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Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N=579) and African-Americans (AAs) (N=407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P<2.03 × 10−3 were observed between LN and MYH9 in EAs (N=4620), with the most pronounced association at rs2157257 (P=4.7 × 10−4, odds ratio (OR)=1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P=0.0019, OR=2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

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Acknowledgements

We thank all study participants, SLE and controls in this study as well as all the staff who assisted in their recruitment. We gratefully acknowledge the following individuals for their generous contribution in genotyping samples: Dr Peter K Gregersen, Drs Sandra D’Alfonso (Italy), Rafaella Scorza (Italy), Peter Junker and Helle Laustrup (Denmark), Marc Bijl (Holland), Emoke Endreffy (Hungary), Carlos Vasconcelos and Berta Martins da Silva (Portugal), Ana Suarez and Carmen Gutierrez (Spain), Iñigo Rúa-Figueroa (Spain) and Dr Cintia Garcilazo (Argentina). For the AADEA collaboration: Norberto Ortego-Centeno (Spain), Juan Jimenez-Alonso (Spain), Enrique de Ramon (Spain) and Julio Sanchez-Roman (Spain). For the GENLES collaboration: Dr Mario Cardiel (Mexico), Dr Ignacio García de la Torre (Mexico), Marco Maradiaga (Mexico), José F Moctezuma (Mexico), Dr Eduardo Acevedo (Peru), Cecilia Castel and Mabel Busajm (Argentina), Jorge Musuruana (Argentina). Other participants from the Argentine Collaborative Group are: Hugo R Scherbarth MD, Pilar C Marino MD, Estela L Motta MD; Susana Gamron MD, Cristina Drenkard MD, Emilia Menso MD; Alberto Allievi MD, Guillermo A Tate MD; Jose L Presas MD; Simon A Palatnik MD, Marcelo Abdala MD, Mariela Bearzotti PhD; Alejandro Alvarellos MD, Francisco Caeiro MD, Ana Bertoli MD; Sergio Paira MD, Susana Roverano MD; Cesar E Graf MD, Estela Bertero PhD; Carolina Guillerón MD, Sebastian Grimaudo PhD, Jorge Manni MD; Luis J Catoggio MD, Enrique R Soriano MD, Carlos D Santos MD; Cristina Prigione MD, Fernando A Ramos MD, Sandra M Navarro MD; Guillermo A Berbotto MD, Marisa Jorfen MD, Elisa J Romero PhD; Mercedes A Garcia MD, Juan C Marcos MD, Ana I Marcos MD; Carlos E Perandones MD, Alicia Eimon MD; Cristina G Battagliotti MD. We also would like to knowledge Mary C Comeau MA; Miranda C Marion MA; Paula S Ramos PhD; Summer Frank MPH and Mai Li Zhu MS for their assistance in genotyping, quality control analyses and clinical data management, and everyone at the Lupus Family Registry and Repository (LFRR) for data collection and maintenance. The work has been funded principally by the US National Institutes of Health grants R01 AI063274 and R01 AR056360 (PMG); R01 AR043274 (KLM); N01 AR62277, R37 24717, R01 AR042460, P01 AI083194, P20 RR020143, R01 DE018209 (JBH); P01 AR49084 (RPK and EEB); R01 AR33062 (RPK); P30 AR055385 (EEB); K08 AI083790, LRP AI071651, UL1 RR024999 (TBN); R01CA141700, RC1 AR058621 (MEAR); R01AR051545-01A2, ULI RR025014-02 (AMS); P30 AR053483, N01 AI50026 (JAJ and JMG); P20 RR015577 (JAJ); R21 AI070304 (SAB); P30 RR031152, U19 AI082714, P30 AR053483, RC1 AR05884 (JAJ and JMG); R01 AR43814 (BPT); P60 AR053308, M01 RR-00079 (LAC); R01 AR043727, UL1 RR025005 (MAP); K24 AR002138, P60-2 AR30692, P01 AR49084, UL1RR025741 (RRG); UL1 RR029882, P60 AR049459 (GSG and DLK). A portion of this study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A080588; SCB). Additional support was granted from the Alliance for Lupus Research (KLM); Merit Award from the US Department of Veterans Affairs (JBH and GSG); the Swedish Research Council for Medicine, Gustaf Vth-80th Jubilee Fund and Swedish Association Against Rheumatism, Instituto de Salud Carlos III, Oklahoma Center for Advancement of Science and Technology (OCAST) HR09-106 (MEAR); the European Science Foundation funds the BIOLUPUS network (MEAR coordinator); Federico Wilhelm Agricola Foundation Research grant (BPE); The Barrett Scholarship Fund OMRF (CJL); Lupus Research Institute (TBN, BPT); The Alliance for Lupus Research (TBN, LAC, MEAR and COJ); the Arthritis National Research Foundation Eng Tan Scholar Award (TBN); Arthritis Foundation (PMG and AMS); the Lupus Foundation of Minnesota (PMG and KLM); the Wellcome Trust (TJV); Arthritis Research UK (TJV); Kirkland Scholar Award (LAC, JAJ) and Wake Forest University Health Sciences Center for Public Health Genomics (CDL). The work reported on in this publication has been in part financially supported by the ESF, in the framework of the Research Networking Programme European Science Foundation-The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS) 07-RNP-083.

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Lin, C., Adrianto, I., Lessard, C. et al. Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis. Genes Immun 13, 232–238 (2012). https://doi.org/10.1038/gene.2011.82

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