Andreia Matos

Oncogenic virus-associated neoplasia: a role for cyclin D1 genotypes influencing the age of onset of disease?

Cyclin D1 (CCND1) is a key regulatory protein at the G1/S checkpoint of the cell cycle. The purpose of our study was to assess the role of CCND1 genotypes influencing the age of onset of oncogenic virus-associated neoplasia. We conducted a hospital-based case-control study of 581 individuals, including 247 controls and 334 cases (108 nasopharyngeal and 226 cervical cancer cases). The polymorphism analysis was performed in blood samples by PCR-RFLP methodology. Age-adjusted logistic regression analysis indicates that individuals carrying two G-alleles have an increased genetic susceptibility for the development of oncogenic virus-associated cancers (aOR=2.02, 95% CI 1.30-3.14, P=0.002). Moreover, our results indicate that the waiting time for onset of oncogenic virus-associated neoplasia in patients homozygous (GG) for CCND1 genotypes (52 years) was 12 years earlier in comparison with patients carrying AG or AA genotypes (60 years) (log-rank test: P=0.0003). Our results may be important in contributing to a more extensive knowledge of the mechanisms involved in oncogenic virus-associated carcinogenesis, as CCND1 may be an important target for the development of new strategies for cancer treatment and prevention.

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.

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.

Sickle cell anemia - nitric oxide related genetic modifiers of hematological and biochemical parameters

BACKGROUND Sickle cell anemia (SCA) is an inherited blood disorder. SCA patients present clinical and hematologic variability that cannot be only explained by the single mutation in the beta-globin gene. Others genetic modifiers and environmental effects are important for the clinical phenotype. SCA patients present arginine deficiency that contributes to a lower nitric oxide (NO) bioactivity. OBJECTIVE The aim of this work is to determine the association between hematological and biochemical parameters and genetic variants from eNOS gene, in pediatric SCA patients. METHODS 26 pediatric SCA patients were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques in three important eNOS gene polymorphisms - rs2070744, rs1799983 and intron 4 VNTR. RESULTS Results from this study show a significant statistical association between some parameters and genetic variants: an increased reticulocyte count and high serum lactate dehydrogenase levels were associated with both the rs2070744_TT and the rs1799983_GG genotypes at eNOS gene and high levels of neutrophils were associated with the eNOS4a allele at intron 4 VNTR. CONCLUSIONS Our results reinforce the importance of NO bioactivity in SCA. We presume that NO, and its precursors might be used as therapy to improve the quality of life of SCA patients.

Characterization of Portuguese Centenarian Eating Habits, Nutritional Biomarkers, and Cardiovascular Risk: A Case Control Study

Background and Aims Eating habits may contribute to longevity. We characterized the eating habits and cardiovascular risk (CVR) biomarkers in Portuguese centenarians (CENT) compared to controls. Methods and Results Centenarians (n = 253), 100.26 ± 1.98 years, were compared with 268 controls (67.51 ± 3.25), low (LCR) and high (HCR) CVR (QRISK®2-2016). Anthropometric and body composition were evaluated by bioimpedance. Abdominal obesity, BMI, and fat mass (FM) cut-offs were according to the WHO. Sarcopenia was defined by muscle mass index cut-off ≤ 16.7 kg/m2. Daily red meat intake, adjusted for age and gender, was sarcopenia protective (OR = 0.25, 95% CI = 0.096–0.670, P = 0.006); however, it contributes for FM excess (OR = 4.946, 95% CI = 1.471–16.626, P = 0.01), overweight, and obesity (OR = 4.804, 95% CI = 1.666–13.851, P = 0.004). This centenarian eating habit (2%) contrasts to HCR (64.3%). The history of red meat (P < 0.0001) and canned/industrialized food intakes (P < 0.0001) was associated with HCR. Basal metabolism was lower in centenarians versus LCR/HCR (CENT = 1176.78 ± 201.98; LCR = 1356.54 ± 170.65; HCR = 1561.33 ± 267.85; P < 0.0001), BMI (CENT = 21.06 ± 3.68; LCR = 28.49 ± 4.69; HCR = 29.56 ± 5.26; P < 0.0001), waist circumference (CENT = 85.29 ± 10.83; LCR = 96.02 ± 11.71; HCR = 104.50 ± 11.84; P < 0.0001), and waist-hip ratio (CENT = 0.88 ± 0.07; LCR = 0.92 ± 0.08; HCR = 1.01 ± 0.08; P < 0.0001). CENT had lower total cholesterol, LDL cholesterol, non-HDL cholesterol, and cholesterol/HDL ratio than controls. Conclusions Frequent consumption of red meat, cholesterol, and heme iron rich may contribute to obesity and increased CVR. The low frequency of this consumption, observed in centenarians, although associated with sarcopenia, may be one of the keys to longevity.

Mechanisms underlying the association between obesity and Hodgkin lymphoma

A solid body of knowledge indicates that overweight and obese subjects are prone to develop cancer, aggressive disease, and death more than their lean counterparts. While obesity has been causally associated with various cancers, only a limited number of studies beheld the link with classical Hodgkin lymphoma (HL). Contemporary meta-analysis and prospective studies confirmed the association of body mass index with HL. Besides epidemiological evidence, excess adiposity is known to influence tumor behavior through adipokines, adipose-derived stem cell migration, and metabolism regulation, and by modulating immunoinflammatory response. Nevertheless, the obesity paradox has been described in few cancers. Considering that adipose tissue is an immunomodulatory organ, and that inflammation is the cornerstone of HL pathophysiology, the rationale for being causally related due to endocrine/paracrine interactions cannot be negligible. In this hypothesis-generating review, we explore the biologically plausible links between excess adiposity and HL in light of recent basic and clinical data, in order to create a basis for understanding the underlying mechanisms and foster applied research. The establishment of an association of excess adiposity with HL will determine public health preventive measures to fight obesity and eventually novel therapeutic approaches in HL patients.

PP004. The polymorphism C677T of methylenetetrahydrofolate reductase (MTHFR), may increase risk for future higher blood pressure in women with previous hypertension in pregnancy

INTRODUCTION The MTHFR is a key enzyme in the folate cycle involved in homocysteine remethylation. The T allele of MTHFR C677T polymorphism is associated with lower activity inhibiting the DNA methylation and protecting from oxidative stress. OBJECTIVES To evaluate the MTHFR genotype-phenotype relationship during and after pregnancy comparing hypertensive with normotensive women. METHOD A sample of 380 women with 32.54±6.478 years old, 181 normotensive (NT) and 199 hypertensive (HBP) being 70.3% above 34 weeks of gestation. A subgroup 63 women with history of preeclampsia were studied 3-6 years postpartum and compared with 59 controls. The MTHFR was evaluated by PCR-RFLP using DNA extracted from peripheral blood. Statistical analysis evaluated with appropriated tests. RESULTS The distribution of genotypes of the MTHFR was different according to blood pressure (BP), it was observed that the TT genotype had lower frequency in HBP (p<0.001). In the subgroup CC+CT the MPO levels were higher in HBP as well as nitrites, leucocytes, neutrophils, Apo B, BMI, waist and ratio waist/hip compared with NT (p<0.001, p=0.04, p=0.042, p=0.035, p=0.03, p=0.022, p=0.026, respectively). There were differences between levels of BP systolic and diastolic between women previously HBP and NT of CC+CT compared with TT carriers (p<0.001). CONCLUSION The MTHFR may modulate blood pressure (BP) and cardiovascular risk. TT genotype with increased expression of antioxidant enzymes, may be a protective factor for future hypertension and cardiovascular risk compared with women CC and CT genotypes with higher levels of circulating biomarkers of inflammation.

ACE polymorphism in asthmatic patients

Background The aim of the this study was to analyse if there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism (287 base pairs, on chromosome 17q23, intron 16 (rs4340)) with asthma severity. ACE plays a vital role in the renin-angiotensinsystem (RAS) which regulates blood pressure by converting angiotensin I into a powerful vasoconstrictor angiotensin II, that also has an important role in airway remodeling and in inactivation of bradykinin and tachykinins. The signaling pathways, related with this polymorphism regulating the cytokine production by T cells, could induce a different Th profile modulating the immune response in asthma.

The role of type 1 angiotensin 2 receptor polymorphism in asthmatic patients

Background It is known that type 1 angiotensin II (Ang II) receptor (AGTR1) could be related with the pathogenesis of bronchial asthma. It is involved in Th polarization, through different signaling pathways modulating allergic airway inflammation, and also may participate in airway remodeling and bronchoconstriction, that could be related with AGTR1 polymorphism. The purpose of this study is to analyze the association between AGTR1 1166A/C (rs5186) gene polymorphism with asthma severity.