Browse > Article
http://dx.doi.org/10.4163/jnh.2017.50.3.217

Salt-sensitive genes and their relation to obesity  

Cheon, Yong-Pil (Division of Developmental Biology and Physiology, School of Bioscience and Chemistry, Sungshin Women's University)
Lee, Myoungsook (Department of Food and Nutrition, Sungshin Women's University)
Publication Information
Journal of Nutrition and Health / v.50, no.3, 2017 , pp. 217-224 More about this Journal
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), ${\alpha}$-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily ${\beta}$-2 ($CYP11{\beta}$-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), $11{\beta}$-hydroxysteroid dehydrogenase type-2 (HSD $11{\beta}$-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, $CYP11{\beta}$-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;
Citations & Related Records
Times Cited By KSCI : 4  (Citation Analysis)
연도 인용수 순위
1 Lee M, Kwon DY, Park J. The impacts of the interaction of genetic variation, CYP11a2 and NEDD4L, with sodium intake on pediatric obesity with gender difference: a 3-year panel study. Int J Obes (Lond) 2017; 41(4): 542-550.   DOI
2 Lefkowitz RJ. G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization. J Biol Chem 1998; 273(30): 18677-18680.   DOI
3 Styne DM. Childhood and adolescent obesity. Prevalence and significance. Pediatr Clin North Am 2001; 48(4): 823-854.   DOI
4 Bengra C, Mifflin TE, Khripin Y, Manunta P, Williams SM, Jose PA, Felder RA. Genotyping of essential hypertension single-nucleotide polymorphisms by a homogeneous PCR method with universal energy transfer primers. Clin Chem 2002; 48(12): 2131-2140.
5 Felder RA, Jose PA. Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity. Nat Clin Pract Nephrol 2006; 2(11): 637-650.   DOI
6 Trivedi M, Lokhandwala MF. Rosiglitazone restores renal D1A receptor-Gs protein coupling by reducing receptor hyperphosphorylation in obese rats. Am J Physiol Renal Physiol 2005; 289(2): F298-F304.   DOI
7 Jose PA, Soares-da-Silva P, Eisner GM, Felder RA. Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation. Biochim Biophys Acta 2010; 1802(12): 1259-1267.   DOI
8 Gu D, Su S, Ge D, Chen S, Huang J, Li B, Chen R, Qiang B. Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese. Hypertension 2006; 47(6): 1147-1154.   DOI
9 Song DY, Park JE, Shim JE, Lee JE. Trends in the major dish groups and food groups contributing to sodium intake in the Korea National Health and Nutrition Examination Survey 1998-2010. Korean J Nutr 2013; 46(1): 72-85.   DOI
10 Libuda L, Kersting M, Alexy U. Consumption of dietary salt measured by urinary sodium excretion and its association with body weight status in healthy children and adolescents. Public Health Nutr 2012; 15(3): 433-441.   DOI
11 Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 1988; 297(6644): 319-328.   DOI
12 Hoffmann IS, Cubeddu LX. Salt and the metabolic syndrome. Nutr Metab Cardiovasc Dis 2009; 19(2): 123-128.   DOI
13 Kitiyakara C, Chabrashvili T, Chen Y, Blau J, Karber A, Aslam S, Welch WJ, Wilcox CS. Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol 2003; 14(11): 2775-2782.   DOI
14 Oberleithner H, Riethmuller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci U S A 2007; 104(41): 16281-16286.   DOI
15 World Health Organization. Guideline: sodium intake for adults and children. Geneva: World Health Organization; 2012.
16 Hoorn EJ, Ellison DH. WNK kinases and the kidney. Exp Cell Res 2012; 318(9): 1020-1026.   DOI
17 Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jonsson A, Wanby P, Lippi G, Minuz P, Hulthen LU, Aurell M, Melander O. Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet 2008; 17(3): 413-418.   DOI
18 Melander O, Orho-Melander M, Bengtsson K, Lindblad U, Rastam L, Groop L, Hulthen UL. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension 2000; 36(3): 389-394.   DOI
19 Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008; 3: 22.   DOI
20 He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials. Lancet 2011; 378(9789): 380-382.   DOI
21 Dengel DR, Brown MD, Ferrell RE, Supiano MA. Role of angiotensin converting enzyme genotype in sodium sensitivity in older hypertensives. Am J Hypertens 2001; 14(12): 1178-1184.   DOI
22 Arroyo JP, Lagnaz D, Ronzaud C, Vazquez N, Ko BS, Moddes L, Ruffieux-Daidie D, Hausel P, Koesters R, Yang B, Stokes JB, Hoover RS, Gamba G, Staub O. Nedd4-2 modulates renal Na+-Clcotransporter via the aldosterone-SGK1-Nedd4-2 pathway. J Am Soc Nephrol 2011; 22(9): 1707-1719.   DOI
23 Yilmaz M, Sari I, Bagci B, Gumus E, Ozdemir O. Aldosterone synthase CYP11B2 gene promoter polymorphism in a Turkish population with chronic kidney disease. Iran J Kidney Dis 2015; 9(3): 209-214.
24 Kim YR, Kim SH, Kang SH, Kim HJ, Kong MH, Hong SH. Association of CYP11B2 polymorphisms with metabolic syndrome patients. Biomed Rep 2014; 2(5): 749-754.   DOI
25 Kim JH, Shin HD, Park BL, Moon MK, Cho YM, Hwang YH, Oh KW, Kim SY, Lee HK, Ahn C, Park KS. SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Diabetes 2006; 55(3): 843-848.   DOI
26 Svetkey LP, Sacks FM, Obarzanek E, Vollmer WM, Appel LJ, Lin PH, Karanja NM, Harsha DW, Bray GA, Aickin M, Proschan MA, Windhauser MM, Swain JF, McCarron PB, Rhodes DG, Laws RL. The DASH Diet, Sodium Intake and Blood Pressure Trial (DASHsodium): rationale and design. DASH-Sodium Collaborative Research Group. J Am Diet Assoc 1999; 99(8 Suppl): S96-S104.   DOI
27 Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension 2001; 37(2 Pt 2): 429-432.   DOI
28 Jung J, Lee M. Effects of interaction between SLC12A3 polymorphism, salt-sensitive gene, and sodium intake on risk of child obesity. J Nutr Health 2017; 50(1): 32-40.   DOI
29 Wang XF, Lin RY, Wang SZ, Zhang LP, Qian J, Lu DR, Wen H, Jin L. Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China. Clin Chim Acta 2008; 388(1-2): 95-98.   DOI
30 Pamies-Andreu E, Ramirez-Lorca R, Stiefel Garcia-Junco P, Muniz-Grijalbo O, Vallejo-Maroto I, Garcia Morillo S, Miranda- Guisado ML, Ortiz JV, Carneado de la Fuente J. Renin-angiotensin- aldosterone system and G-protein beta-3 subunit gene polymorphisms in salt-sensitive essential hypertension. J Hum Hypertens 2003; 17(3): 187-191.   DOI
31 Yang SJ, Kim S, Park H, Kim SM, Choi KM, Lim Y, Lee M. Sexdependent association between angiotensin-converting enzyme insertion/deletion polymorphism and obesity in relation to sodium intake in children. Nutrition 2013; 29(3): 525-530.   DOI
32 Strazzullo P, Galletti F. Genetics of salt-sensitive hypertension. Curr Hypertens Rep 2007; 9(1): 25-32.   DOI
33 Castaneda-Bueno M, Gamba G. Mechanisms of sodium-chloride cotransporter modulation by angiotensin II. Curr Opin Nephrol Hypertens 2012; 21(5): 516-522.   DOI
34 Mangrum AJ, Gomez RA, Norwood VF. Effects of AT(1A) receptor deletion on blood pressure and sodium excretion during altered dietary salt intake. Am J Physiol Renal Physiol 2002; 283(3): F447-F453.   DOI
35 Soltysiak M, Miazgowski T, Ziemak J, Soltysiak P, Widecka K. Associations of the -344T>Cpolymorphism of CYP11B2 gene with 24-hour blood pressure profiles in middle-aged women with essential hypertension. Arter Hypertens 2015; 19(1): 23-28.   DOI
36 Marques FZ, Campain AE, Yang YH, Morris BJ. Meta-analysis of genome-wide gene expression differences in onset and maintenance phases of genetic hypertension. Hypertension 2010; 56(2): 319-324.   DOI
37 Lee Y, Park SM, Lee M. Validation of G-protein beta-3 subunit gene C825T polymorphism as predictor of obesogenic epidemics in overweight/obese Korean children. J Nutr Health 2016; 49(4): 223-232.   DOI
38 Li K, Guo D, Zhu H, Hering-Smith KS, Hamm LL, Ouyang J, Dong Y. Interleukin-6 stimulates epithelial sodium channels in mouse cortical collecting duct cells. Am J Physiol Regul Integr Comp Physiol 2010; 299(2): R590-R595.   DOI
39 Gu D, Kelly TN, Hixson JE, Chen J, Liu D, Chen JC, Rao DC, Mu J, Ma J, Jaquish CE, Rice TK, Gu C, Hamm LL, Whelton PK, He J. Genetic variants in the renin-angiotensin-aldosterone system and salt sensitivity of blood pressure. J Hypertens 2010; 28(6): 1210-1220.
40 Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 2004; 217(1-2): 67-74.   DOI
41 Matsubara M, Sato T, Nishimura T, Suzuki M, Kikuya M, Metoki H, Michimata M, Tsuji I, Ogihara T, Imai Y. CYP11B2 polymorphisms and home blood pressure in a population-based cohort in Japanese: the Ohasama Study. Hypertens Res 2004; 27(1): 1-6.   DOI
42 Pan XQ, Zhang YH, Liu YY, Tong WJ. Interaction between the C(- 344)T polymorphism of CYP11B2 and alcohol consumption on the risk of essential hypertension in a Chinese Mongolian population. Eur J Epidemiol 2010; 25(11): 813-821.   DOI
43 Ryu SK, Park HY, Im EK, Yoon YW, Jang Y, Yoon YW, Shim WH, Cho SY. The effects of an aldosterone synthase (CYP11B2) gene polymorphism on the risk of myocardial infarction. Korean Circ J 2001; 31(12): 1261-1266.   DOI
44 Samarina O, Kovtun O, Chuykov A, Sozonov A, Ustiuzhanina M, Trunova Y Averianov O. Association of aldosterone synthase (CYP11B2) gene polymorphisms with obesity in essential hypertensive children and adolescents from the Urals. J Hypertens 2016; 34; e317.
45 Stella P, Bigatti G, Tizzoni L, Barlassina C, Lanzani C, Bianchi G, Cusi D. Association between aldosterone synthase (CYP11B2) polymorphism and left ventricular mass in human essential hypertension. J Am Coll Cardiol 2004; 43(2): 265-270.   DOI
46 Felder RA, White MJ, Williams SM, Jose PA. Diagnostic tools for hypertension and salt sensitivity testing. Curr Opin Nephrol Hypertens 2013; 22(1): 65-76.   DOI
47 Kang MS, Kim CH, Jeong SJ, Park TS. Dietary Sodium intake in people with diabetes in Korea: the Korean National Health and Nutrition Examination Survey for 2008 to 2010. Diabetes Metab J 2016; 40(4): 290-296.   DOI
48 Lee M, Kim MK, Kim SM, Park H, Park CG, Park HK. Genderbased differences on the association between salt-sensitive genes and obesity in Korean children aged between 8 and 9 years. PLoS One 2015; 10(3): e0120111.   DOI
49 Re RN. Obesity-related hypertension. Ochsner J 2009; 9(3): 133-136.
50 Khan KS, Kunz R, Kleijnen J, Antes G. Five steps to conducting a systematic review. J R Soc Med 2003; 96(3): 118-121.   DOI
51 Poch E, Gonzalez D, Giner V, Bragulat E, Coca A, de La Sierra A. Molecular basis of salt sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene polymorphisms. Hypertension 2001; 38(5): 1204-1209.   DOI
52 Morrison AC, Boerwinkle E, Turner ST, Ferrell RE. Genome-wide linkage study of erythrocyte sodium-lithium countertransport. Am J Hypertens 2005; 18(5 Pt 1): 653-656.   DOI
53 Sanada H, Yatabe J, Midorikawa S, Hashimoto S, Watanabe T, Moore JH, Ritchie MD, Williams SM, Pezzullo JC, Sasaki M, Eisner GM, Jose PA, Felder RA. Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clin Chem 2006; 52(3): 352-360.   DOI
54 Geiebisch G, Windhager E. Integration of salt and water balance. In: Boron WF, Boulpaep EL, editors. Medical Physiology: a Cellular and Molecular Approach. 2nd ed. Philadelphia (PA): Elsevier Saunders; 2005. p.866-880.
55 Hamada T, Kotani K, Nagai N, Tsuzaki K, Sano Y, Matsuoka Y, Fujibayashi M, Kiyohara N, Tanaka S, Yoshimura M, Egawa K, Kitagawa Y, Kiso Y, Moritani T, Sakane N. Genetic polymorphisms of the renin-angiotensin system and obesity-related metabolic changes in response to low-energy diets in obese women. Nutrition 2011; 27(1): 34-39.   DOI
56 Engeli S, Gorzelniak K, Kreutz R, Runkel N, Distler A, Sharma AM. Co-expression of renin-angiotensin system genes in human adipose tissue. J Hypertens 1999; 17(4): 555-560.   DOI
57 Premaratna SD, Manickam E, Begg DP, Rayment DJ, Hafandi A, Jois M, Cameron-Smith D, Weisinger RS. Angiotensin-converting enzyme inhibition reverses diet-induced obesity, insulin resistance and inflammation in C57BL/6J mice. Int J Obes (Lond) 2012; 36(2): 233-243.   DOI
58 Fatini C, Guiducci S, Abbate R, Matucci-Cerinic M. Vascular injury in systemic sclerosis: angiotensin-converting enzyme insertion/deletion polymorphism. Curr Rheumatol Rep 2004; 6(2): 149-155.   DOI
59 de la Sierra A, Giner V, Bragulat E, Coca A. Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension. J Hum Hypertens 2002; 16(4): 255-260.   DOI
60 Sanada H, Jones JE, Jose PA. Genetics of salt-sensitive hypertension. Curr Hypertens Rep 2011; 13(1): 55-66.   DOI
61 Ministry of Health and Welfare, Korea Centers for Disease Control and Prevention. Korea Health Statistics 2014: Korea National Health and Nutrition Examination Survey (KNHANES VI-2). Cheongju: Korea Centers for Disease Control and Prevention; 2015.
62 Oh K, Jang MJ, Lee NY, Moon JS, Lee CG, Yoo MH, Kim YT. Prevalence and trends in obesity among Korean children and adolescents in 1997 and 2005. Korean J Pediatr 2008; 51(9): 950-955.   DOI