Abstract
The renin–angiotensin system (RAS) is a strong candidate as a mediator for the development and progression of lupus nephritis (LN). We performed an ethnically stratified analysis of 642 systemic lupus erythematosus (SLE) patients to determine whether various functional RAS gene polymorphisms are associated with SLE renal outcomes. Patients were genotyped for two angiotensin-converting enzyme (ACE) gene polymorphisms: Alu insertion/deletion (I/D) and 23 949 (CT)2/3, and for two angiotensinogen (Atg) gene polymorphisms: M235T and C-532T. Multivariate analyses demonstrated associations between the ACE I/D, ACE (CT)2/3 and Atg C-532T functional polymorphisms and LN among Asians. In stratified analyses among LN cases according to high vs low glomerular filtration rate (GFR), associations remained significant for the ACE D (odds ratio (OR) 5.9, P=0.001) and (CT)2 (OR 6.2, P=0.001) alleles among Asian subjects with low GFR. Lastly, we found allelic dose-dependent associations between the ACE I/D (P=0.003), ACE (CT)2/3 (P=0.005) and Atg M235T (P=0.04) polymorphisms, and GFR analyzed as a continuous variable among Asians. These findings suggest a significant role for ACE and Atg gene sequence variation and severity of LN among Asians with SLE.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cervera R, Khamashta MA, Font J et al. Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1000 patients. European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1999; 78: 167–175.
Deapen D, Escalante A, Weinrib L et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311–317.
Freedman BI, Wilson CH, Spray BJ, Tuttle AB, Olorenshaw IM, Kammer GM . Familial clustering of end-stage renal disease in blacks with lupus nephritis. Am J Kidney Dis 1997; 29: 729–732.
Schelling JR, Zarif L, Sehgal A, Iyengar S, Sedor JR . Genetic susceptibility to end-stage renal disease. Curr Opin Nephrol Hypertens 1999; 8: 465–472.
Tsao BP . Genetic susceptibility to lupus nephritis. Lupus 1998; 7: 585–590.
Theofilopoulos AN, Kono DH . Genetics of systemic autoimmunity and glomerulonephritis in mouse models of lupus. Nephrol Dial Transplant 2001; 16 (Suppl 6): 65–67.
Taal MW, Omer SA, Nadim MK, Mackenzie HS . Cellular and molecular mediators in common pathway mechanisms of chronic renal disease progression. Curr Opin Nephrol Hypertens 2000; 9: 323–331.
Klahr S, Morrissey JJ . The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney International 2000; 57 (Suppl 75): S7–S14.
Nataraj C, Oliverio MI, Mannon RB et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J Clin Invest 1999; 104: 1693–1701.
Suzuki Y, Ruiz-Ortega M, Egido J . Angiotensin II: a double-edged sword in inflammation. J Nephrol 2000; 13 (Suppl 3): S101–S110.
Lai KN, Leung JC, Lai KB, To WY, Yeung VT, Lai FM . Gene expression of the renin–angiotensin system in human kidney. J Hypertens 1998; 16: 91–102.
Taal MW, Chertow GM, Rennke HG et al. Mechanisms underlying renoprotection during renin–angiotensin system blockade. Am J Physiol Renal Physiol 2001; 280: F343–F355.
Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE . Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000; 35: 695–707.
Parsa A, Peden E, Lum RF et al. Association of angiotensin-converting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families. Genes Immun 2002; 3 (Suppl 1): S42–S46.
Mizuiri S, Hemmi H, Kumanomidou H et al. Angiotensin-converting enzyme (ACE) I/D genotype and renal ACE gene expression. Kidney Int 2001; 60: 1124–1130.
Paillard F, Chansel D, Brand E et al. Genotype–phenotype relationships for the renin–angiotensin–aldosterone system in a normal population. Hypertension 1999; 34: 423–429.
Staessen JA, Wang JG, Ginocchio G et al. The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk. J Hypertens 1997; 15 (Part 2): 1579–1592.
Kunz R, Bork JP, Fritsche L, Ringel J, Sharma AM . Association between the angiotensin-converting enzyme-insertion/deletion polymorphism and diabetic nephropathy: a methodologic appraisal and systematic review. J Am Soc Nephrol 1998; 9: 1653–1663.
Zhu X, Bouzekri N, Southam L et al. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet 2001; 68: 1139–1148.
Lalouel JM, Rohrwasser A, Terreros D, Morgan T, Ward K . Angiotensinogen in essential hypertension: from genetics to nephrology. J Am Soc Nephrol 2001; 12: 606–615.
Staessen JA, Kuznetsova T, Wang JG, Emelianov D, Vlietinck R, Fagard R . M235T angiotensinogen gene polymorphism and cardiovascular renal risk. J Hypertens 1999; 17: 9–17.
Brand E, Chatelain N, Paillard F et al. Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis. Eur J Hum Genet 2002; 10: 715–723.
Nakajima T, Jorde LB, Ishigami T et al. Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet 2002; 70: 108–123.
Lovati E, Richard A, Frey BM, Frey FJ, Ferrari P . Genetic polymorphisms of the renin–angiotensin–aldosterone system in end-stage renal disease. Kidney Int 2001; 60: 46–54.
Rogus JJ, Moczulski D, Freire MB, Yang Y, Warram JH, Krolewski AS . Diabetic nephropathy is associated with AGT polymorphism T235: results of a family-based study. Hypertension 1998; 31: 627–631.
Hsu SI, Ramirez SB, Winn MP, Bonventre JV, Owen WF . Evidence for genetic factors in the development and progression of IgA nephropathy. Kidney Int 2000; 57: 1818–1835.
McLaughlin KJ, Harden PN, Ueda S, Boulton-Jones JM, Connell JM, Jardine AG . The role of genetic polymorphisms of angiotensin-converting enzyme in the progression of renal diseases. Hypertension 1996; 28: 912–915.
Guan T, Lui Z, Chen Z . Angiotensin-converting enzyme gene polymorphism and the clinical pathological features and progression in lupus nephritis. Zhonghua Nei Ke Za Zhi 1997; 36: 461–464.
Uhm WS, Lee HS, Chung YH et al. Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE. Lupus 2002; 11: 227–233.
Akai Y, Sato H, Iwano M et al. Association of an insertion polymorphism of angiotensin-converting enzyme gene with the activity of lupus nephritis. Clin Nephrol 1999; 51: 141–146.
Tassiulas IO, Aksentijevich I, Salmon JE et al. Angiotensin I converting enzyme gene polymorphisms in systemic lupus erythematosus: decreased prevalence of DD genotype in African American patients. Clin Nephrol 1998; 50: 8–13.
Kaufman KM, Kelly J, Gray-McGuire C et al. Linkage analysis of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and systemic lupus erythematosus. Mol Cell Endocrinol 2001; 177: 81–85.
Prkacin I, Novak B, Sertic J, Mrzljak A . Angiotensin-converting enzyme gene polymorphism in patients with systemic lupus. Acta Med Croat 2001; 55: 73–76.
Molad Y, Gal E, Magal N et al. Renal outcome and vascular morbidity in systemic lupus erythematosus (SLE): lack of association with the angiotensin-converting enzyme gene polymorphism. Semin Arthritis Rheum 2000; 30: 132–137.
Zabaleta-Lanz M, Vargas-Arenas RE, Tapanes F, Daboin I, Atahualpa Pinto J, Bianco NE . Silent nephritis in systemic lupus erythematosus. Lupus 2003; 12: 26–30.
Seligman VA, Lum RF, Olson JL, Li H, Criswell LA . Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med 2002; 112: 726–729.
Barr RG, Seliger S, Appel GB et al. Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity. Nephrol Dial Transplant 2003; 18: 2039–2046.
Sayed-Tabatabaei FA, Houwing-Duistermaat JJ, van Duijn CM, Witteman JC . Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis. Stroke 2003; 34: 1634–1639.
Ortiz MA, De Prado A, Donate T et al. Angiotensin-converting enzyme polymorphism gene and evolution of nephropathy to end-stage renal disease. Nephrology (Carlton) 2003; 8: 171–176.
Yoshida H, Kon V, Ichikawa I . Polymorphisms of the renin–angiotensin system genes in progressive renal diseases. Kidney Int 1996; 50: 732–744.
Lee WC . Searching for disease-susceptibility loci by testing for Hardy–Weinberg disequilibrium in a gene bank of affected individuals. Am J Epidemiol 2003; 158: 397–400.
Cox R, Bouzekri N, Martin S et al. Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides. Hum Mol Genet 2002; 11: 2969–2977.
Zhu X, Yan D, Cooper RS et al. Linkage disequilibrium and haplotype diversity in the genes of the renin–angiotensin system: findings from the family blood pressure program. Genome Res 2003; 13: 173–181.
Rothman KJ . No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–46.
Savitz DA, Olshan AF . Multiple comparisons and related issues in the interpretation of epidemiologic data. Am J Epidemiol 1995; 142: 904–908.
Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.
Hochberg MC . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997; 40: 1725.
Patel SS, Kimmel PL, Singh A . New clinical practice guidelines for chronic kidney disease: a framework for K/DOQI. Semin Nephrol 2002; 22: 449–458.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D . A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–470.
Bali D, Gourley S, Kostyu DD et al. Genetic analysis of multiplex rheumatoid arthritis families. Genes Immun 1999; 1: 28–36.
Acknowledgements
This work was supported by NIH R01 AR44804, K24 AR02175, ES09911, T32 DK07219, DK 39776 and a grant from the National Kidney Foundation. This study was carried out in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01 RR-00079, US Public Health Service.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Parsa, A., Lovett, D., Peden, E. et al. Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis. Genes Immun 6, 217–224 (2005). https://doi.org/10.1038/sj.gene.6364179
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gene.6364179
Keywords
This article is cited by
-
The beneficial role of vitamin D in systemic lupus erythematosus (SLE)
Clinical Rheumatology (2012)