Trends of LSS rs2254524, LSS rs2254522, and NEDD4L rs4149601 Genetic Variants of Hypertension Among Obese Adolescents

Fitrisia Amelin, Rinang Mariko, Nur Indrawaty Lipoeto, Arni Amir

Abstract


BACKGROUND: Polymorphisms in genes regulating renal sodium handling, such as lanosterol synthase (LSS) and neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), as well as the urinary sodium-to-potassium (Na/K) ratio have been proposed as determinants of blood pressure among obese adolescents, but evidence on gene-environment interactions remains limited. This study was conducted to examine associations between LSS (rs2254524) and NEDD4L (rs4149601) polymorphisms and the urinary Na/K ratio and hypertension in obese adolescents.

METHODS: This cross-sectional comparative study enrolled 202 obese adolescents (101 hypertensive, 101 normotensive) aged 15–18 years old. Genotyping was performed by polymerase chain reaction (PCR) followed by Sanger sequencing. An ion-selective electrode was used to measure the spot urinary sodium and potassium for the calculation of Na/K ratio. Associations of the gene polymorphism and urinary sodium and potassium interaction were then statistically analyzed.

RESULTS: Male gender, body weight, height, body mass index (BMI), and waist circumference were significantly higher in the hypertensive group (all p<0.0001). Though hypertension was numerically more common among obese adolescents carrying LSS variants (rs2254524, rs2254522) and NEDD4L variant (rs4149601), neither LSS (A>C, A>G) nor NEDD4L genotypes were significantly associated with hypertension in bivariate analyses (all p>0.05). The urinary Na/K ratio did not differ between groups (p=0.889).

CONCLUSION: Genetic variants of LSS rs2254524, LSS rs2254522, and NEDD4L rs4149601 are showing trends of hypertension among obese adolescents in this study. Greater adiposity and male gender, by contrast, were significantly associated with hypertension and remained the dominant correlates of blood pressure.

KEYWORDS: LSS, NEDD4L, polymorphism, sodium-potassium ratio, hypertension, obesity, adolescent, gene-environment interaction


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References


Abarca-Gómez L, Abdeen ZA, Hamid ZA, Abu-Rmeileh NM, Acosta-Cazares B, Acuin C, et al. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: A pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet. 2017; 390(10113): 2627-42, CrossRef.

Kotchen TA. Obesity-Related hypertension: Epidemiology, pathophysiology, and clinical management. Am J Hypertens. 2010; 23(11): 1170-8, CrossRef.

Ramayani OR. Childhood hyperuricemia as risk factor of hypertension in adulthood. Indones Biomed J. 2012; 4(1): 12-6, CrossRef.

Susilo H, Pikir BS, Thaha M, Alsagaff MY, Suryantoro SD, Wungu CDK, et al. The role of klotho G395A gene polymorphism in atherosclerotic cardiovascular disease and mortality risk scores in non-dialysis chronic kidney disease. Indones Biomed J. 2022; 14(3): 294-302, CrossRef.

Susilo H, Marvella DC, Avinda LM, Wungu CDK, Kaldis L, Christodoulou RC, et al. TGFB1 rs1800470 polymorphism is associated with circulating TGF-β1 levels and left ventricular geometry in hypertensive patients. Indones Biomed J. 2026; 18(3): 243-51, CrossRef.

Ramadhanti R, Helda H. Association of hypertension and chronic kidney disease in population aged ≥18 years old. Mol Cell Biomed Sci. 2021; 5(3): 137-44, CrossRef.

Song P, Zhang Y, Yu J, Zha M, Zhu Y, Rahimi K, et al. Global prevalence of hypertension in children: A systematic review and meta-analysis. JAMA Pediatr. 2019; 173(12): 1154, CrossRef.

Hall JE, Do Carmo JM, Da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: Interaction of neurohumoral and renal mechanisms. Circ Res. 2015; 116(6): 991-1006, CrossRef.

Iwahori T, Miura K, Ueshima H, Chan Q, Dyer AR, Elliott P, et al. Estimating 24-h urinary sodium/potassium ratio from casual ('spot') urinary sodium/potassium ratio: The INTERSALT Study. Int J Epidemiol. 2016; 2016: dyw287, CrossRef.

Chiu HF, Venkatakrishnan K, Golovinskaia O, Wang CK. Impact of micronutrients on hypertension: Evidence from clinical trials with a special focus on meta-analysis. Nutrients. 2021; 13(2): 588, CrossRef.

Zhang Y, Miyai N, Utsumi M, Miyashita K, Arita M. Spot urinary sodium-to-potassium ratio is associated with blood pressure levels in healthy adolescents: The Wakayama Study. J Hum Hypertens. 2023; 38(3): 238-44, CrossRef.

Citterio L, Faienza S, Messaggio E, Zagato L, Lanzani C, Simonini M, et al. Salt sensitivity is modulated by lanosterol synthase rs2254524 polymorphism. J Hypertens. 2023; 41(Suppl 3): e43, CrossRef.

Lanzani C, Gatti G, Citterio L, Messaggio E, Delli Carpini S, Simonini M, et al. Lanosterol synthase gene polymorphisms and changes in endogenous ouabain in the response to low sodium intake. Hypertension. 2016; 67(2): 342-8, CrossRef.

Iatrino R, Lanzani C, Bignami E, Casamassima N, Citterio L, Meroni R, et al. Lanosterol synthase genetic variants, endogenous ouabain, and both acute and chronic kidney injury. Am J Kidney Dis Off J Natl Kidney Found. 2019; 73(4): 504-12, CrossRef.

Luo F, Wang Y, Wang X, Sun K, Zhou X, Hui R. A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension. Hypertension. 2009; 54(4): 796-801, CrossRef.

Nicolas HA, Kulik R, Lamothe G, Bolongo PM, McRae K, Kingsbury C, et al. Abstract 28: Increased blood pressure response to salt intake in hypertensive G carriers of the NEDD4L SNP rs4149601. Hypertension. 2012; 60(Suppl 1): A28, CrossRef.

Svensson-Färbom P, Wahlstrand B, Almgren P, Dahlberg J, Fava C, Kjeldsen S, et al. A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients. J Hypertens. 2011; 29(2): 388-95, CrossRef.

Tunesi F, Simonini M, Zagato L, Citterio L, Vezzoli G, Manunta P, et al. Heterogeneity of clinical response to low salt diet in naïve essential hypertensive patients. J Hypertens. 2025; 43(Suppl 1): e36, CrossRef.

Grillo A, Salvi L, Coruzzi P, Salvi P, Parati G. Sodium intake and hypertension. Nutrients. 2019; 11(9): 1970, CrossRef.

Utami SL, Simamora D, Idawati I, Widjaja JH. ACE I/D and A2350G polymorphisms are correlated with body mass index, but not with body weight and essential hypertension: Study in Javanese postmenopausal women. Mol Cell Biomed Sci. 2024; 8(2): 96-104, CrossRef.

Lukito AA, Bakri S, Kabo P, Wijaya A. The mechanism of coronary artery calcification in centrally obese non-diabetic men: study on the interaction of leptin, free leptin index, adiponectin, hs-c reactive protein, bone morphogenetic protein-2 and matrix gla protein. Mol Cell Biomed Sci. 2020; 4(2): 88-93, CrossRef.

Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002; (246): 1-190, Article.

Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017; 140(3): e20171904, CrossRef.

Yoo EG. Waist-to-height ratio as a screening tool for obesity and cardiometabolic risk. Korean J Pediatr. 2016; 59(11): 425, CrossRef.

Lo K, Wong M, Khalechelvam P, Tam W. Waist-to-height ratio, body mass index and waist circumference for screening paediatric cardio-metabolic risk factors: A meta-analysis. Obes Rev. 2016; 17(12): 1258-75, CrossRef.

Ashwell M, Gunn P, Gibson S. Waist-to-height ratio is a better screening tool than waist circumference and BMI for adult cardiometabolic risk factors: Systematic review and meta-analysis. Obes Rev. 2012; 13(3): 275-86, CrossRef.

Visniauskas B, Kilanowski-Doroh I, Ogola BO, Mcnally AB, Horton AC, Imulinde Sugi A, et al. Estrogen-mediated mechanisms in hypertension and other cardiovascular diseases. J Hum Hypertens. 2022; 37(8): 609-18, CrossRef.

Isıyel E. Assessment of spot urine sodium to potassium ratio in obese hypertensive children. Turk J Pediatr Dis. 2019; 13(5): 382-6, CrossRef.

Groenland EH, Vendeville JPAC, Bots ML, Visseren FLJ, Musson REA, Spiering W. Validation of spot urine in estimating 24-h urinary sodium, potassium and sodium-to-potassium ratio during three different sodium diets in healthy adults. Blood Press. 2023; 32(1): 2170868, CrossRef.

Stamler J. The INTERSALT Study: Background, methods, findings, and implications. Am J Clin Nutr. 1997; 65(2): 626S-642S, CrossRef.

Park Y, Kwock C, Kim K, Kim J, Yang Y. Interaction between single nucleotide polymorphism and urinary sodium, potassium, and sodium-potassium ratio on the risk of hypertension in korean adults. Nutrients. 2017; 9(3): 235, CrossRef.

Simonyte S, Kuciene R, Dulskiene V, Lesauskaite V. Associations of the adrenomedullin gene polymorphism with prehypertension and hypertension in Lithuanian children and adolescents: a cross-sectional study. Sci Rep. 2019; 9(1): 6807, CrossRef.

Bigazzi R, Zagato L, Lanzani C, Fontana S, Messaggio E, Delli Carpini S, et al. Hypertension in high school students: Genetic and environmental factors: The HYGEF Study. Hypertension. 2020; 75(1): 71-8, CrossRef.

Umano GR, Cirillo G, Rondinelli G, Sanchez G, Marzuillo P, Guarino S, et al. LSS rs2254524 increases the risk of hypertension in children and adolescents with obesity. Genes. 2023; 14(8): 1618, CrossRef.

Dahlberg J, Nilsson LO, Von Wowern F, Melander O. Polymorphism in NEDD4L is associated with increased salt sensitivity, reduced levels of P-renin and increased levels of Nt-proANP. PLoS ONE. 2007; 2(5): e432, CrossRef.

McDonough CW, Burbage SE, Duarte JD, Gong Y, Langaee TY, Turner ST, et al. Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics. J Hypertens. 2013; 31(4): 698-704, CrossRef.

Wang YL, Liang HY, Gao YH, Wu XJ, Chen X, Pan BY, et al. A functional variant of NEDD4L is associated with obesity and related phenotypes in a Han Population of Southern China. Int J Mol Sci. 2013; 14(4): 7433-44, CrossRef.




DOI: https://doi.org/10.18585/inabj.v18i5.4322

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