Skip to main content
Top
Published in: BMC Medical Genetics 1/2012

Open Access 01-12-2012 | Research article

The Renalase Asp37Glu polymorphism is not associated with hypertension and cardiovascular events in an urban-based prospective cohort: the Malmö Diet and cancer study

Authors: Cristiano Fava, Martina Montagnana, Elisa Danese, Marketa Sjögren, Peter Almgren, Gunnar Engström, Bo Hedblad, Gian Cesare Guidi, Pietro Minuz, Olle Melander

Published in: BMC Medical Genetics | Issue 1/2012

Login to get access

Abstract

Background

Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies delineate a possible role of this enzyme in blood pressure (BP) maintenance and cardiac protection and two single nucleotide polymorphisms, RNLS rs2576178 A > G and rs2296545 C > G have been associated with hypertension. The latter SNP leads to a non synonymous Asp to Glu substitution deleting a flavin adenine dinucleotide (FAD) binding site with possible impaired functionality. We tested the hypothesis that these polymorphisms could affect BP levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes.

Methods

The polymorphisms were genotyped in 5696 participants of the population-based Cardiovascular Cohort of the "Malmö Diet and Cancer" (MDC-CC). The incidence of cardiovascular events (coronary events [n = 408], strokes [n = 330], heart failure [n = 190] and atrial fibrillation/flutter [n = 406]) was monitored for an average of approximately 15 years of follow-up.

Results

Both before and after adjustment for sex, age and BMI the polymorphisms did not show any effect on BP level and hypertension prevalence. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for cardiac and cerebrovascular events was not significantly different in carriers of different genotypes. A significant interaction was found between the rs2296545 C > G and age with respect to BP/hypertension.

Conclusions

Our data do not support a major role for these RNLS polymorphisms in determining BP level and incident events at population level. The positive interaction with age suggest that the effect of the rs2296545 C > G polymorphism, if any, could vary between different ages.
Appendix
Available only for authorised users
Literature
1.
go back to reference Desir GV: Regulation of blood pressure and cardiovascular function by renalase. Kidney Int. 2009, 76: 366-370. 10.1038/ki.2009.169.CrossRefPubMed Desir GV: Regulation of blood pressure and cardiovascular function by renalase. Kidney Int. 2009, 76: 366-370. 10.1038/ki.2009.169.CrossRefPubMed
2.
go back to reference Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S, Desir GV: Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 2005, 115: 1275-1280.CrossRefPubMedPubMedCentral Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S, Desir GV: Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 2005, 115: 1275-1280.CrossRefPubMedPubMedCentral
3.
go back to reference Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, Desir GV: Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008, 117: 1277-1282. 10.1161/CIRCULATIONAHA.107.732032.CrossRefPubMed Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, Desir GV: Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008, 117: 1277-1282. 10.1161/CIRCULATIONAHA.107.732032.CrossRefPubMed
4.
go back to reference Ghosh SS, Krieg RJ, Sica DA, Wang R, Fakhry I, Gehr T: Cardiac hypertrophy in neonatal nephrectomized rats: the role of the sympathetic nervous system. Pediatr Nephrol. 2009, 24: 367-377. 10.1007/s00467-008-0978-8.CrossRefPubMed Ghosh SS, Krieg RJ, Sica DA, Wang R, Fakhry I, Gehr T: Cardiac hypertrophy in neonatal nephrectomized rats: the role of the sympathetic nervous system. Pediatr Nephrol. 2009, 24: 367-377. 10.1007/s00467-008-0978-8.CrossRefPubMed
5.
go back to reference Wu Y, Xu J, Velazquez H, Wang P, Li G, Liu D, Sampaio-Maia B, Quelhas-Santos J, Russell K, Russell R, Flavell RA, Pestana M, Giordano F, Desir GV: Renalase deficiency aggravates ischemic myocardial damage. Kidney Int. 2011, 79: 853-860. 10.1038/ki.2010.488.CrossRefPubMed Wu Y, Xu J, Velazquez H, Wang P, Li G, Liu D, Sampaio-Maia B, Quelhas-Santos J, Russell K, Russell R, Flavell RA, Pestana M, Giordano F, Desir GV: Renalase deficiency aggravates ischemic myocardial damage. Kidney Int. 2011, 79: 853-860. 10.1038/ki.2010.488.CrossRefPubMed
6.
go back to reference Gu R, Lu W, Xie J, Bai J, Xu B: Renalase deficiency in heart failure model of rats-a potential mechanism underlying circulating norepinephrine accumulation. PLoS One. 2011, 6: e14633-10.1371/journal.pone.0014633.CrossRefPubMedPubMedCentral Gu R, Lu W, Xie J, Bai J, Xu B: Renalase deficiency in heart failure model of rats-a potential mechanism underlying circulating norepinephrine accumulation. PLoS One. 2011, 6: e14633-10.1371/journal.pone.0014633.CrossRefPubMedPubMedCentral
7.
go back to reference Zhao Q, Fan Z, He J, Chen S, Li H, Zhang P, Wang L, Hu D, Huang J, Qiang B, Gu D: Renalase gene is a novel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population. J Mol Med. 2007, 85: 877-885. 10.1007/s00109-006-0151-4.CrossRefPubMed Zhao Q, Fan Z, He J, Chen S, Li H, Zhang P, Wang L, Hu D, Huang J, Qiang B, Gu D: Renalase gene is a novel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population. J Mol Med. 2007, 85: 877-885. 10.1007/s00109-006-0151-4.CrossRefPubMed
8.
go back to reference Farzaneh-Far R, Desir GV, Na B, Schiller NB, Whooley MA: A functional polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, dysfunction, and ischemia: data from the heart and soul study. PLoS One. 2010, 5: e13496-10.1371/journal.pone.0013496.CrossRefPubMedPubMedCentral Farzaneh-Far R, Desir GV, Na B, Schiller NB, Whooley MA: A functional polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, dysfunction, and ischemia: data from the heart and soul study. PLoS One. 2010, 5: e13496-10.1371/journal.pone.0013496.CrossRefPubMedPubMedCentral
9.
go back to reference Berglund G, Elmstahl S, Janzon L, Larsson SA: The Malmo Diet and Cancer Study. Design and feasibility. J Intern Med. 1993, 233: 45-51. 10.1111/j.1365-2796.1993.tb00647.x.CrossRefPubMed Berglund G, Elmstahl S, Janzon L, Larsson SA: The Malmo Diet and Cancer Study. Design and feasibility. J Intern Med. 1993, 233: 45-51. 10.1111/j.1365-2796.1993.tb00647.x.CrossRefPubMed
10.
go back to reference Zia E, Hedblad B, Pessah-Rasmussen H, Berglund G, Janzon L, Engstrom G: Blood pressure in relation to the incidence of cerebral infarction and intracerebral hemorrhage. Hypertensive hemorrhage: debated nomenclature is still relevant. Stroke. 2007, 38: 2681-2685. 10.1161/STROKEAHA.106.479725.CrossRefPubMed Zia E, Hedblad B, Pessah-Rasmussen H, Berglund G, Janzon L, Engstrom G: Blood pressure in relation to the incidence of cerebral infarction and intracerebral hemorrhage. Hypertensive hemorrhage: debated nomenclature is still relevant. Stroke. 2007, 38: 2681-2685. 10.1161/STROKEAHA.106.479725.CrossRefPubMed
11.
go back to reference Nilsson PM, Engstrom G, Hedblad B: The metabolic syndrome and incidence of cardiovascular disease in non-diabetic subjects–a population-based study comparing three different definitions. Diabet Med. 2007, 24: 464-472. 10.1111/j.1464-5491.2007.02142.x.CrossRefPubMed Nilsson PM, Engstrom G, Hedblad B: The metabolic syndrome and incidence of cardiovascular disease in non-diabetic subjects–a population-based study comparing three different definitions. Diabet Med. 2007, 24: 464-472. 10.1111/j.1464-5491.2007.02142.x.CrossRefPubMed
12.
go back to reference Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B: Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007, 25: 1105-1187. 10.1097/HJH.0b013e3281fc975a.CrossRefPubMed Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B: Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007, 25: 1105-1187. 10.1097/HJH.0b013e3281fc975a.CrossRefPubMed
13.
go back to reference Cui JS, Hopper JL, Harrap SB: Antihypertensive treatments obscure familial contributions to blood pressure variation. Hypertension. 2003, 41: 207-210. 10.1161/01.HYP.0000044938.94050.E3.CrossRefPubMed Cui JS, Hopper JL, Harrap SB: Antihypertensive treatments obscure familial contributions to blood pressure variation. Hypertension. 2003, 41: 207-210. 10.1161/01.HYP.0000044938.94050.E3.CrossRefPubMed
14.
go back to reference Smith JG, Newton-Cheh C, Almgren P, Struck J, Morgenthaler NG, Bergmann A, Platonov PG, Hedblad B, Engström G, Wang TJ, Melander O: Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation. J Am Coll Cardiol. 2010, 56: 1712-1719. 10.1016/j.jacc.2010.05.049.CrossRefPubMedPubMedCentral Smith JG, Newton-Cheh C, Almgren P, Struck J, Morgenthaler NG, Bergmann A, Platonov PG, Hedblad B, Engström G, Wang TJ, Melander O: Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation. J Am Coll Cardiol. 2010, 56: 1712-1719. 10.1016/j.jacc.2010.05.049.CrossRefPubMedPubMedCentral
15.
go back to reference Hoek FJ, Kemperman FA, Krediet RT: A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant. 2003, 18: 2024-2031. 10.1093/ndt/gfg349.CrossRefPubMed Hoek FJ, Kemperman FA, Krediet RT: A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant. 2003, 18: 2024-2031. 10.1093/ndt/gfg349.CrossRefPubMed
16.
go back to reference Ingelsson E, Arnlov J, Sundstrom J, Lind L: The validity of a diagnosis of heart failure in a hospital discharge register. Eur J Heart Fail. 2005, 7: 787-791. 10.1016/j.ejheart.2004.12.007.CrossRefPubMed Ingelsson E, Arnlov J, Sundstrom J, Lind L: The validity of a diagnosis of heart failure in a hospital discharge register. Eur J Heart Fail. 2005, 7: 787-791. 10.1016/j.ejheart.2004.12.007.CrossRefPubMed
17.
go back to reference Hammar N, Alfredsson L, Rosen M, Spetz CL, Kahan T, Ysberg AS: A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. Int J Epidemiol. 2001, 30 (Suppl 1): S30-S34. 10.1093/ije/30.suppl_1.S30.CrossRefPubMed Hammar N, Alfredsson L, Rosen M, Spetz CL, Kahan T, Ysberg AS: A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. Int J Epidemiol. 2001, 30 (Suppl 1): S30-S34. 10.1093/ije/30.suppl_1.S30.CrossRefPubMed
18.
go back to reference Smith JG, Platonov PG, Hedblad B, Engstrom G, Melander O: Atrial fibrillation in the Malmo Diet and Cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol. 2010, 25: 95-102. 10.1007/s10654-009-9404-1.CrossRefPubMed Smith JG, Platonov PG, Hedblad B, Engstrom G, Melander O: Atrial fibrillation in the Malmo Diet and Cancer study: a study of occurrence, risk factors and diagnostic validity. Eur J Epidemiol. 2010, 25: 95-102. 10.1007/s10654-009-9404-1.CrossRefPubMed
19.
go back to reference Livak KJ: Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal. 1999, 14: 143-149. 10.1016/S1050-3862(98)00019-9.CrossRefPubMed Livak KJ: Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal. 1999, 14: 143-149. 10.1016/S1050-3862(98)00019-9.CrossRefPubMed
20.
go back to reference Desir GV: Renalase is a novel renal hormone that regulates cardiovascular function. J Am Soc Hypertens. 2007, 1: 99-103. 10.1016/j.jash.2006.12.001.CrossRefPubMed Desir GV: Renalase is a novel renal hormone that regulates cardiovascular function. J Am Soc Hypertens. 2007, 1: 99-103. 10.1016/j.jash.2006.12.001.CrossRefPubMed
21.
go back to reference Puddu PE, Menotti A, Tolonen H, Nedeljkovic S, Kafatos AG: Determinants of 40-year all-cause mortality in the European cohorts of the Seven Countries Study. Eur J Epidemiol. 2011, 26: 595-608. 10.1007/s10654-011-9600-7.CrossRefPubMed Puddu PE, Menotti A, Tolonen H, Nedeljkovic S, Kafatos AG: Determinants of 40-year all-cause mortality in the European cohorts of the Seven Countries Study. Eur J Epidemiol. 2011, 26: 595-608. 10.1007/s10654-011-9600-7.CrossRefPubMed
22.
go back to reference Menotti A, Lanti M, Kafatos A, Nissinen A, Dontas A, Nedeljkovic S, Kromhout D, Seven Countries Study: The role of a baseline casual blood pressure measurement and of blood pressure changes in middle age in prediction of cardiovascular and all-cause mortality occurring late in life: a cross-cultural comparison among the European cohorts of the Seven Countries Study. J Hypertens. 2004, 22: 1683-1690. 10.1097/00004872-200409000-00011.CrossRefPubMed Menotti A, Lanti M, Kafatos A, Nissinen A, Dontas A, Nedeljkovic S, Kromhout D, Seven Countries Study: The role of a baseline casual blood pressure measurement and of blood pressure changes in middle age in prediction of cardiovascular and all-cause mortality occurring late in life: a cross-cultural comparison among the European cohorts of the Seven Countries Study. J Hypertens. 2004, 22: 1683-1690. 10.1097/00004872-200409000-00011.CrossRefPubMed
23.
go back to reference Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G, Melander O: Association between adducin-1 G460W variant and blood pressure in Swedes is dependent on interaction with body mass index and gender. Am J Hypertens. 2007, 20: 981-989. 10.1016/j.amjhyper.2007.04.007.CrossRefPubMed Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G, Melander O: Association between adducin-1 G460W variant and blood pressure in Swedes is dependent on interaction with body mass index and gender. Am J Hypertens. 2007, 20: 981-989. 10.1016/j.amjhyper.2007.04.007.CrossRefPubMed
24.
go back to reference Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G, Melander O: The functional variant of the CLC-Kb channel T481S is not associated with blood pressure or hypertension in Swedes. J Hypertens. 2007, 25: 111-116. 10.1097/HJH.0b013e3280103a5a.CrossRefPubMed Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G, Melander O: The functional variant of the CLC-Kb channel T481S is not associated with blood pressure or hypertension in Swedes. J Hypertens. 2007, 25: 111-116. 10.1097/HJH.0b013e3280103a5a.CrossRefPubMed
25.
go back to reference Fava C, Montagnana M, Almgren P, Rosberg L, Lippi G, Hedblad B, Engström G, Berglund G, Minuz P, Melander O: The V433M variant of the CYP4F2 is associated with ischemic stroke in male Swedes beyond its effect on blood pressure. Hypertension. 2008, 52: 373-380. 10.1161/HYPERTENSIONAHA.108.114199.CrossRefPubMed Fava C, Montagnana M, Almgren P, Rosberg L, Lippi G, Hedblad B, Engström G, Berglund G, Minuz P, Melander O: The V433M variant of the CYP4F2 is associated with ischemic stroke in male Swedes beyond its effect on blood pressure. Hypertension. 2008, 52: 373-380. 10.1161/HYPERTENSIONAHA.108.114199.CrossRefPubMed
Metadata
Title
The Renalase Asp37Glu polymorphism is not associated with hypertension and cardiovascular events in an urban-based prospective cohort: the Malmö Diet and cancer study
Authors
Cristiano Fava
Martina Montagnana
Elisa Danese
Marketa Sjögren
Peter Almgren
Gunnar Engström
Bo Hedblad
Gian Cesare Guidi
Pietro Minuz
Olle Melander
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2012
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-13-57

Other articles of this Issue 1/2012

BMC Medical Genetics 1/2012 Go to the issue