1.010-1.022), and regular consumption of red meat 22.363 (13.987-35.755). Genetic aspects particularly for HCR individuals ACE II (OR: 3.96 (1.83-8.56), p < 0.0001) and NOS3 TT (OR: 3.11 (1.70-5.70), p < 0.0001) genotypes were also risk associate. Obesity, smoking, hypercholesterolemia, and frequent consumption of red meat have an additive action to hypertension in the longevity process. There was a synergistic interaction between the endothelial NOS3 genotypes and the severity of arterial hypertension. An epistatic interaction between functional genetic variants of GRK4 and angiotensinogen was also observed. CONCLUSIONS: Cardiovascular risk-related genetic and multifactorial or predominantly lifestyle aspects and its interactions might influence the aging process and contribute to exceptional longevity in Portuguese centenarians. Besides lifestyle, the activity of nitrite oxide synthase may be one of the main physiologic regulators of cardiovascular protection in the path of longevity.

Hypertension and longevity: role of genetic polymorphisms in renin-angiotensin-aldosterone system and endothelial nitric oxide synthase.

Hypertension (HT), a common age-related disorder, is an important risk factor for cardiovascular disease. This study aims to identify the prevalence of HT in Portuguese centenarians and evaluate whether gene polymorphisms encoding key molecules in blood pressure (BP) regulation are associated with longevity. There were recruited 253 centenarians (100.26 ± 1.98 years) and 268 control subjects (67.51 ± 3.25 years). Hypertension (ESH/ESC2013 and JNC8) and diabetes (WHO) were evaluate. Genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) and NOS3 were determined. The prevalence of HT among centenarians was 64.4% and the majority (58.9%) were controlled, differing from control group both on frequency (P < 0.001) and on their control (P < 0.001). We found that HT is a risk factor for not achieving longevity (OR 2.531, 95% CI 1.688-3.793, P < 0.001), the same for diabetes (OR 5.669 95% CI 2.966-10.835, P < 0.001), and male gender (OR 2.196, 95% CI 1.493-3.29, P < 0.001). Hypertension, adjusted for gender and diabetes, was independent risk factor anti-longevity (OR 2.007, 95% CI 1320-3.052, P = 0.001). The ACE_D and NOS3_G alleles were more frequent in centenarians compared to controls (P < 0.001, both cases). ACE_II and NOS3_TT genotypes, adjusted for BP, gender and diabetes, increased risk in 3.748 (95% CI 1.887-7.444) and 2.533 (95% CI 1.483-4.327), respectively, in relation to ACE_DD (P < 0.001) and NOS3_GG (P = 0.001), against longevity. Our findings suggest that the prevalence of hypertension was lower in Portuguese centenarians than in the elderly, reinforcing the importance of better cardiovascular risk profiles to achieve longevity even in the presence of genetic condition.

Epistatic Interaction of CYP1A1 and COMT Polymorphisms in Cervical Cancer.

There is a clear association between the excessive and cumulative exposure to estrogens and the development of cancer in hormone-sensitive tissues, such as the cervix. We studied the association of CYP1A1 M1 (rs4646903) and COMT (rs4680) polymorphisms in 130 cervical cancer cases (c-cancer) and 179 controls. The CYP1A1 TT genotype was associated with a lower risk for c-cancer (OR = 0.39, p = 0.002). The allele C of CYP1A1 was a risk for c-cancer (OR = 2.29, p = 0.002). Women with COMT LL genotype had a higher risk of developing c-cancer (OR = 4.83, p < 0.001). For the interaction of the CYP1A1&COMT, we observed that TC&HL genotypes had a greater risk for c-cancer (OR = 6.07, p = 0.006) and TT&HL genotypes had a protection effect (OR = 0.24, p < 0.001). The CYP1A1 TT and COMT LL genotypes had higher estradiol levels in c-cancer (p < 0.001 and p = 0.037, resp.). C-cancer is associated with less production of 2-methoxy-estradiol resultant of functional polymorphisms of CYP1A1 and COMT, separately. CYP1A1 and COMT work in a metabolic sequence and their interaction could lead to an alternative pathway of estrogen metabolism with production of 16-OH-estrone that is more proliferative.

In women with previous pregnancy hypertension, levels of cardiovascular risk biomarkers may be modulated by haptoglobin polymorphism.

Preeclampsia (PE) may affect the risk for future cardiovascular disease. Haptoglobin (Hp), an acute phase protein with functional genetic polymorphism, synthesized in the hepatocyte and in many peripheral tissues secondary of oxidative stress of PE, may modulate that risk through the antioxidant, angiogenic, and anti-inflammatory differential effects of their genotypes. We performed a prospective study in 352 women aged 35 ± 5.48 years, which 165 had previous PE, 2 to 16 years ago. We studied demographic, anthropometric, and haemodynamic biomarkers such as C-reactive protein (CRP), myeloperoxidase (MPO), and nitric oxide metabolites (total and nitrites), and others associated with liver function (AST and ALT) and lipid profile (total LDL and cholesterol HDL, non-HDL, and apolipoproteins A and B). Finally, we study the influence of Hp genetic polymorphism on all these biomarkers and as a predisposing factor for PE and its remote cardiovascular disease prognosis. Previously preeclamptic women either hypertensive or normotensive presented significant differences in those risk biomarkers (MPO, nitrites, and ALT), whose variation may be modulated by Hp 1/2 functional genetic polymorphism. The history of PE may be relevant, in association with these biomarkers to the cardiovascular risk in premenopausal women.

Sex steroid hormones influence the risk for cervical cancer: modulation by haptoglobin genetic polymorphism.

Sex steroid hormones ingestion (contraceptives and replacement therapy) may influence cervical carcinogenesis. Haptoglobin (Hp), an acute phase protein that has genetic polymorphism, can influence immune response to tumor. Our objective was to study the influence of haptoglobin genetic polymorphism on the risk for development of cervical cancer dependent on sex steroid hormones. A total of 492 Caucasian women, 196 pathologic [high-grade squamous intraepithelial lesions and invasive cervical cancer (HSIL + ICC)], ranging in age from 18 to 81 years, were phenotyped for plasma Hp using a polyacrylamide gel electrophoresis method. The effect of the interaction between the Hp genetic phenotype and steroid hormone therapy was analyzed using a multinomial logistic regression. Hp 1/1 genetic phenotype was associated with the risk for cervical cancer of steroid hormone ingestion: general risk odds ratio (OR)=5.388, P<0.001; for the interaction with carriers of Hp 1/1, OR=6.765, P<0.001; with carriers of Hp 2/1, OR=6.499, P<0.001; and with carriers of Hp 2/2, OR=3.903, P=0.001. The linear trend of risks that result from that interaction is also significant (chi2 =31.8, P<0.001). The higher risk for HSIL + ICC observed in carriers of increasing allele 1 of Haptoglobin probably results from the intense immune suppressor effect of this form of Hp, in addition to that of steroid hormones ingestion.