Elevated blood pressure: Our family’s fault? The genetics of essential hypertension

Table 1 Genetic associations with essential hypertension according to cohort

Cohort	Genes
Framingham offspring cohort	CCL20-WDR69, CDH13, TGFBR2, STK39
Amish cohort	STK39
AGEN	NPR3, CYP17A1, FGF5, MTHFR, NPPA, NPPB, ATP2B1, CSK, ZNF652
BP-extremes	UMOD
BRIGHT	BCAT1
CARe	c21orf91, GPR98 and ARRDC3
CBPgen	CYP17A1, CACNB2, PLEKHA7, SH2B3, TBX3, TBX 4, TBX5, ULK4
CHARGE	CPLX3, PLEKHA7, TBX3, UMOD, CYP17A1, CSK-ULK3, CYP1A2, NT5C2, CYP171A, PLCD3, SH2B3-ATXN2, CACNB2, SH2B3, TBX3, TBX4, TBX5, ULK4, c10orf107, BLK-GATA4, CASZ1, FGF5, MTHFR, NPPA, NPPB, ATP2B1, CSK
FHS	ANKMY, FOXD3
GBPgen	UMOD, CSK-ULK3, CYP1A2, NT5C2, CYP171A, PLCD3, SH2B3-ATXN2,ATXN2, c10orf107, GNAS-EDN3, MECOM (MDS1 locus), FGF5, MTHFR, NPPA, NPPB, ATP2B1, CSK, ZNF652
GENE-centric	SOX6, AGT, LSP1-TNNT3, MTHFR, NPPA, NPPB, ATP2B1, HFE
Health2	ATP2B1
HUFS	IPO7, MYLIP, PMS1, SLC24A4, YWHAZ, CACANA1H
Hypergenes	NOS3
ICBP	ADAMTS-8, ADM, BAT2-BAT5, CHIC2-PDGFRA1, EBF1, FES, FIGN, FLJ32810-TMEM133, GOSR2, GUCY1A3-GUCY1B3, JAG1, MOV10, NOV, NPR3-c5orf23, PIK3CG, PLCE1, SLC39A8, SLC4A7, NPR3, CYP17A1, CACNB2, PLEKHA7, SH2B3, TBX3-TBX5, ULK4, GNAS-EDN3, MECOM (MDS1 locus), FGF5, MTHFR, NPPA, NPPB, ATP2B1, CSK, ZNF652, HFE
KARE	ATP2B1
KORA S3	CCNG1
Suita study	CCBE1
WGHS	BLK-GATA4, CASZ1
Study reference not mentioned in article	ADD1, ADD2, ADRB1, ADRB2, APOB, CACNA1A, CACNA1C, CLCNKB, CYBA, CYP11B2, CYP2C8, EDN1, EDNRA, GNB3, SCNN1A, SCNN1B, SCNN1G, SGK1, KCNJ1, ACE, ADRB2, AGT, APLNR, BDKRB2, CAPN13, CYP11B2, CYP19A, GNB3, MMP3

Bolded genes are ones are found in multiple cohorts. The genes are identified and listed according to their respective cohorts, with a separate category to identify genes without specific references in any of the articles reviewed. Specific locations for the genes are provided where possible. Novel genes are identified, as are genes associated with physical properties.

Table 2 Genes with their identified physiological pathway and genes identified with their associated physiological functions related to essential hypertension

Genes	Pathway related to EH
NOS3	RAAS pathway[22]
SH2B3	Endothelial cell function[17]
AGT	Renal electrolyte balance[17]
NPPA	Control of extracellular fluid volume and electrolyte homeostasis[23]
NPPB	Involved in vasorelaxation and inhibition of renin and aldosterone[24]
NPR3	Involved with regulating blood volume and pressure, pulmonary hypertension, and cardiac function[25]
UMOD	Constitutive inhibitor of calcium crystallization in renal fluids[26]
CYP17A1	Involved with steroid/aldosterone synthesis. Enzyme dysfunction leads to increased levels of mineralocorticoid activating hormones[17]
ATP2B1	Codes for enzymes that have a critical role in intracellular calcium homeostasis[27]
CACNB2	Encodes for a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily[28]
SLC24A4	Encodes for a member of the potassium-dependent sodium/calcium exchanger protein family[29]
YWHAZ	Protein interacts with insulin receptor substrate 1 protein, suggesting a role in regulating insulin sensitivity[30]
ADAMTS-8	Enzyme encoded by the gene disrupts angiogenesis in vivo[31]
ADM	Protein encoded by gene may function as a hormone in circulation control[32]
c5 site between SUB1 and NPR3	SNP associated with SBP
	NPR3 encodes natriuretic peptide receptor C/guanylate cyclase C for natriuretic peptide clearance[33-35]
	Also found relationship with DBP
CACANA1H	Codes for α1 subunit of voltage-dependent calcium channel for heart contractions and associated with SBP in African Americans[36]
ENPEP	Facilitates production of angiotensinII in RAAS pathway and associated with SBP and DBP[33]
ADD1 and ACE	ADD1 codes for α-adducin protein that interacts with sodium channel of Na/K co-transporter and Na/K ATPase[37]
	Angiotensin converting enzyme produces angiotensin-converting enzyme which converts angiotensin I to angiotensin II in RAAS pathway[38]
ADD2	β-adducin is a cytoskeletal actin-binding protein implicated in glomerular lesions[39]
CYP11B2	Contributes to aldosterone synthesis in RAAS pathway[40]
AGT	Encodes angiotensinogen in RAAS pathway[41]
LOC344371 and RASGRP3	Activation decreases vascular responsiveness to endothelin-1 and angiotensin II in rats[41]
EDN3	Endothelin-3 involved in vasoconstriction[42]
BCAT1	Associated with salt sensitivity[43]
CASZ1	Zinc-finger transcription factor that is associated with DBP[33]
ADRB2	Ion channel involved with regulation of vasoconstriction[12]
CYP11B2	Enzymatic defects results in decreased aldosterone and increased salt-wasting[12,17]
MMP3	Gene variants affect arterial stiffness and endothelial function[44]
NR3C2	Involved with aldosterone signaling[12]
SCNN1B	C terminus deletion leads to reduced ENaC clearance and increased ENaC activity[12]
APLNR	Mediator of cardiovascular disease[45]
BDKRB2	Involved in catecholamine synthesis[46]
MTHFS	Involved with catecholamine binding[47]
SOX6	Required in transcription for maintenance of cardiac and skeletal muscle cells[17]
CACNA1A	Involved with regulating SBP[48]
CCNG1	Involved with regulation of SBP and DBP and is component of regulating hypertension[15]
CPLX3	Involved with regulating DBP[15]
CSK	Cytoplasmic tyrosine kinase involved with angiotensin II-dependent vascular smooth muscle cell contraction[17]
CACNA1C	Regulates calcium influx after depolarization[49]
CLCNKB	Involved in renal salt absorption[50]
EDN1	Endothelin-1 involved in vasoconstriction[51]
EDNRA	Endothelin receptor type A involved in vasoconstriction[52]
KCNJ1	Potassium channel involved with potassium homeostasis[53]
SCNN1A	Involved with renal sodium regulation[54]
SCNN1B	Involved with renal sodium regulation[55]
SCNN1G	Involved with renal sodium regulation[56]
SGK1	Activation of certain potassium, sodium and chloride channels, playing a role in cellular stress response[57]
SLC12A1	Cotransporter involved in sodium and chloride reabsorption in the distal convoluted tubule[58]
SLC12A3	Cotransporter involved in sodium and chloride reabsorption in the loop of Henle[59]
TNNT3	Involved in calcium-induced muscle contraction[60]
WNK1	Kinase involved with sodium and chloride transport[61]
WNK4	Kinase regulates balance between sodium chloride and potassium reabsorption in kidneys[62]
GOSR2	Interacts with target-localized SNAREs, allowing angiotensinogen to move between Golgi compartments, possibly leading to vasoconstriction[63]
GUCY1B3	Receptor for nitric oxide involved with vasodilation[64]
ATXN2	Possible association with regulation of GFR[65]
SLC4A7	Possible transporter of sodium and bicarbonate ions[66]
CDH13	Regulates endothelial cell growth[67]
Identifier information	Gene
Non- European genes	NPR3, IPO7, MYLIP, PMS1, SLC24A4, TBX3, YWHAZ, FIGN-GRB14, ALDH2, c5 site between SUB1 and NPR3, CACANA1H, SNP upstream of CCBE1, ENPEP, ST7L-CAPZA1
Gene-gene interaction	ADD1 and ACE, ADD1 and ADD2, ADD1 and CYP11B2, AGT and ACE, c20q12, IMPG1, LOC344371 and RASGRP3, PCDH15, NPR3-c5orf23, CSK-ULK3, BAT2-BAT5, BLK-GATA4, GNAS-EDN3
Gene- environment interaction	Body Mass Index: ADD1, ADRB2, CAPN13, CYP11B2, CYP19A1, MMP3 Black, Male: AGT Level of physical activity: GNB3, NR3C2, SCNN1B, APLNR, BDKRB2 Oral contraceptive use: COL25A1 Preterm birth: MTHFS
Unknown function/ function could not be determined	GNAS-EDN3, NPR3-c5orf23, BLK-GATA4, ST7L-CAPZA1, CSK-ULK3, FIGN-GRB14, c10orf107, c21orf91, LSP1-TNNT3, GNAS-EDN3, BAT2, IPO7, MYLIP, PMS1, TBX3, TBX4, TBX5, ANKMY, BAT2, BAT3, BAT4, BAT5, ALDH2, SNP upstream of CCBE1, BCAT1, PCDH15, c20q12, IMPG1, CAPN13, CYP19A1, GNB3, COL25A1, PCDH15, IMPG1, c5 site between SUB1 and NPR3, CHIC2-PDGRA1, APOB, HFE, CYPBA, CYP1A2, CYP2C8, EBF1, FES, FGF5, FIGN, FLJ32810, GNB3, LSP1, NOS3, TMEM133, FOXD3, GPR98, ARRDC3, GUCY1A3, JAG1, MECOM (MD1 locus), MOV10, NOV, NPR3-c5orf23, NT5C2-CYP171A, PIK3CG, PLCD3, PLCE1, PLEKHA7, RPL6-PTPN11-ALDH2, SLC39A8, ULK4, ZNF652, CCL20, WDR69, TGFBR2, STK39

Only genes with pathways related to EH were identified. Genes identified with their associated physiological functions associated with EH. If there were genes that coded for proteins, but these proteins were not found to affect EH, then it was listed as unknown function or the function could not be determined. Genes with hyphens indicate genome wide association studies associated genomic regionsin, in which the genetic pathway could not be determined and properly evaluated for its involvement with EH. EH: Essential hypertension; RAAS: Renin-angiotensin-aldosterone system; SBP: Stolic blood pressure; DBP: Diastolic blood pressure.

Table 3 DNA methylation and histone modification associated with essential hypertension

Ref.	Study	Subjects	Results	Site of modification and type
Smolarek et al[68]		Humans	5-mC significantly higher in healthy subjects than entire group of patients with EH	N/A
Wang et al[69]		Humans	Increased methylation levels observed at 2-CpG sites in comparison with normotensive controls	SULF1: Methylation
Liang et al[70]		Humans	Regulation of renal sodium reabsorption β-2 adrenergic stimulation → inhibition of histone deacetylase-8 in kidney → increased histone acetylation and decreased genetic transcription of WNK4 caused increased blood pressure 11β-hydroxysteroid dehydrogenase type 2–converts active glucocorticoids to inactive glucocorticoids Promoter methylation of HSD11B2 gene decreased expression of renal 11β-hydroxysteroid dehydrogenase type 2 affects regulation of volume and BP homeostasis ENaCα-epithelial sodium channel–affects Na+ reabsorption in the distal nephron Proposed mechanism: Methylation of Lys79 of histone H3 suppresses ENaCα transcription ACE1-Angiotensin-converting enzyme ACE1-up-regulated in association with increased binding of histone 3 acetylation (H3Ac) and 4th lysine trimethylation (H3K4me3) and in association with decreased binding of histone ninth lysine residue demethylation (H3K9me2)	WNK4: Decreased transcription and increased histone acetylation HSD11B2: Promoter methylation ENaCα: Methylation of Lys79 of histone H3 H3K4me3: Histone 3 acetylation and 4th lysine trimethylation. H3K9me2: Decreased binding of histone 9th lysine residue demethylation
Udali et al[71]	Friso et al[72]	Humans	11β-hydroxysteroid dehydrogenase 2 methylation at HSD11B2 promoter in DNA of PBMCs of hypertensive patients inversely related to enzyme function Promoter methylation of HSD11B2 gene plays a role in HTN	HSD11B2: Methylation in promoter region
	Lee et al[73]	Rats	Na+-K+-2 Cl- cotransporter 1 (NKCC1) Methylation status of NKCC1 promoter–elevated in hearts of spontaneously hypertensive rats SHRs–significant hypomethylation of NKCC1 associated with increase in gene expression contributing to HTN	NKCC1: Methylation in promoter region NKCC1: Hypomethylation in promoter region
	Riviere et al[74]	Human endothelial cell lines and rats in vivo	Somatic angiotensin-converting enzyme (= ACE1) Promoter methylation levels: Higher levels of methylation associated with transcriptional repression Therefore hypomethylation of promoter region of sACE could contribute to HTN	sACE: Methylation in promoter region
Millis[75]		Human	Methyl CpG binding protein-2 (MECP-2) Methylates and thereby silences the expression of the norepinephrine transporter gene Phenyl-ethanolamine N-methyltransferase (PMNT)–converts Norepinephrine into Epinephrine Also mimics gene-silencing actions of MECP-2 Leads to increased synaptic levels of catecholamines (increased Epinephrine release and decreased Norepinephrine reuptake) CTGF Lysine methyltransferase that methylates the histone H3K79 site of nucleosomes that inhibits the expression of CTGF (in the cells of the collecting ducts)	MECP-2: Methylation PMNT: Methylation H3K79: Methylation of histone site of nucleosomes

As demonstrated in Table 3, many of the genes identified undergo methylation. If the reviews discuss results from individual studies, then the separate studies are placed in the second column. The results are listed based on the gene/site of modification, along with a description of what occurs as a result of the modification. The last column provides a summary of the gene/site of modification and the type of modification that occurs at that particular site. CTGF: Connective tissue growth factor.

Table 4 MiRNA targets associated with essential hypertension

Ref.	Subjects	Results	miRNA targets
Xu et al[76]	Human plasma	hcmv-miR-UL112; miR-605; miR-623; let-7e;miR-516b; miR-600; kshv-miR-K12-6-3p; miR-602; miR-1252 miR-296-5p; miR-133b; miR-30 d; miR-625*; miR- 1236; miR-518b; miR-1227; miR-664; miR-615-5p; miR-18b*; miR- 1249; miR-324-3p; ebv-miRBART17-3p; miR-634; ebvmiR-miRBART19-5p; miR-486-5p; kshvmiR-K12-10a; kshv-miR-K12-10b	INF-1 is direct target of hmcv-miR-UL112 Indicates link between CMV infection and EH
Batkai et al[77]	Human	Endothelial miRNA miR-126 miR-217 miR-122 miR-21 miR-24 miR-27b, -130a, -210, -378, -17–92, let-7f miR-15, -16, -20a, -20b, -24, -221, -222 Renal miRNA miR-29b miR-200a, miR-200b, miR-141, miR-429, miR-205, miR-192 miRNA targeting RAAS miR-155 miR-526b and -578 miR-34a, and -34c miR-765 miR-383 miR-9 miR-124 and miR-135a miRNA targeting smooth muscle cells miR-143 and miR-145 miR-21 miR-21, -26b, -98, and -1826 miR-221 and -222 miRNA in other etiologic factors miR-296-5p, let-7e, hcmv-miR-UL112 hcmv-miR-UL1 miR-637	SPRED-1; PIK3 regulatory subunit-2; VCAM-1; CXCL12; RhoB SirT1 SLC7A1 Nitric oxide pathway Hypoxia-induced mechanism Pro-angiogenic Anti-angiogenic Fibrotic pathway; collagen genes; Mmp2; Itgb1 Biomarkers of nephrosclerosis AGTR1AVPR1ABDKRB2TBXA2RNR3C2NFATc3NR3C2 Actin stress fibers; ACE; KLF5; myocardin; MRTF-B; calmodulin kinase II-δ PTEN; Bcl-2; cGMP signaling Nitric oxide and ANP pathway p27(Kip1), p57(Kip2) and/or c-kit Association with hypertension IRF-1 ATP6V0A1, chromaffin granule function
Fung et al[78]	Human	miR-155	Suppress expression of AGTR1

Table 4 demonstrates how miRNAs affect different aspects of blood pressure regulation. Also, there appears to be a link between cytomegalovirus (CMV) infections and essential hypertension; miRNA has been identified as a possible mediator of this connection. The asterisk identified for some miRNAs[78] are not defined in the original article, but are assumed to be a part of the proper notation for that miRNA. EH: Essential hypertension.