MYH9 polymorphisms have been described to be associated with the risk of CKD in non-diabetic nephropathy, HIV nephropathy and FSGS. Predominating in black descendants, MHY9 genetic variants could partially explain the excess risk of CKD associated with African ancestry. However, recent data suggests that APOL1 gene co-segregate with MYH9, and could be the gene truly associated with CKD risk. In this study, we evaluated the role of MYH9 and APOL1 gene polymorphisms in the risk of CKD in Brazilian patients with lupus nephritis (LN). A retrospective analysis of 196 LN patients was done. MYH9 rs4821480, rs2032487, rs4821481 and rs3752462, APOL 1rs73885319, rs16996616, rs60910145, rs71785313, and APOL3 rs11089781 gene polymorphisms were determined. Genetic ancestry was ascertained both by autossomal ancestry and mitochondrial haplogroup. Primary outcome was defined as doubling of serum creatinine (DC) or end stage renal disease (ESRD). Sixty-two patients presented the PO. In our population, MYH9 and APOL1 were not in LD. None APOL polymorphism was associated with the PO, whereas rs3752462 MYH9 polymorphism showed a positive association (HR3.72, 95%CI 1.47–9.38, p = 0.005). When we analyzed the MYH9 E1 haplotype, the GCCT carriers (1 or 2 alelles present in 29.7% in the PO group vs. 18.5% in controls) showed a significant association to the risk of PO, even after adjustments for baseline estimated creatinine clearance and autossomal ancestry (HR 2.0, 95%CI 1.2–3.4, p = 0.01). Our results show that in our population MYH9, but not APOL1, gene polymorphisms confer an increased risk of CKD in LN patients, independently of race.
References
[1]
Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, et al. (2008) MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40: 1185–92. doi: 10.1038/ng.232
[2]
Freedman BI, Hicks PJ, Bostrom MA, Cunningham ME, Liu Y, et al. (2009) Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans. Kidney Int 75: 736–45. doi: 10.1038/ki.2008.701
[3]
Behar DM, Rosset S, Tzur S, Selig S, Yudkovsky G, et al. (2010) African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans. Hum Mol Genet 19: 1816–27. doi: 10.1093/hmg/ddq040
[4]
Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, et al. (2008) MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Gene t40: 1175–84. doi: 10.1038/ng.226
[5]
Bostrom MA, Freedman BI (2010) The Spectrum of MYH9-Associated Nephropathy. Clin J Am Soc Nephrol 5: 1107–13. doi: 10.2215/cjn.08721209
[6]
Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, et al. (2010) Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 128: 345–50. doi: 10.1007/s00439-010-0861-0
[7]
Genovese G, Tonna SJ, Knob AU, Appel GB, Katz A, et al. (2010) A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. Kidney Int 78: 698–704. doi: 10.1038/ki.2010.251
[8]
Franceschini N, Voruganti VS, Haack K, Almasy L, Laston S, et al. (2010) The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study. Hum Genet 127: 295–301. doi: 10.1007/s00439-009-0769-8
[9]
Alarcón GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, et al. (1999) Systemic lupus erythematosus in three ethnic groups: III. A comparison of characteristics early in the natural history of the LUMINA cohort. LUpus in MInority populations: NAture vs. Nurture. Lupus 8: 197–209. doi: 10.1191/096120399678847704
[10]
Freedman BI, Edberg JC, Comeau ME, Murea M, Bowden DW, et al. (2010) The non-muscle Myosin heavy chain 9 gene (MYH9) is not associated with lupus nephritis in African Americans. Am J Nephrol 32: 66–72. doi: 10.1159/000314688
[11]
Lin CP, Adrianto I, Lessard CJ, Kelly JA, Kaufman KM, et al. (2012) Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis. Genes Immun 13: 232–8. doi: 10.1038/gene.2011.82
[12]
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: 1271–7. doi: 10.1002/art.1780251101
[13]
Churg J, Bernstein J, Glassock RJ (1995) Renal Disease: Classification and Atlas of Glomerular Diseases. 2o ed. Igaku-Shoin Medical Pub
[14]
Buhaescu I, Covic A, Deray G (2007) Treatment of proliferative lupus nephritis—a critical approach. Semin Arthritis Rheum 36: 224–37.
[15]
Austin HA 3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, et al. (1986) Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314: 614–9. doi: 10.1056/nejm198603063141004
[16]
Sánchez E, Rasmussen A, Riba L, Acevedo-Vasquez E, Kelly JA, et al. (2012) Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations. Arthritis Rheum 64: 3687–94. doi: 10.1002/art.34650
[17]
Cardena MM, Ribeiro-Dos-Santos A, Santos S, Mansur AJ, Pereira AC, et al. (2013) Assessment of the Relationship between Self-Declared Ethnicity, Mitochondrial Haplogroups and Genomic Ancestry in Brazilian Individuals. PLoS One 8: e62005. doi: 10.1371/journal.pone.0062005
[18]
Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 35: 630–40. doi: 10.1002/art.1780350606
[19]
Levey AS, Lan SP, Corwin HL, Kasinath BS, Lachin J, et al. (1992) Progression and remission of renal disease in the Lupus Nephritis Collaborative Study. Results of treatment with prednisone and short-term oral cyclophosphamide. Ann Intern Med 116: 114–23. doi: 10.7326/0003-4819-116-2-114
[20]
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215. doi: 10.1093/nar/16.3.1215
[21]
Matsha TE, Masconi K, Yako YY, Hassan MS, Macharia M, et al. (2012) Polymorphisms in the non-muscle myosin heavy chain gene (MYH9) are associated with lower glomerular filtration rate in mixed ancestry diabetic subjects from South Africa. PLoS One 7: e52529. doi: 10.1371/journal.pone.0052529
[22]
Genovese G, Friedman DJ, Pollak MR (2013) APOL1 variants and kidney disease in people of recent African ancestry. Nat Rev Nephrol 9: 240–4. doi: 10.1038/nrneph.2013.34
[23]
Behar DM, Shlush LI, Maor C, Lorber M, Skorecki K (2006) Absence of HIV-associated nephropathy in Ethiopians. Am J Kidney Dis 47: 88–94. doi: 10.1053/j.ajkd.2005.09.023
[24]
Papeta N, Kiryluk K, Patel A, Sterken R, Kacak N, et al. (2011) APOL1variants increase risk for FSGS and HIVAN but not IgA nephropathy. J Am Soc Nephrol 22: 1991–6. doi: 10.1681/asn.2011040434
[25]
Larsen CP, Beggs ML, Saeed M, Walker PD (2013) Apolipoprotein l risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 24: 722–5. doi: 10.1681/asn.2012121180
[26]
Kanji Z, Powe CE, Wenger JB, Huang C, Ankers E, et al. (2011) Genetic variation in APOL1 associates with younger age at hemodialysis initiation. J Am Soc Nephrol 22: 2091–7. doi: 10.1681/asn.2010121234
[27]
Zhang Y, Conti MA, Malide D, Dong F, Wang A, et al. (2012) Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A. Blood 119: 238–50. doi: 10.1182/blood-2011-06-358853
[28]
Johnstone DB, Zhang J, George B, Léon C, Gachet C, et al. (2011) Podocyte-specific deletion of Myh9 encoding nonmuscle myosin heavy chain 2A predisposes mice to glomerulopathy. Mol Cell Biol 31: 2162–70. doi: 10.1128/mcb.05234-11
[29]
Müller T, Rumpel E, Hradetzky S, Bollig F, Wegner H, et al. (2011) Non-muscle myosin IIA is required for the development of the zebrafish glomerulus. Kidney Int 80: 1055–63. doi: 10.1038/ki.2011.256
[30]
Hays T, D'Agati VD, Garellek JA, Warren T, Trubin ME, et al. (2012) Glomerular MYH9 expression is reduced by HIV-1. AIDS 26: 797–803. doi: 10.1097/qad.0b013e328351f6cf
[31]
Monajemi H, Fontijn RD, Pannekoek H, Horrevoets AJ (2002) The apolipoprotein L gene cluster has emerged recently in evolution and is expressed in human vascular tissue. Genomics 79: 539–46. doi: 10.1006/geno.2002.6729
[32]
O'Toole JF, Madhavan SM, Konieczkowski M, Ganesan S, Barisoni LMC, et al. (2012) APOL1 Expression and Localization Pattern in Kidney Diseases with and without Association to Risk Genotype. J Am Soc Nephrol 23: 323A.
[33]
Chen Z, Freedman BI, Graham WD, Ross NA, Pollak MR, et al. (2012) Dose-Dependent Expression of APOL1 Protein Sensitizes Cell Death Pathways. J Am Soc Nephrol 23: 136A.
[34]
Hoy WE, Hughson MD, Winkler CA, Nelson GW, Douglas-Denton RN, et al. (2012) APOL1 Genotype and Kidney Microanatomy: Insights into the Predisposition of African Americans to Kidney Disease. J Am Soc Nephrol 23: 77A.
[35]
Estrella MM, Li M, Kao WHL, Gange SJ, Parekh RS (2012) APOL1 Is Associated with Proteinuria in HIV. J Am Soc Nephrol 23: 248A.
