FACTORES DE RIESGOS CORONARIOS

Hipertensión Arterial Familiar

Los niveles de presión arterial (BP) se ven afectados por factores modificables como la sal, el consumo de alcohol, obesidad, actividad física y estrés crónico. Sin embargo, el 30 a 50% del riesgo individual de desarrollar HTA proviene de factores genéticos.
 
El antecedente familiar de HTA incrementa el riesgo de HTA por cuatro veces en comparación de quienes no tienen familiares de primer orden con HTA.
 
GENÉTICA
Las formas genéticas que participan en la HTA son:
 
- Monogénica
 
- Poligenética
 
- Epigenética
 
 
HTA por mutaciones monogénicas
La forma monogénica con patrón de herencia mendeliana es observada hasta en el 20 % de las familias con HTA. En la siguiente Tabla se enumeran las principales formas monogénicas mendelianas de HTA.
 

 

HTA MONOGÉNICA

 

SÍNDROME CLÍNICO

 

GEN

 

PROTEINA ALTERADA

Hiperaldosteronismo Familiar
I
CYP11B2
Aldosterone Syntethase
III
KCNJ5
G-Protein Coupled Inwardly
Rectifying Potassium Channel 4
IV
CACNA1H
Voltage Dependent T-Type Calcium Channel
Aldosteronismo Primario con Convulsiones y Alteraciones Neurológicas (PASNA)
CACNA1D
Voltage Dependent L-Type
Calcium Channel
Síndrome de Liddle
SCNN1B
SCNN1G
Epithelial Sodium Channel
Síndrome de Apparent
HSD11B2
11β-hydroxysteroid
Exceso de mineralocorticoide
 
Dehydrogenase
Síndrome de HTA con bradidactilia
PDE3A
Phosphodiesterase 3A
Hiperplasia Adrenal Congénita
CYP21
Steroid 21-hydroxylase
CYP17A1
Steroid 17a-monooxygenase
Síndrome de Gitelman
SLC12A3
Sodium Chloride Co-Transporter
Síndrome de Bartter
I
SLC12A1
Na-K-Cl Cotransporter
II
KCNJ1
Renal outer medullary K channel (ROMK)
III
CLCNKB
Chloride Channel Kb
IV
BSND
Barttin
V
CASR
Calcium-Sensing Receptor
Pseudohipoaldosteronismo I
SCNN1A
SCNN1B
SCNN1G
Epithelial Sodium Channel
NR3C2
Mineralocorticoid receptor
HTA exacerbada por embarazo
Pseudohipoaldosteronismo II
(Síndrome de Gordon)
WKN1
WKN4
Serine/Threonine Protein Kinase
KLHL3
CUL3
Kelch Like Family Member 3
Cullin 3

 

 

 

Hipertensión Arterial Familiar
HTA poligenética (facilitada por Polimorfismos -SNP-)
Una serie de Polimorfismos identificados principalmente por Estudios de Asociación y Ligamiento Genómico brindan susceptibilidad para el desarrollo de HTA. Algunas de las variables polimórficas se mencionan en la TABLA siguiente.
 
 

 

 POLIMORFISMOS PRESISPONENTES PARA HTA

SNP GEN LOCUS FUNCION
rs880315 CASZ 1p36.22 Zinc finger transcription factor that acts as tumour suppressor
rs4846049 MTHFR(3’) -NPPB 1p36.22 MTHFR catalyse the conversion of 5,10-MTH in 5-MTH and it is involved in homocysteine metabolism.NPPB encodes for the B natriuretic peptide.
rs17367504 MTHFR(5´)-NPPB
rs17030613 ST7L-CAPZA1 1p13.2 ST7L is a tumour suppressor factor. CAPZA1 regulates growth of actin filaments.
rs2932538 MOV10 1p13.2 A component of the RISC complex RNA helicase.
rs2004776 AGT 1q42.2 Pre-angiotensinogen.
rs16849225 FIGN-GRB14 2q24.3 FIGN regulates microtubules synthesis.GRB4 is a growth factor receptor-binding protein, which interacts with insulin receptors and insulin-like growth factors.
rs13082711 SLC4A7 3p24.1 Sodium bicarbonate co-transporter in neuronal cells, involved in visual and auditory transmission.
rs3774372 ULK4 3p22.1 Serine/Threonine kinase involved in neurite branching and elongation and neuronal migration.
rs319690 MAP4 3p21.31 Promotion of microtubule assembly.
rs419076 MECOM 3q26.2 Transcriptional regulator and oncoprotein involved in apoptosis, hematopoiesis, cell differentiation and proliferation.
rs1458038 FGF5 4q21.21 Fibroblast growth factor 5, involved in embryonic development, cell growth, morphogenesis, tissue repair, tumour growth and invasion.
rs13107325 SLC39A8 4q24 Mitochondrial cellular import of zinc, involved in inflammation.
rs6825911 ENPEP 4q25 Glutamyl aminopeptidase; associated with renal neoplasm.
rs13139571 GUCY1A3-1B3 4q32.1 Guanylate cyclase 1 soluble subunit , involved in nitric oxide pathway transduction.
rs1173771 NPR3-C5orf23 5p13.3 Natriuretic peptide receptor 3, responsible for clearing natriuretic peptides through endocytosis of the receptor.
rs11953630 EBF1 5q33.3 Early B-cell factor 1, associated with central obesity, B-lymphocytes differentiation and Hodgkin lymphoma.
rs1799945 HFE 6p22.2 Hemochromatosis protein; regulation of iron absorption.
rs805303 BAT2-BAT5 6p21.33 Genes cluster localized near genes for TNF
 and
, involved in inflammatory process and associated with insulin dependent diabetes and rheumatoid arthritis.
rs17477177 PIK3CG 7q22.3 A catalytic subunit of PI3K, involved in the immune response.
rs3918226 NOS3 7q36.1 Endothelial nitric oxide synthase.
rs2898290 BLK-GATA4 8p23.1 BLK is a tyrosine kinase involved in cell proliferation and differentiation. GATA4 is a zinc finger transcription factor involved in embryogenesis and myocardial differentiation and function.
rs1799998 CYP11B2 8q24.3 Aldosterone synthase.
rs4373814 CACNB2(5’) 10p12.33 Member of a voltage-gated calcium channel superfamily, associated with Brugada and Lambert-Eaton myasthenic syndrome.
rs1813353 CACNB2(3’)
rs4590817 C10orf107 10q21.2 Chromosome 10 open reading frame 107. Unknown function.
rs932764 PLCE1 10q23.33 Phospholipase involved in Ras pathway, associated with early onset nephrotic syndrome.
rs11191548 CYP17A1-NT5C2 10q24.32 CYP17A1 is the 17 hydroxylase, involved in the steroidogenic pathway; mutated in congenital adrenal hyperplasia.NT5C2 is a hydrolase involved in purine nucleotides metabolism.
rs1801253 ADRB1 10q25.3 Adrenoreceptor
1, which mediate physiological effects of epinephrine and norepinephrine.
rs7129220 ADM 11p15.4 Pre-hormone cleaved in adrenomedullin and pro-adrenomedullin, which act as vasodilator, hormone secretion regulators and angiogenesis promoters.
rs381815 PLEKHA7 11p15.2 Pleckstrin homology domain containing A7 associated with breast carcinomas and glaucoma
rs633185 FLJ32810-TMEM133 11q22.1 FLJ32810 is a regulator of vascular tone.TMEM133 is a transmembrane protein; unknown function.
rs17249754 ATP2B1 12q21.33 Calcium ATPase with critical role in intracellular Ca2+ homeostasis
rs3184504 SH2B3 12q24.12 Signalling activities by growth factor and cytokine receptors; associated with celiac disease and insulin-dependent diabetes.
rs11066280 ALDH2 12q24.12 Mitochondrial aldehyde dehydrogenase 2, involved in the oxidative pathway of alcohol metabolism.
rs10850411 TBX5-TBX3 12q24.21 T-box protein family encoding for transcriptional factors regulating heart and limbs developmental processes.
rs1378942 CYP1A1-ULK3 15q24.1 CYP1A1 is a mono-oxygenases involved in drug catabolism and synthesis of cholesterol, steroid and other lipids.ULK3 is a serine/threonine kinase; unknown function.
rs2521501 FURIN-FES 15q26.1 FURIN is a protease, involved in the catabolism of PTH, TGF
1 and other growth factors. FES is a tyrosine kinase, involved in hematopoiesis and cytokine receptor signalling.
rs13333226 UMOD 16p12.3 Regulation of renal sodium handling. See text.
rs17608766 GOSR2 17q21.32 Trafficking membrane protein.
rs12940887 ZNF652 17q21.32 Zinc finger protein, associated with breast and prostate cancer.
rs1327235 JAG1 20p12.2 Hematopoiesis regulation through notch 1 signalling.
rs6015450 GNAS-EDN3 20q13.32 GNAS is a G-protein that activates adenylyl cyclase with a wide variety of cellular responses. EDN3 encode for endothelin 3, implicated also in neural crest-derived cell lineages differentiation.
 
Gen: se refiere al de proximidad del SNP