Hipertensión arterial e inflamación: análisis de polimorfismos genéticos y su correlación clínica y biológica
[EN] HYPERTENSION AND INFLAMATION: GENETIC POLYMORPHISMS ANALYSIS AND CLINICAL AND BIOLOGICAL CORRELATION 1. INTRODUCTION Human hypertension is an example of a complex, multifactorial, polygenic disease influenced by the genetic background although the underlying genetics components remain unknown....
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| Tipo de recurso: | tesis doctoral |
| Fecha de publicación: | 2013 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/123063 |
| Acceso en línea: | http://hdl.handle.net/10366/123063 |
| Access Level: | acceso abierto |
| Palabra clave: | clinical genetics cardiovascular pathology Tesis y disertaciones académicas Universidad de Salamanca (España) Academic dissertations Genética clínica Patología cardiovascular 3207.04 Patología Cardiovascular |
| Sumario: | [EN] HYPERTENSION AND INFLAMATION: GENETIC POLYMORPHISMS ANALYSIS AND CLINICAL AND BIOLOGICAL CORRELATION 1. INTRODUCTION Human hypertension is an example of a complex, multifactorial, polygenic disease influenced by the genetic background although the underlying genetics components remain unknown. Polymorphisms in several genes have been associated with blood pressure levels. An accumulating body of evidence indicates that inflammation plays a pivotal role in the patho¬genesis of cardiovascular disease and hypertension. An inflammatory expression pattern of endothelium is the main substrate underlying atherosclerotic lesions of vascular walls. Endothelial dysfunction along with unfavorable blood flow and hypercholesterolemia leads to the impairment of the vascular tone. Hypertension is associated with an increase in vascular inflammatory responses, which contributes to vascular dysfunction. The idea that hypertension and inflammation are linked emerges from cross sectional and prospective studies showing that circulating inflammatory molecules are increased in hypertensive patients, and their levels predict the onset of hypertension. Some cross-sectional studies showed that, compared to normotensives, the plasma levels of inflammatory markers, cytokines, chemokines, and adhesion molecules, are increased in patients with essential hypertension and no evidence of cardiovascular disease. This association has been also observed in patients with pre-hypertension. In fact, these subjects exhibit higher plasma levels of inflammatory markers compared to controls. It has been shown that hypertensive patients also have increased plasma soluble CD40L level and elevated CD40/CD40L expression on platelets. Furthermore in a prospective study was observed that among healthy men without hypertension those with high plasma levels of fibrinogen, ¿1-antitrypsin, haptoglobin, ceruloplasmin and orosomucoid were at higher risk of becoming hypertensive. In particular, the risk of future hypertension was higher among subjects with a concomitant increase of more than three proteins, underlining the importance of the level of inflammation, more than the effect attributable to a single molecule. In the same way it has been shown, in a cohort of 20525 patients, that the levels of high-sensitive C reactive protein (CRP) predicted the development of hypertension, during a follow-up of 7.8 years. This association was independent of the baseline levels of systolic blood pressure and diastolic blood pressure and was also observed among those with very low initial blood pressure. This data has been confirmed, during a follow-up of 11 years, middle-aged men with CRP levels >3.0 mg/l are at increased risk of developing hypertension as compared to those with CRP <1.0 mg/l. Interestingly, they also observed that the association between the low-grade inflammatory condition and the risk of becoming hypertensive, remained statistically significant even after adjustment for features of the metabolic syndrome. However in the best of our knowledge there are only a few studies analyzing the association of polymorphisms in genes that encode inflammation molecules and hypertension. And there is no study analyzing this association with resistant hypertension. We therefore hypothesized that variations in polymorphisms in genes that encode inflammation molecules may modulate the susceptibility to hypertension and refractory hypertension. In the present study, we have analyzed IL10 -627 C>A, IL12B -1188 A>C, TNFA -238 G>A, TNFA -308G>A and CD40 -1 C>T polymorphisms in three different study groups (controls, hypertensive patients and refractory hypertension patients) involving a total of 440 subjects. 2. METHODS Design An observational case-control study was performed. Study Population After sample size calculation, we included in this study 50 resistant hypertension patients, 284 hypertensive patients and 160 sex and aged matched healthy controls. Hypertension was defined as resistant to treatment, or refractory, when a therapeutic plan that had included attention to lifestyle measures and the prescription of at least three drugs including a diuretic in adequate doses failed to achieve goal blood pressure (BP) (<140/90 mmHg or < 130/80 in diabetics). Hypertension population was defined as having a systolic/diastolic BP of >140/90 mm Hg or >130/80 mmHg in diabetics on 3 separate occasions but controlled after treatment during the follow-up. Normotensive subjects had a BP < 140/90 mm Hg or <130/80 mmHg in diabetics. All the hypertensive patients were controlled every month, and 24-hour ambulatory blood pressure monitoring was performed in the refractory group at least twice. We considered a patient as refractory to treatment if a blood pressure <140/90 mmHg or <130/80 mmHg in diabetics were never achieved. Target organ damage was determined by an echocardiogram, and a funduscopy. Treatment adherence was confirmed in all the patients with analytic control and adherence tests. All the patients were treated according to the recommendations of the Joint National Committee VII and European Society of Cardiology guidelines with full doses. Informed consent was obtained from all subjects before participation. The study was approved by the Ethical Committee of University of Salamanca and was in accordance with the principles of the Declaration of Helsinki. Measurements Blood pressure was measured in the resting state in duplicates or triplicates using a Hawksley random zero mercury sphygmomanometer with an appropriate cuff size and verified three times with a Omron Automatic Blood Pressure Monitor, Model #HEM-773AC. 24 h ambulatory blood pressure monitoring was measured using a MAPA SPACE-LABS modelo 90207, Spacelabs Inc, US. Measurements were performed early in the morning before drawing of blood samples and with the participant in a supine position with slightly elevated head. Laboratory methods DNA was extracted from whole blood using a QIAamp DNA Blood Mini Kit (Qiagen). The presence of the studied alleles was determined by polymerase chain reaction ¿restriction fragment length polymorphism analysis. For each analysis we used the previously reported primers. Digested samples were separated on a 3% ethidium bromide¿stained agarose gels and visualized by UV transillumination. Statistical Analysis All genotype groups obeyed the Hardy¿Weinberg equilibrium. Normally distributed parametric data are expressed as mean ± standard deviation, and compared with Student¿s t-test. Chi Square or if appropriated Fisher exact test were applied to examine differences in allele frequencies between subjects. p < 0.05 was regarded as significant. Odds ratio and 95% confidence limits (OR 95% CI) were also calculated. All analyses were performed using Statistical Package for Social Science (SPSS) version 18.0. 3. RESULTS IL10 -627 C>A There were differences in the distribution of genotypes and alleles of the IL10 -627 C>A polymorphism between controls and hypertensive patients (p 0.005 OR 1.78 (1.19-2.64)). There were no differences between controlled hypertensive patients and resistant hypertension patients. No significant association was observed when we studied the distribution of IL10 -627 C>A genotypes and the mean value of inflammatory markers or target organ damage. IL12B -1188 A>C No significant association was observed when we studied the distribution of genotypes and alleles of the IL12B -1188 A>C polymorphism between resistant hypertensive and controlled hypertensive groups, and between controls and hypertensive patients. No significant association was observed when we studied the distribution IL12B -1188 A>C genotypes and the mean value of inflammatory markers or target organ damage. TNFA -238G>A No significant association was observed when we studied the distribution of genotypes and alleles of the TNFA -238G>A polymorphism between resistant hypertensive and controlled hypertensive groups, and between controls and hypertensive patients. No significant association was observed when we studied the distribution TNFA -238G>A genotypes and the mean value of inflammatory markers or target organ damage. TNFA-308 G>A No significant association was observed when we studied the distribution of genotypes and alleles of the TNFA-308 G>A polymorphism between controls and hypertensive patients. However there were differences in the distribution of genotypes and alleles of the TNFA-308 G>A polymorphism between controlled hypertensive patients and resistant hypertensive patients (p 0.02). No significant association was observed when we studied the distribution of TNFA-308 G>A genotypes and the mean value of inflammatory markers or target organ damage. CD40 -1C>T No significant association was observed when we studied the distribution of genotypes and alleles of the CD40 -1C>T polymorphism between resistant hypertensive and controlled hypertensive groups, and between controls and hypertensive patients. No significant association was observed when we studied the distribution CD40 -1C>T genotypes and the mean value of inflammatory markers or target organ damage. 4. CONCLUSIONS Main Objectives The population included in this study presents similar demographic features and cardiovascular risk factors profile to other populations described in Spain. The prevalence of left ventricular hypertrophy and retinopathy, as well as the number of antihypertensive drugs used and the pharmacological class of these drugs, are as expected for the type of population studied. There are differences in genotype distribution of polymorphisms of genes that encode inflammation molecules between hypertensive and non-hypertensive patients. There are differences in genotype distribution of polymorphisms of genes that encode inflammation molecules between hypertensive and resistant hypertensive patients. Secondary objectives Variations in IL10 -627C>A polymorphisms are associated with high blood pressure and variations in TNFA -308 G>A polymorphisms are associated to resistant hypertension. However, variations in IL12B -1188 A>C, TNFA -238G>A and CD40 -1C>T polymorphisms are associated neither to high blood pressure nor to resistant hypertension. There are no differences between controlled hypertensive patients and resistant hypertensive patients in the mean value of several inflammatory markers. In the same way there are no differences in the mean value of several inflammatory markers when patients are grouped by variations in IL10 -627 C>A, IL12B -1188 A>C, TNFA -238 G>A, TNFA -308G>A and CD40 -1 C>T polymorphisms. Mean values of inflammatory markers are not related to target organ damage. Variations in IL10 -627 C>A, IL12B -1188 A>C, TNFA -238 G>A, TNFA -308G>A and CD40 -1 C>T polymorphisms are not related to target organ damage. |
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