Is There a Role for Genomics in the Management of Hypertension?
Abstract
:1. Introduction
2. Monogenic Forms of Hypertension
3. Large-Scale Genome-Wide Associations Studies
4. Epigenetic Modifications in Hypertensive Patients
5. Pharmacogenomics
6. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
References
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Monogenic Syndrome | Inheritance | Gene | Locus | Phenotype | Therapeutic Indications |
---|---|---|---|---|---|
Pheochromocytomas/Paragangliomas | Autosomal dominant | SDHA SDHB SDHC SDHD SDHAF2 TMEM127 MAX | 5p15.3 1p36.13 1q23.3 11q23.1 11q12.2 2q11.2 14q23.3 | Paragangliomas or pheochromocytomas. | Surgery/α adrenergic blockers |
von Hippel–Lindau syndrome | Autosomal dominant | VHL | 3p25.3 | Retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma, pheochromocytomas, pancreatic tumours. | Surgery/α adrenergic blockers (for pheochromocytoma) |
Multiple endocrine neoplasia, type 2A | Autosomal dominant | RET | 10q11.2 | Medullary thyroid carcinoma, parathyroid adenomas, pheochromocytoma. | Surgery/α adrenergic blockers (for pheochromocytoma) |
Neurofibromatosis type 1 | Autosomal dominant | NF1 | 17q11.2 | Skin pigmentation, skin neurofibromas and brain tumours. Pheochromocytoma. | Surgery/α adrenergic blockers (for pheochromocytoma) |
GRA–familial hyperaldosteronism type 1 | Autosomal dominant | CYP11B1 CYP11B2 | 8q24.3 | Familial form of PA | Glucocorticoids |
Familial hyperaldosteronism type 2 | Autosomal dominant | N.A. | 7p22.3-7p22.1 | Familial form of PA | Mineralocorticoid receptor antagonist/unilateral adrenalectomy (for APA) |
Familial hyperaldosteronism type 3 | Autosomal dominant | KCNJ5 | 8q24.3 | Severe form of PA with bilateral adrenal hyperplasia | Bilateral adrenalectomy in drug-resistant patients |
Familial hyperaldosteronism type 4 | Autosomal dominant | CACNA1H | 16p13.3 | Familial form of PA | Mineralocorticoid receptor antagonist |
PASNA syndrome | N.A. | CACNA1D | 3p21.3 | PA and complex neurological disorders (seizures and functional neurological abnormalities, resembling cerebral palsy). | N.A. |
Sporadic APA | N.A. | KCNJ5 ATP1A1 ATP2B3 CACNA1D | 11q24.3 1p31.1 Xq28 3p21.3 | Sporadic forms of PA. | Adrenalectomy |
Pseudohypoaldosteronism, type 2 (Gordon’s syndrome) | Autosomal dominant (*dominant/recessive) | WNK1 WNK4 CUL3 KLHL3 * | 12p12.3 17q21.2 2q36.2 5q31.2 | HyperK+ hyperCl− metabolic acidosis. Low PRA and low-normal AC. | Thiazide diuretics |
Apparent mineralocorticoid excess (AME) Syndrome | Autosomal recessive | HSD11B2 | 16q22.1 | Hypokalemia. Low PRA and AC. Increased cortisol/cortisone ratio. | Mineralocorticoid receptor antagonist |
Liddle’s syndrome | Autosomal dominant | SCNN1B, SCNN1G | 16p12.2 | ENaC constitutive activation. Hypokalemia. Low PRA and AC. | ENaC blockers (amiloride, triamterene) |
11β-hydroxylase deficiency | Autosomal recessive | CYP11B1 | 8q24.3 | Virilisation, short stature. Low PRA and AC. HypoK+ alkalosis. | Glucocorticoids to inhibit ACTH-driven adrenal hyperpasia |
17α-hydroxylase deficiency | Autosomal recessive | CYP17A1 | 10q24.3 | HypoK+ alkalosis. Absent sexual maturation. Androgen deficiency. | Glucocorticoids to inhibit ACTH-driven adrenal hyperpasia |
Hypertension with brachydactyly Type E | Autosomal dominant | PDE3A | 12p12.3 12p12.1 | Brachydactyly, short phalanges and metacarpals. | N.A. |
Hypertension exacerbated by pregnancy | Autosomal dominant | NR3C2 | 4q31.23 | Early onset hypertension exacerbated during pregnancy. | N.A. |
SNPs | Nearest Gene(s) | Position | Encoded Protein Function |
---|---|---|---|
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 α, 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 α and β, 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 17α 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 β1, 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, TGFβ1 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. |
Epigenetic Modification | Findings/Effectors | Reference |
---|---|---|
DNA methylation | Amount of 5mC in DNA inversely proportional to BP levels | Smolarek et al. [57] |
HSD11B2 promoter methylation associated with HTN onset at young age | Friso et al. [58] | |
RAA system gene hypomethylation associated with HTN in offspring, BP regulation and ACE inhibitor response. | Goyal et al. [59] Pei et al. [61] Rivière et al. [62] | |
Hypomethylation of SIC2A2 associated with NKCC1 overexpression, Na+ reabsorption and HTN. | Lee et al. [60] | |
Histones acetylation/deacetylation | Acetylation/deacetylation of endothelial cells nucleosomes regulate eNOS expression | Fish et al. [63] |
Nucleosomes modifications regulate ACE transcription | Lee et al. [64] | |
Nucleosomes modifications regulate NKCC1 transcription and sodium renal reabsorption | Cho et al. [65] | |
WNK4 down-regulation determines histones acetylation and NCC overexpression. | Mu et al. [66] | |
Non coding RNA | miR-27a and -27b down-regulate ACE1 mRNA | Goyal et al. [59] |
miR-155 down-regulate AGTR1 mRNA | Cheng et al. [67] | |
miR-181a and -663 down-regulate renin mRNA and are under-expressed in HTN-patients | Marquez et al. [68] | |
miR-425 down-regulate NNPA, leading to ANP under-production and salt overload | Arora et al. [69] |
Genetic Association | Effect | Reference |
---|---|---|
NEDD4L, PRKCA, GNAS-EDN3, TET2, CSMD1, HSD3B1 | Enhanced response to thiazide diuretics | Dahlberg et al. [85] Duarte et al. [86] Chittani et al. [87] Salvi et al. [88] |
ADRB1 | Enhanced response to metoprolol | Ganesh et al. [89] |
ADRB1 | Enhanced response to carvedilol | Mialet-Perez et al. [90] |
ADRB1 | Greater mortality in patients treated with verapamil than with atenolol | Karlsson et al. [91] |
CYP2D6 | Decrease in metoprolol clearance | Rau et al. [92] |
GRK4 | Enhanced response to atenolol | Bhatnagar et al. [93] |
SIGLEC12, A1BG, F5 | Higher risk of treatment-related adverse CV outcomes in patients treated with CCB | Hannila et al. [94] |
CAMK1D | Enhanced response to losartan | Frau et al. [75] |
ADD1 | Enhanced response to rostafuroxin | Staessen et al. [79] |
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Burrello, J.; Monticone, S.; Buffolo, F.; Tetti, M.; Veglio, F.; Williams, T.A.; Mulatero, P. Is There a Role for Genomics in the Management of Hypertension? Int. J. Mol. Sci. 2017, 18, 1131. https://doi.org/10.3390/ijms18061131
Burrello J, Monticone S, Buffolo F, Tetti M, Veglio F, Williams TA, Mulatero P. Is There a Role for Genomics in the Management of Hypertension? International Journal of Molecular Sciences. 2017; 18(6):1131. https://doi.org/10.3390/ijms18061131
Chicago/Turabian StyleBurrello, Jacopo, Silvia Monticone, Fabrizio Buffolo, Martina Tetti, Franco Veglio, Tracy A. Williams, and Paolo Mulatero. 2017. "Is There a Role for Genomics in the Management of Hypertension?" International Journal of Molecular Sciences 18, no. 6: 1131. https://doi.org/10.3390/ijms18061131