Journal List > J Nutr Health > v.50(1) > 1081508

J Nutr Health. 2017 Feb;50(1):32-40. Korean.
Published online February 28, 2017.
© 2017 The Korean Nutrition Society
Effects of interaction between SLC12A3 polymorphism, salt-sensitive gene, and sodium intake on risk of child obesity
Joohyun Jung,1 and Myoungsook Lee1,2
1Department of Food and Nutrition, Sungshin Women's University, Seoul 01133, Korea.
2Research Institute of obesity Sciences, Sungshin Women's University, Seoul 01133, Korea.

To whom correspondence should be addressed. tel: +82-2-920-7211, Email:
Received January 11, 2017; Revised January 23, 2017; Accepted February 02, 2017.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.



Obesogenic environments in children, in particular excessive intake of sodium, generate hypertension, which is a major risk factor for chronic diseases.


In all, 725 children, 379 boys and 373 girls, aged 8∼9 years were recruited from seven elementary schools in Kuro-ku, Seoul. To evaluate whether or not obesity risk was modulated by salt-sensitive genes, Solute Carrier Familiy 12 member 3 (SLC12A3) was used as the target. After children were assigned into obese (BMI > 85 percentile) or non-obese groups, anthropometry, blood biochemistry, and dietary intakes were measured according to the genotypes GG (wild) or GA+AA (hetero+mutant).


Without gender differences, high TG and low HDLc were detected in the obese group compared to the non-obese group. Regardless of obesity, weight gain and blood pressure (BP) increased in the SLC12A3 GA+AA genotype rather than in the GG type. HDLc was associated with obesity risk without genotype difference. Odd ratios for risk of obesity were 15.57 (95% CI 2.192∼110.654), 22.84 (95% CI 1.565∼333.469), and 9.32 (95%CI 1.262∼68.817) in boys and girls with GA+AA genotypes as sodium intake increased above 4,000 mg/day. Dietary calcium, sodium, folate, and vit C were associated with obesity risk according to gender or genotype differences. Since high folate intake reduced obesity risk in only boys with GG type. Risk for overweight and obesity increased in boys with GA+AA genotypes and dietary habits with high sodium and cholesterol and low folate.


The A allele of SLC12A3 rs11643718 was sensitive to development of obesity in children as sodium intake increased.

Keywords: children obesity; sodium intake; salt sensitive gene; SLC12A3


Fig. 1
Experimental design of the cross-sectional study
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Fig. 2
Odd ratio of the risk of obesity by categories of plasma HDLc and insulin levels according to SLC12A3 genotypes, GG vs GA + AA. Categories of HDLc levels or in each tertiles of total subjects are > 51.92, 51.92 ∼ 60.34, ≥ 60.35 mg/day, insulin levels in each tertile are < 4.40, 4.41 ∼ 7.33, ≥ 7.34 mg/day.
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Fig. 3
Odd ratio of the risk of obesity by categories of dietary factors according to SLC12A3 genotypes, GG vs GA + AA. Categories of dietary intakes in each tertile are < 288.48, 288.48 ∼ 387.55, ≥ 387.56 mg/day for cholesterol, and < 206.54, 206.54 ∼ 266.11, ≥ 266.12 ug/day for folate, and < 3,326.73, 3,326.73 ∼ 3955, ≥ 3,955.01 mg/day for sodium.
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Table 1
Relative frequencies of SLC12A3 rs11643718 genotypes in obese and non-obese boys and girls
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Table 2
Anthropometry and blood biochemistry in obese and non-obese boys and girls according to SLC12A3 rs11643718 genotypes
Click for larger image

1. Ministry of Health and Welfare, Korea Centers for Disease Control and Prevention. Korea Health Statistics 2012: Korea National Health and Nutrition Examination Survey (KNHANES V-3). Cheongwon: Korea Centers for Disease Control and Prevention; 2013.
2. 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.
3. Korean Educational Development Institute. Statistics of school health examination survey: 2011. Seoul: Korean Educational Development Institute; 2011.
4. Kim JH, Kim EK. The relationship among insulin resistance, blood profiles and nutrient intake in overweight or obese children and adolescents. Korean J Community Nutr 2012;17(5):530–542.
5. Styne DM. Childhood and adolescent obesity. Prevalence and significance. Pediatr Clin North Am 2001;48(4):823–854.
6. Lee HH, Choi SK, Seo JS. Obesity index and related factors among elementary school students visiting pediatric department of general hospital. J Korean Diet Assoc 2012;18(2):186–199.
7. Lee SK, Kim MK. Relationship of sodium intake with obesity among Korean children and adolescents: Korea National Health and Nutrition Examination Survey. Br J Nutr 2016;115(5):834–841.
8. Yoon YS, Oh SW. Sodium density and obesity; the Korea National Health and Nutrition Examination Survey 2007-2010. Eur J Clin Nutr 2013;67(2):141–146.
9. Lee M, Kim MK, Kim SM, Park H, Park CG, Park HK. Gender-based 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.
10. Lee J, Lee H, Kim K, Park JH, Kim S, Oh J. A higher salt intake leads to a lower rate of adequate blood pressure control. J Korean Med Sci 2014;29 Suppl 2:S103–S108.
11. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. BMJ 1988;297(6644):319–328.
12. 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.
13. Hoffmann IS, Cubeddu LX. Salt and the metabolic syndrome. Nutr Metab Cardiovasc Dis 2009;19(2):123–128.
14. World Health Organization. Guideline. Sodium intake for adults and children. Geneva: World Health Organization; 2012.
15. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360(9349):1903–1913.
16. He FJ, MacGregor GA. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials. Lancet 2011;378(9789):380–382.
17. Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319(1):38–50.
18. Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jönsson A, Wanby P, Lippi G, Minuz P, Hulthèn 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.
19. Melander O, Orho-Melander M, Bengtsson K, Lindblad U, Râstam L, Groop L, Hulthén UL. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension 2000;36(3):389–394.
20. Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008;3(1):22.
21. Hoorn EJ, Ellison DH. WNK kinases and the kidney. Exp Cell Res 2012;318(9):1020–1026.
22. Mercier-Zuber A, O'Shaughnessy KM. Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. Curr Opin Nephrol Hypertens 2011;20(5):534–540.
23. McCormick JA, Mutig K, Nelson JH, Saritas T, Hoorn EJ, Yang CL, Rogers S, Curry J, Delpire E, Bachmann S, Ellison DH. A SPAK isoform switch modulates renal salt transport and blood pressure. Cell Metab 2011;14(3):352–364.
24. Castañeda-Bueno M, Gamba G. Mechanisms of sodium-chloride cotransporter modulation by angiotensin II. Curr Opin Nephrol Hypertens 2012;21(5):516–522.
25. Arroyo JP, Lagnaz D, Ronzaud C, Vázquez N, Ko BS, Moddes L, Ruffieux-Daidié D, Hausel P, Koesters R, Yang B, Stokes JB, Hoover RS, Gamba G, Staub O. Nedd4-2 modulates renal Na+-Cl-cotransporter via the aldosterone-SGK1-Nedd4-2 pathway. J Am Soc Nephrol 2011;22(9):1707–1719.
26. Moon JS, Lee SY, Nam CM, Choi JM, Choe BK, Seo JW, Oh K, Jang MJ, Hwang SS, Yoo MH, Kim YT, Lee CG. 2007 Korean National Growth Charts: review of developmental process and an outlook. Korean J Pediatr 2008;51(1):1–25.
27. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18(6):499–502.
28. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28(7):412–419.
29. Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 1997;65 4 Suppl:1220S–1228S.
30. Magnussen CG, Thomson R, Cleland VJ, Ukoumunne OC, Dwyer T, Venn A. Factors affecting the stability of blood lipid and lipoprotein levels from youth to adulthood: evidence from the Childhood Determinants of Adult Health Study. Arch Pediatr Adolesc Med 2011;165(1):68–76.
31. Cesa CC, Sbruzzi G, Ribeiro RA, Barbiero SM, de Oliveira Petkowicz R, Eibel B, Machado NB, Marques R, Tortato G, dos Santos TJ, Leiria C, Schaan BD, Pellanda LC. Physical activity and cardiovascular risk factors in children: meta-analysis of randomized clinical trials. Prev Med 2014;69:54–62.
32. Marcovecchio ML, Mohn A, Chiarelli F. Obesity and insulin resistance in children. J Pediatr Gastroenterol Nutr 2010;51 Suppl 3:S149–S150.
33. Bahrami E, Mirmoghtadaee P, Ardalan G, Zarkesh-Esfahani H, Tajaddini MH, Haghjooy-Javanmard S, Najafi H, Kelishadi R. Insulin and leptin levels in overweight and normal-weight Iranian adolescents: the CASPIAN-III study. J Res Med Sci 2014;19(5):387–390.
34. Del Mar Bibiloni M, Maffeis C, Llompart I, Pons A, Tur JA. Dietary factors associated with subclinical inflammation among girls. Eur J Clin Nutr 2013;67(12):1264–1270.
35. García OP, Ronquillo D, Caamaño Mdel C, Camacho M, Long KZ, Rosado JL. Zinc, vitamin A, and vitamin C status are associated with leptin concentrations and obesity in Mexican women: results from a cross-sectional study. Nutr Metab (Lond) 2012;9(1):59.
36. Wang YL, Qi Y, Bai JN, Qi ZM, Li JR, Zhao HY, Wang YF, Lu CZ, Xiao Y, Jia N, Wang B, Niu WQ. Tag polymorphisms of solute carrier family 12 member 3 gene modify the risk of hypertension in northeastern Han Chinese. J Hum Hypertens 2014;28(8):504–509.
37. Gopinath B, Flood VM, Burlutsky G, Louie JC, Baur LA, Mitchell P. Dairy food consumption, blood pressure and retinal microcirculation in adolescents. Nutr Metab Cardiovasc Dis 2014;24(11):1221–1227.
38. Yuan WL, Kakinami L, Gray-Donald K, Czernichow S, Lambert M, Paradis G. Influence of dairy product consumption on children's blood pressure: results from the QUALITY cohort. J Acad Nutr Diet 2013;113(7):936–941.
39. Yang SJ, Kim S, Park H, Kim SM, Choi KM, Lim Y, Lee M. Sex-dependent association between angiotensin-converting enzyme insertion/deletion polymorphism and obesity in relation to sodium intake in children. Nutrition 2013;29(3):525–530.
40. Enquobahrie DA, Feldman HA, Hoelscher DH, Steffen LM, Webber LS, Zive MM, Rimm EB, Stampfer MJ, Osganian SK. Serum homocysteine and folate concentrations among a US cohort of adolescents before and after folic acid fortification. Public Health Nutr 2012;15(10):1818–1826.
41. Hoey L, McNulty H, Askin N, Dunne A, Ward M, Pentieva K, Strain J, Molloy AM, Flynn CA, Scott JM. Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults. Am J Clin Nutr 2007;86(5):1405–1413.
42. Gallistl S, Sudi K, Mangge H, Erwa W, Borkenstein M. Insulin is an independent correlate of plasma homocysteine levels in obese children and adolescents. Diabetes Care 2000;23(9):1348–1352.
43. Ullegaddi R, Powers HJ, Gariballa SE. B-group vitamin supplementation mitigates oxidative damage after acute ischaemic stroke. Clin Sci (Lond) 2004;107(5):477–484.
44. Folsom AR, Desvarieux M, Nieto FJ, Boland LL, Ballantyne CM, Chambless LE. B vitamin status and inflammatory markers. Atherosclerosis 2003;169(1):169–174.
45. Voutilainen S, Virtanen JK, Rissanen TH, Alfthan G, Laukkanen J, Nyyssönen K, Mursu J, Valkonen VP, Tuomainen TP, Kaplan GA, Salonen JT. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2004;80(2):317–323.