Abstract
The T-786C, Glu298Asp, and 27 bp variable number of tandem repeats (27 bp-VNTR-a/b) polymorphsims of the endothelial nitric oxide synthase (eNOS) gene are thought to alter nitric oxide production and contribute to the development of vascular and renal disease risk. The objective of this study is to investigate whether these three polymorphisms examined previously by others are associated with cardiovascular and renal disease risk in Mexican Americans. Study participants (N = 848; 21 families) were genotyped for T-786C, Glu298Asp, and 27 bp-VNTR-a/b polymorphisms by PCR followed by restriction digestion. Association analyses were performed by a measured genotype approach implemented in the program SOLAR. Of the phenotypes (type 2 diabetes, hypertension, body mass index, waist circumference, total cholesterol, high density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure, albumin to creatinine ratio (ACR), and estimated glomerular filtration rate) examined for association, the 27 bp-VNTR-a/b variant exhibited statistically significant association with ACR (P = 0.047) after accounting for the trait specific covariate effects. In addition, the promoter variant (T-786C) showed a significant association with triglycerides (P = 0.034) after accounting for covariate influences. In conclusion, the present study adds evidence to the role of eNOS candidate gene polymorphisms in modulating the risk factors related to cardiovascular-renal disease in Mexican Americans although the magnitude of the genetic effect is small.
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An P, Freedman BI, Hanis CL, Chen YD, Weder AB, Schork NJ et al (2005) Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the national heart, lung, and blood institute family blood pressure program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. Diabetes 54(3):909–914. doi:10.2337/diabetes.54.3.909
Love-Gregory L, Sherva R, Sun L, Wasson J, Schappe T, Doria A et al (2008) Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol. Hum Mol Genet 17:1695–1704. doi:10.1093/hmg/ddn060
Schelling JR, Abboud HE, Nicholas SB, Pahl MV, Sedor JR, Adler SG et al (2008) Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 57:235–243. doi:10.2337/db07-0313
Mount PF, Power DA (2006) Nitric oxide in the kidney: functions and regulation of synthesis. Acta Physiol (Oxf) 187:433–446. doi:10.1111/j.1748-1716.2006.01582.x
Moncada S, Higgs EA (2006) Nitric oxide and the vascular endothelium. Handb Exp Pharmacol 176:213–254. doi:10.1007/3-540-32967-6_7
Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A et al (1998) Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun 245:190–193. doi:10.1006/bbrc.1998.8267
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H et al (1999) T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99:2864–2870
Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J (2000) Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 97:2832–2835. doi:10.1073/pnas.97.6.2832
Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingorani AD (2006) Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review. Am J Epidemiol 164:921–935. doi:10.1093/aje/kwj302
MacCluer JW, Stern MP, Almasy L, Atwood LA, Blangero J, Comuzzie AG et al (1999) Genetics of atherosclerosis risk factors in Mexican Americans. Nutr Rev 57:S59–S65
Arar NH, Voruganti VS, Nath SD, Thameem F, Bauer R, Cole SA et al (2008) A genome-wide search for linkage to chronic kidney disease in a community-based sample: the SAFHS. Nephrol Dial Transplant 23:3184–3191
Dyke B (1994) PEDSYS, a Pedigree Data Management System. User’s manual. Population genetics laboratory technical report No. 2, 2nd edn. Southwest Foundation for Biomedical Research, San Antonio, TX 78245, 226 pp
Almasy L, Blangero J (2004) Exploring positional candidate genes: linkage conditional on measured genotype. Behav Genet 34:173–177. doi:10.1023/B:BEGE.0000013731.03827.69
Abecasis GR, Cookson WO, Cardon LR (2000) Pedigree tests of transmission disequilibrium. Eur J Hum Genet 8:545–551. doi:10.1038/sj.ejhg.5200494
Havill LM, Dyer TD, Richardson DK, Mahaney MC, Blangero J (2005) The quantitative trait linkage disequilibrium test: a more powerful alternative to the quantitative transmission disequilibrium test for use in the absence of population stratification. BMC Genet 6:S91. doi:10.1186/1471-2156-6-S1-S91
Burg M, Menne J, Ostendorf T, Kliem V, Floege J (1997) Genepolymorphisms of angiotensin converting enzyme and endothelial nitric oxide synthase in patients with primary glomerulonephritis. Clin Nephrol 48:205–211
Yokoyama K, Tsukada T, Matsuoka H et al (1998) High accumulation of endothelial nitric oxide synthase (ecNOS): a gene polymorphism in patients with end-stage renal disease. Nephron 79:360–361. doi:10.1159/000045069
Wang Y, Kikuchi S, Suzuki H, Nagase S, Koyama A (1999) Endothelial nitric oxide synthase gene polymorphism in intron 4 affects the progression of renal failure in non-diabetic renal diseases. Nephrol Dial Transplant 14:2898–2902. doi:10.1093/ndt/14.12.2898
Morita T, Ito H, Suehiro T, Tahara K, Matsumori A, Chikazawa H (1999) Effect of a polymorphism of endothelial nitric oxide synthase gene in Japanese patients with IgA nephropathy. Clin Nephrol 52:203–209
Fujita H, Narita T, Meguro H, Ishii T, Hanyu O, Suzuki K (2000) Lack of association between an ecNOS gene polymorphism and diabetic nephropathy in type 2 diabetic patients with proliferative diabetic retinopathy. Horm Metab Res 32:80–83. doi:10.1055/s-2007-978594
Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS (2000) Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int 57:405–413. doi:10.1046/j.1523-1755.2000.00860.x
Majid DS, Navar LG (2001) Nitric oxide in the control of renal hemodynamics and excretory function. Am J Hypertens 14:74S–82S. doi:10.1016/S0895-7061(01)02073-8
Majid DS, Williams A, Navar LG (1993) Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anaesthetized dogs. Am J Physiol Renal Physiol 262:F718–F722
Ochodnicky P, Henning RH, van Dokkum RP, de Zeeuw D (2006) Microalbuminuria and endothelial dysfunction: emerging targets for primary prevention of end-organ damage. J Cardiovasc Pharmacol 47:S151–S162. doi:10.1097/00005344-200606001-00009
Kone BC, Baylis C (1997) Biosynthesis and homeostatic roles of nitric oxide in the normal kidney. Am J Physiol 272:F561–F578
Thameem F, Puppala S, Arar NH et al (2008) Endothelial nitric oxide synthase (eNOS) gene polymorphisms and their association with type 2 diabetes-related traits in Mexican Americans. Diab Vasc Dis Res 5:109–113. doi:10.3132/dvdr.2008.018
Hoffmann IS, Tavares-Mordwinkin R, Castejon AM, Alfieri AB, Cubeddu LX (2005) Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Hum Hypertens 19:233–240
Puppala S, Arya R, Thameem F, Arar NH, Bhandari K, Lehman DM (2007) Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans. Diabetes 56:2818–2828. doi:10.2337/db06-0984
Freedman BI, Bowden DW, Rich SS, Xu J, Wagenknecht LE, Ziegler J et al (2008) Genome-wide linkage scans for renal function and albuminuria in Type 2 diabetes mellitus: the diabetes heart study. Diabet Med 25:268–276. doi:10.1111/j.1464-5491.2007.02361.x
Acknowledgments
We thank the members of SAFHS for their participation and cooperation. This study was supported by the Grant-in-Aid from the American Heart Association (FT), Carl W. Gottschalk Research Scholars of the American Society of Nephrology (FT), George O’Brien Kidney Research Center (P50 DK061597; HEA, FT), Norman S. Coplan grant from the Satellite Healthcare (FT), San Antonio Area Foundation (FT), VA-MERIT Review (HEA, NHA). The SAFHS is supported by NIH grant P01 HL45522. The development of SOLAR was supported by R01 MH59490. This work was supported by the National Center for Research Resources contracts UL1 RR025767 and KL2 RR025766 for the Institute for Integration of Medicine and Science.
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Nath, S.D., He, X., Voruganti, V.S. et al. The 27-bp repeat polymorphism in intron 4 (27 bp-VNTR) of endothelial nitric oxide synthase (eNOS) gene is associated with albumin to creatinine ratio in Mexican Americans. Mol Cell Biochem 331, 201–205 (2009). https://doi.org/10.1007/s11010-009-0159-5
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DOI: https://doi.org/10.1007/s11010-009-0159-5