Yong-Pil Cheon; Myoungsook Lee

doi:10.4163/jnh.2017.50.3.217

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Cheon and Lee: Salt-sensitive genes and their relation to obesity∗

Review

J Nutr Health 2017;50(3):217-224.

Published online: 20 January 2017

DOI: https://doi.org/10.4163/jnh.2017.50.3.217

Salt-sensitive genes and their relation to obesity^∗

Yong-Pil Cheon¹, Myoungsook Lee^†

¹Division of Developmental Biology and Physiology, School of Bioscience and Chemistry, Sungshin Women's University, Seoul 01133, Korea

²Department of Food and Nutrition, Sungshin Women's University, Seoul 01133, Korea

^†To whom correspondence should be addressed. tel: +82-2-920-7211, E-mail: mlee@sungshin.ac.kr

^∗ ∗This work was supported by grants from Sungshin Women's university Research Grant of 2016.

Received 19 May 2017 Revised 29 May 2017 Accepted 16 June 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Although it is well known thatmortality and morbidity due to cardiovascular diseases are higher in salt-sensitive subjects than in salt-resistant subjects, their underlying mechanisms related to obesity remain unclear. Here, we focused on salt-sensitive gene variants unrelated to monogenic obesity that interacted with sodium intake in humans. Methods: This review was written based on the modified 3^rd step of Khans' systematic review. Instead of the literature, subject genes were based on candidate genes screened from our preliminary Genome-Wide Association Study (GWAS). Finally, literature related to five genes strongly associated with salt sensitivity were analyzed to elucidate the mechanism of obesity. Results: Salt sensitivity is a measure of how blood pressure responds to salt intake, and people are either salt-sensitive or salt-resistant. Otherwise, dietary sodium restriction may not be beneficial for everyone since salt sensitivity may be associated with inherited susceptibility. According to our previous GWAS studies, 10 candidate genes and 11 single nucleotide polymorphisms (SNPs) associated with salt sensitivity were suggested, including angiotensin converting enzyme (ACE), α-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily β-2 (CYP11β-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), 11β-hydroxysteroid dehydrogenase type-2 (HSD 11β-2), neural precursor cell-expressed developmentally down regulated 4 like (NEDD4L), and solute carrier family 12(sodium/chloride transporters)-member 3 (SLC 12A3). We found that polymorphisms of salt-sensitive genes such as ACE, CYP11β-2, GRK4, SLC12A3, and GNB3 may be positively associated with human obesity. Conclusion: Despite gender, ethnic, and age differences in genetics studies, hypertensive obese children and adults who are carriers of specific salt-sensitive genes are recommended to reduce their sodium intake. We believe that our findings can contribute to the prevention of early-onset of chronic diseases in obese children by facilitating personalized diet-management of obesity from childhood to adulthood.

Keywords: sodium-sensitive genes, GWAS, obesity, hypertension

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Table 1.

The characteristics of the candidate genes on the prevalence of salt-sensitive hypertensive obesity

Gene	locus	SNP	rs number	Gene Summary
Angiotensin converted enzyme (ACE)	17q23.3	I/D	rs4341	• Involved in catalyzing the conversion of angiotensin I into a potent vasopressor and aldosterone-stimulating peptide, angiotensin II (Key role in RAAS.) • Associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme or cardiovascular pathophysiologies
α-addicin1 (ADD1)	4p16.3	G460W	rs4961	• A family of cytoskeleton proteins encoded by three genes (α-, β- & γ-) • Binds with high affinity to Ca(2+)/calmodulin with protein kinases A & C
Angiotensinogen (AGT)	1q42.2	M235T	rs699	• Encoded by this gene, pre-angiotensinogen or angiotensinogen precursor, is expressed in the liver and it is involved in the pathogenesis of essential hypertension and preeclampsia. • Mutations in this gene are associated with susceptibility to essential hypertension, a severe disorder of renal tubular development, non-familial structural atrial fibrillation, and inflammatory bowel disease.
Cytochrome P450, family 11 subfamily B polypeptide 2 (CYP11β-2)	8q24.3	C-344T	rs1799998	• Encodes a member of the cytochrome P450 superfamily of enzymes located in mitochondrial inner membrane • The cytochrome P450s are monooxygenases involved in drug metabolism and has steroid 18-hydroxylase to synthesize aldosterone and 18-oxocortisol as well as 11β-hydroxylase.• Mutations in this gene cause corticosterone methyl oxidase deficiency.
Epithelial sodium channel (ENaC)	α (12p13) β/γ (16p12)	SCNN1A /SCNN1G	rs11064153/ rs4401050	• The α subunit of ENaC, encoded by SCNN1A on 12p13, supports sodium conductance, whereas the β and γ subunits encoded by SCNN1B and SCNN1G on 16p12 appear to have a structural and/or regulatory role when coexpressed with the α subunit. • Multiple mutations in the ENaC β and γ subunits have been related to Liddle syndrome, a monogenic disorder characterized by severe hypertension and low K+ concentrations.
G-protein β3 subunit (GNB3)	12p13.31	C825T	rs5443	• Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. • A SNP C825T in this gene is associated with essential hypertension and obesity.
G protein-coupled receptor kinases type 4 (GRK4)	4p16.3	A142V /A486V	rs1024323 /rs1801058	• Encodes a member of G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family • Linked to both genetic and acquired hypertension
Neural precursor cell-expressed developmentally down regulated-4 like (NEDD4L)	18q21.31	–	rs2288774	• Encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases • The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC.
				• SNP in this gene may be associated with essential hypertension.
Solute carrier family 12 (sodium/ chloride transporters)-member 3 (SLC12A3)	16q13	R904Q	rs11643718	• Encodes a renal thiazide-sensitive Na-Cl cotransporter that is important for electrolyte homeostasis • Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemia combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal BP.

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