Issue
Contribution of polymorphisms in the LEP, LEPR and RETN genes on serum leptin and resistin levels in young adults from Mexico
Corresponding Author(s) : J. Sánchez-Corona
Cellular and Molecular Biology,
Vol. 63 No. 8: Issue 8
Abstract
Polymorphisms in the LEP (G–2548A and A19G), LEPR (A326G, A668G and G3057A) and RETN (C–420G and G+62A) genes were documented according to their association with alterations in biochemical parameters such as glucose, insulin and lipid profiles, along with serum leptin and resistin concentrations. The aim of the study was to establish any contribution of the G-2548A and A19G polymorphisms of the LEP gene, the A326G, A668G and G3057A polymorphisms of the LEPR gene, and the C-420G and G+62A polymorphisms of the RETN gene to serum leptin and resistin levels in Mexican young adults. Clinical and biochemical variables, serum leptin and resistin levels, and genotype profiles were analysed in 66 Mexican young adults. Seven polymorphisms in the LEP, LEPR and RETN genes were genotyped using polymerase chain reaction–restriction fragment length polymorphisms analysis. Individuals carrying allele 3057A of the G3057A polymorphism in the LEPR gene showed significantly higher leptin concentrations than those bearing the genotype G/G (43.78 ± 39.11 vs 28.20 ± 14.12 ng/mL; p = 0.021). There were no associations of serum leptin or resistin levels according to the genotype of the other six analysed polymorphisms. Our results suggest that the allele 3057A of the LEPR G3057A polymorphism contributes to increased serum leptin levels in Mexican young adults.
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- Leal V de O, Mafra D. Adipokines in obesity. Clin Chim Acta 2013; 419:87–94.
- Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol 2014; 63:250–259.
- Jung U, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15:6184–6223.
- Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014; 2014:943162.
- Ben Ali S, Kallel A, Sediri Y, Ftouhi B, Feki M, Slimene H et al. LEPR p.Q223R Polymorphism influences plasma leptin levels and body mass index in Tunisian obese patients. Arch Med Res 2009: 40:186–190.
- Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm 2010; 2010:535918.
- Choquet H, Meyre D. Molecular basis of obesity: current status and future prospects. Curr Genomics 2011; 12:154–168.
- Fourati M, Mnif M, Kharrat N, Charfi N, Kammoun M, Fendri N et al. Association between leptin gene polymorphisms and plasma leptin level in three consanguineous families with obesity. Gene 2013; 527:75–81.
- Woo HY, Park H, Ki CS, Park YL, Bae WG. Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 2006; 237:137–142.
- Constantin A, Costache G, Sima AV, Glavce CS, Vladica M, Popov DL. Leptin G-2548A and leptin receptor Q223R gene polymorphisms are not associated with obesity in Romanian subjects. Biochem Biophys Res Commun 2010; 391:282–286.
- de Silva AM, Walder KR, Aitman TJ, Gotoda T, Goldstone AP, Hodge AM etal. Combination of polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males. Int J Obes Relat Metab Disord 1999; 23:816–822.
- Fan SH, Say YH. Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population. J Physiol Anthropol 2014; 33:15.
- Ukkola O, Kunnari A, Kesäniemi YA. Genetic variants at the resistin locus are associated with the plasma resistin concentration and cardiovascular risk factors. Regul Pept 2008; 149:56–59.
- Tsukahara T, Nakashima E, Watarai A, Hamada Y, Naruse K, Kamiya H et al. Polymorphism in resistin promoter region at −420 determines the serum resistin levels and may be a risk marker of stroke in Japanese type 2 diabetic patients. Diabetes Res Clin Pract 2009; 84:179–186.
- Chavarria-ívila E, Ruíz Quezada SL, Guzmán-Ornelas MO, Castro-Albarrán J, Aguila Aldrete ME, Vásquez-Del Mercado M, et al. [Association of resistin gene 3'UTR +62G>A polymorphism with insulin resistance, adiposity and the adiponectin-resistin index in Mexican population]. Nutr Hosp 2013; 28:1867–1876.
- Gustincich S, Manfioletti G, Del Sal G, Schneider C, Carninci P. A fast method for high-quality genomic DNA extraction from whole human blood. Biotechniques 1991; 11:298–300.
- Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD et al. Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet 1997; 6:869–876.
- Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T et al. Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity. Diabetologia 1997; 40:1204–1210.
- Karvonen MK, Pesonen U, Heinonen P, Laakso M, Rissanen A, Naukkarinen H et al. Identification of new sequence variants in the leptin gene. J Clin Endocrinol Metab 1998; 83:3239–3242.
- Krízová J, Dolinková M, Lacinová Z, Sulek S, Dolezalová R, Housová J et al. Adiponectin and resistin gene polymorphisms in patients with anorexia nervosa and obesity and its influence on metabolic phenotype. Physiol Res 2008; 57:539–546.
- Gaukrodger N, Mayosi BM, Imrie H, Avery P, Baker M, Connell JMC et al. A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families. J Med Genet 2005; 42:474–478.
- Cieslak J, Bartz M, Stachowiak M, Skowronska B, Majewska KA, Harasymczuk J et al. Effect of three common SNPs in 5ï‚¢-flanking region of LEP and ADIPOQ genes on their expression in Polish obese children and adolescents. Mol Biol Rep 2012; 39:3951–3955.
- Hinuy H, Hirata M, Forti N, Diament J, Sampaio M, Armaganijan D et al. Leptin G-2548A promoter polymorphism is associated with increased plasma leptin and BMI in Brazilian women. Arq Bras Endocrinol Metab 2008; 52:611–616.
- Ben Ali S, Kallel A, Ftouhi B, Sediri Y, Feki M, Slimane H et al. Association of G-2548A LEP polymorphism with plasma leptin levels in Tunisian obese patients. Clin Biochem 2009; 42:584–588.
- Lucantoni R, Ponti E, Berselli ME, Savia G, Minocci A, Calò G et al. The A19G polymorphism in the 5ï‚¢ untranslated region of the human obese gene does not affect leptin levels in severely obese patients. J Clin Endocrinol Metab 2000; 85:3589–3591.
- Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C et al. PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci U S A 2002; 99:11848–11853.
- Minokoshi Y, Kim YB, Peroni OD, Fryer LGD, Müller C, Carling D et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002; 415:339–343.
- Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 2015; 64:24–34.
- Ogawa T, Hirose H, Yamamoto Y, Nishikai K, Miyashita K, Nakamura H et al. Relationships between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population. Metabolism 2004; 53:879–885.
- Becer E, Mehmetçik G, Bareke H, Serakinci N. Association of leptin receptor gene Q223R polymorphism on lipid profiles in comparison study between obese and non-obese subjects. Gene 2013; 529:16–20.
- Répásy J, Bokor S, Erhardt í‰, Molnár D. Association of Gln223 Arg polymorphism of the leptin receptor gene with indicators of energy expenditure in obese children. Nutrition 2014; 30:837–840.
- Ben Ali S, Sediri Y, Kallel A, Ftouhi B, Haj-Taib S, Omar S et al. The G3057A LEPR polymorphism is associated with obesity in Tunisian women. Nutr Metab Cardiovasc Dis 2011; 21:591–596.
- Osawa H, Yamada K, Onuma H, Murakami A, Ochi M, Kawata H et al. The G/G genotype of a resistin single-nucleotide polymorphism at −420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am J Hum Genet 2004; 75:678–686.
- Gouni-Berthold I, Giannakidou E, Faust M, Kratzsch J, Berthold HK, Krone W. Resistin gene 3ï‚¢-untranslated region +62Gïƒ A polymorphism is associated with hypertension but not diabetes mellitus type 2 in a German population. J Intern Med 2005; 258:518–526.
- Kumar S, Gupta V, Srivastava N, Gupta V, Mishra S, Mishra S et al. Resistin 420C/G gene polymorphism on circulating resistin, metabolic risk factors and insulin resistance in adult women. Immunol Lett 2014; 162:287–291.
- Chung SS, Choi HH, Kim KW, Cho YM, Lee HK, Park KS. Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site. Diabetologia 2005; 48:1150–1158.
- Jupe ER, Badgett AA, Neas BR, Craft MA, Mitchell DS, Resta R et al. Single nucleotide polymorphism in prohibitin 3' untranslated region and breast-cancer susceptibility. Lancet 2001; 357:1588–1589.
- Pesole G, Mignone F, Gissi C, Grillo G, Licciulli F, Liuni S. Structural and functional features of eukaryotic mRNA untranslated regions. Gene 2001; 276:73–81.
- Di Paola R, Frittitta L, Miscio G, Bozzali M, Baratta R, Centra M et al. A variation in 3ï‚¢ UTR of hPTP1B increases specific gene expression and associates with insulin resistance. Am J Hum Genet 2002; 70:806–812.
- Ikeda Y, Tsuchiya H, Hama S, Kajimoto K, Kogure K. Resistin affects lipid metabolism during adipocyte maturation of 3T3-L1 cells. FEBS J 2013; 280:5884–5895.
References
Leal V de O, Mafra D. Adipokines in obesity. Clin Chim Acta 2013; 419:87–94.
Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol 2014; 63:250–259.
Jung U, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15:6184–6223.
Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014; 2014:943162.
Ben Ali S, Kallel A, Sediri Y, Ftouhi B, Feki M, Slimene H et al. LEPR p.Q223R Polymorphism influences plasma leptin levels and body mass index in Tunisian obese patients. Arch Med Res 2009: 40:186–190.
Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm 2010; 2010:535918.
Choquet H, Meyre D. Molecular basis of obesity: current status and future prospects. Curr Genomics 2011; 12:154–168.
Fourati M, Mnif M, Kharrat N, Charfi N, Kammoun M, Fendri N et al. Association between leptin gene polymorphisms and plasma leptin level in three consanguineous families with obesity. Gene 2013; 527:75–81.
Woo HY, Park H, Ki CS, Park YL, Bae WG. Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 2006; 237:137–142.
Constantin A, Costache G, Sima AV, Glavce CS, Vladica M, Popov DL. Leptin G-2548A and leptin receptor Q223R gene polymorphisms are not associated with obesity in Romanian subjects. Biochem Biophys Res Commun 2010; 391:282–286.
de Silva AM, Walder KR, Aitman TJ, Gotoda T, Goldstone AP, Hodge AM etal. Combination of polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males. Int J Obes Relat Metab Disord 1999; 23:816–822.
Fan SH, Say YH. Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population. J Physiol Anthropol 2014; 33:15.
Ukkola O, Kunnari A, Kesäniemi YA. Genetic variants at the resistin locus are associated with the plasma resistin concentration and cardiovascular risk factors. Regul Pept 2008; 149:56–59.
Tsukahara T, Nakashima E, Watarai A, Hamada Y, Naruse K, Kamiya H et al. Polymorphism in resistin promoter region at −420 determines the serum resistin levels and may be a risk marker of stroke in Japanese type 2 diabetic patients. Diabetes Res Clin Pract 2009; 84:179–186.
Chavarria-ívila E, Ruíz Quezada SL, Guzmán-Ornelas MO, Castro-Albarrán J, Aguila Aldrete ME, Vásquez-Del Mercado M, et al. [Association of resistin gene 3'UTR +62G>A polymorphism with insulin resistance, adiposity and the adiponectin-resistin index in Mexican population]. Nutr Hosp 2013; 28:1867–1876.
Gustincich S, Manfioletti G, Del Sal G, Schneider C, Carninci P. A fast method for high-quality genomic DNA extraction from whole human blood. Biotechniques 1991; 11:298–300.
Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD et al. Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet 1997; 6:869–876.
Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T et al. Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity. Diabetologia 1997; 40:1204–1210.
Karvonen MK, Pesonen U, Heinonen P, Laakso M, Rissanen A, Naukkarinen H et al. Identification of new sequence variants in the leptin gene. J Clin Endocrinol Metab 1998; 83:3239–3242.
Krízová J, Dolinková M, Lacinová Z, Sulek S, Dolezalová R, Housová J et al. Adiponectin and resistin gene polymorphisms in patients with anorexia nervosa and obesity and its influence on metabolic phenotype. Physiol Res 2008; 57:539–546.
Gaukrodger N, Mayosi BM, Imrie H, Avery P, Baker M, Connell JMC et al. A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families. J Med Genet 2005; 42:474–478.
Cieslak J, Bartz M, Stachowiak M, Skowronska B, Majewska KA, Harasymczuk J et al. Effect of three common SNPs in 5ï‚¢-flanking region of LEP and ADIPOQ genes on their expression in Polish obese children and adolescents. Mol Biol Rep 2012; 39:3951–3955.
Hinuy H, Hirata M, Forti N, Diament J, Sampaio M, Armaganijan D et al. Leptin G-2548A promoter polymorphism is associated with increased plasma leptin and BMI in Brazilian women. Arq Bras Endocrinol Metab 2008; 52:611–616.
Ben Ali S, Kallel A, Ftouhi B, Sediri Y, Feki M, Slimane H et al. Association of G-2548A LEP polymorphism with plasma leptin levels in Tunisian obese patients. Clin Biochem 2009; 42:584–588.
Lucantoni R, Ponti E, Berselli ME, Savia G, Minocci A, Calò G et al. The A19G polymorphism in the 5ï‚¢ untranslated region of the human obese gene does not affect leptin levels in severely obese patients. J Clin Endocrinol Metab 2000; 85:3589–3591.
Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C et al. PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci U S A 2002; 99:11848–11853.
Minokoshi Y, Kim YB, Peroni OD, Fryer LGD, Müller C, Carling D et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002; 415:339–343.
Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 2015; 64:24–34.
Ogawa T, Hirose H, Yamamoto Y, Nishikai K, Miyashita K, Nakamura H et al. Relationships between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population. Metabolism 2004; 53:879–885.
Becer E, Mehmetçik G, Bareke H, Serakinci N. Association of leptin receptor gene Q223R polymorphism on lipid profiles in comparison study between obese and non-obese subjects. Gene 2013; 529:16–20.
Répásy J, Bokor S, Erhardt í‰, Molnár D. Association of Gln223 Arg polymorphism of the leptin receptor gene with indicators of energy expenditure in obese children. Nutrition 2014; 30:837–840.
Ben Ali S, Sediri Y, Kallel A, Ftouhi B, Haj-Taib S, Omar S et al. The G3057A LEPR polymorphism is associated with obesity in Tunisian women. Nutr Metab Cardiovasc Dis 2011; 21:591–596.
Osawa H, Yamada K, Onuma H, Murakami A, Ochi M, Kawata H et al. The G/G genotype of a resistin single-nucleotide polymorphism at −420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. Am J Hum Genet 2004; 75:678–686.
Gouni-Berthold I, Giannakidou E, Faust M, Kratzsch J, Berthold HK, Krone W. Resistin gene 3ï‚¢-untranslated region +62Gïƒ A polymorphism is associated with hypertension but not diabetes mellitus type 2 in a German population. J Intern Med 2005; 258:518–526.
Kumar S, Gupta V, Srivastava N, Gupta V, Mishra S, Mishra S et al. Resistin 420C/G gene polymorphism on circulating resistin, metabolic risk factors and insulin resistance in adult women. Immunol Lett 2014; 162:287–291.
Chung SS, Choi HH, Kim KW, Cho YM, Lee HK, Park KS. Regulation of human resistin gene expression in cell systems: an important role of stimulatory protein 1 interaction with a common promoter polymorphic site. Diabetologia 2005; 48:1150–1158.
Jupe ER, Badgett AA, Neas BR, Craft MA, Mitchell DS, Resta R et al. Single nucleotide polymorphism in prohibitin 3' untranslated region and breast-cancer susceptibility. Lancet 2001; 357:1588–1589.
Pesole G, Mignone F, Gissi C, Grillo G, Licciulli F, Liuni S. Structural and functional features of eukaryotic mRNA untranslated regions. Gene 2001; 276:73–81.
Di Paola R, Frittitta L, Miscio G, Bozzali M, Baratta R, Centra M et al. A variation in 3ï‚¢ UTR of hPTP1B increases specific gene expression and associates with insulin resistance. Am J Hum Genet 2002; 70:806–812.
Ikeda Y, Tsuchiya H, Hama S, Kajimoto K, Kogure K. Resistin affects lipid metabolism during adipocyte maturation of 3T3-L1 cells. FEBS J 2013; 280:5884–5895.