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Grant Details

Grant Number: 1R01CA141700-01 Interpret this number
Primary Investigator: Alarcon-Riquelme, Marta
Organization: Oklahoma Medical Research Foundation
Project Title: Fine Mapping and Replication of a Genome-Wide Association Scan for Sle in Hispani
Fiscal Year: 2009


Abstract

DESCRIPTION (provided by applicant): The International Consortium on the Genetics of Lupus (SLEGEN) published a genome wide association study (GWAS) with multiple replications of the major associations with Systemic Lupus Erythematosus (SLE) (Nat Gen 40:204, 2008), identifying 18 genetic effects, 13 of which were not previously described. This study was confined to European-ancestry women and we know that there are major differences between ancestral groups with regard to lupus susceptibility. For example, the Hispanics studied to date do not have a strong HLA association, which in European-ancestry women is the strongest association (OR=2.36, p<10E-50). We propose to use the resources of this RFA-CA-09-003 "Replication and Fine-Mapping Studies for the Genes Environment and Health Initiative (GEI)" to replicate candidate associations from the GWAS and other studies in Amerindian admixed Hispanics by testing 38,000 bead types (about 33,000 markers) in 3440 Amerindian admixed Hispanics, half cases and half controls. We will maximize the Amerindian component selecting populations that have high Amerindian content and low African ancestry. Data cleaning and stratification correction will follow our previous experience and exploit recent advances (e.g., random projection). These Amerindian admixed Hispanics will make possible completing an experiment underway with 38,000 bead types in 14,000 subjects (lupus cases and controls) of European, African-American, and East Asian ancestry (funded from other sources). This will make trans-ancestry mapping of genetic effects possible. Trios and additional Amerindian admixed Hispanic case and control materials are available for additional replication, fine mapping, and sequencing, which will be organized subsequently, beyond the funding requested herein. We expect to identify genes important for Amerindian admixed Hispanics, to identify whether the risk alleles are from European or Native American genomes, and to use subjects from other ancestral origins to further restrict their genomic location. These genes are important in lupus pathogenesis and their discovery and character will spawn new diagnostic and therapeutic approaches to this deadly disorder.



Publications

Transancestral mapping and genetic load in systemic lupus erythematosus.
Authors: Langefeld C.D. , Ainsworth H.C. , Cunninghame Graham D.S. , Kelly J.A. , Comeau M.E. , Marion M.C. , Howard T.D. , Ramos P.S. , Croker J.A. , Morris D.L. , et al. .
Source: Nature Communications, 2017-07-17 00:00:00.0; 8, p. 16021.
EPub date: 2017-07-17 00:00:00.0.
PMID: 28714469
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Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production.
Authors: Deng Y. , Zhao J. , Sakurai D. , Sestak A.L. , Osadchiy V. , Langefeld C.D. , Kaufman K.M. , Kelly J.A. , James J.A. , Petri M.A. , et al. .
Source: Annals Of The Rheumatic Diseases, 2016 Nov; 75(11), p. 2007-2013.
PMID: 26783109
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Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
Authors: Alarcón-Riquelme M.E. , Ziegler J.T. , Molineros J. , Howard T.D. , Moreno-Estrada A. , Sánchez-Rodríguez E. , Ainsworth H.C. , Ortiz-Tello P. , Comeau M.E. , Rasmussen A. , et al. .
Source: Arthritis & Rheumatology (hoboken, N.j.), 2016 Apr; 68(4), p. 932-43.
PMID: 26606652
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Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA.
Authors: Zhao J. , Giles B.M. , Taylor R.L. , Yette G.A. , Lough K.M. , Ng H.L. , Abraham L.J. , Wu H. , Kelly J.A. , Glenn S.B. , et al. .
Source: Annals Of The Rheumatic Diseases, 2016 Jan; 75(1), p. 242-52.
PMID: 25180293
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Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus.
Authors: Zhao J. , Wu H. , Langefeld C.D. , Kaufman K.M. , Kelly J.A. , Bae S.C. , Marta E. Alarcón-Riquelme for the BIOLUPUS and GENLES networks , Alarcón G.S. , Anaya J.M. , Criswell L.A. , et al. .
Source: Clinical Immunology (orlando, Fla.), 2015 Dec; 161(2), p. 157-62.
PMID: 26385092
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Genomic Insights into the Ancestry and Demographic History of South America.
Authors: Homburger J.R. , Moreno-Estrada A. , Gignoux C.R. , Nelson D. , Sanchez E. , Ortiz-Tello P. , Pons-Estel B.A. , Acevedo-Vasquez E. , Miranda P. , Langefeld C.D. , et al. .
Source: Plos Genetics, 2015 Dec; 11(12), p. e1005602.
PMID: 26636962
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Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome.
Authors: Vu¿kovi¿ F. , Krišti¿ J. , Gudelj I. , Teruel M. , Keser T. , Pezer M. , Pu¿i¿-Bakovi¿ M. , Štambuk J. , Trbojevi¿-Akma¿i¿ I. , Barrios C. , et al. .
Source: Arthritis & Rheumatology (hoboken, N.j.), 2015 Nov; 67(11), p. 2978-89.
PMID: 26200652
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Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.
Authors: Kariuki S.N. , Ghodke-Puranik Y. , Dorschner J.M. , Chrabot B.S. , Kelly J.A. , Tsao B.P. , Kimberly R.P. , Alarcón-Riquelme M.E. , Jacob C.O. , Criswell L.A. , et al. .
Source: Genes And Immunity, 2015 Jan-Feb; 16(1), p. 15-23.
PMID: 25338677
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GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.
Authors: Armstrong D.L. , Zidovetzki R. , Alarcón-Riquelme M.E. , Tsao B.P. , Criswell L.A. , Kimberly R.P. , Harley J.B. , Sivils K.L. , Vyse T.J. , Gaffney P.M. , et al. .
Source: Genes And Immunity, 2014 Sep; 15(6), p. 347-54.
PMID: 24871463
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Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.
Authors: Guthridge J.M. , Lu R. , Sun H. , Sun C. , Wiley G.B. , Dominguez N. , Macwana S.R. , Lessard C.J. , Kim-Howard X. , Cobb B.L. , et al. .
Source: American Journal Of Human Genetics, 2014-04-03 00:00:00.0; 94(4), p. 586-98.
PMID: 24702955
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Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations.
Authors: Kim-Howard X. , Sun C. , Molineros J.E. , Maiti A.K. , Chandru H. , Adler A. , Wiley G.B. , Kaufman K.M. , Kottyan L. , Guthridge J.M. , et al. .
Source: Human Molecular Genetics, 2014-03-15 00:00:00.0; 23(6), p. 1656-68.
EPub date: 2014-03-15 00:00:00.0.
PMID: 24163247
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Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.
Authors: Kaufman K.M. , Zhao J. , Kelly J.A. , Hughes T. , Adler A. , Sanchez E. , Ojwang J.O. , Langefeld C.D. , Ziegler J.T. , Williams A.H. , et al. .
Source: Annals Of The Rheumatic Diseases, 2013 Mar; 72(3), p. 437-44.
PMID: 22904263
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MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus.
Authors: Deng Y. , Zhao J. , Sakurai D. , Kaufman K.M. , Edberg J.C. , Kimberly R.P. , Kamen D.L. , Gilkeson G.S. , Jacob C.O. , Scofield R.H. , et al. .
Source: Plos Genetics, 2013; 9(2), p. e1003336.
PMID: 23468661
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Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4.
Authors: Manku H. , Langefeld C.D. , Guerra S.G. , Malik T.H. , Alarcon-Riquelme M. , Anaya J.M. , Bae S.C. , Boackle S.A. , Brown E.E. , Criswell L.A. , et al. .
Source: Plos Genetics, 2013; 9(7), p. e1003554.
PMID: 23874208
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Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.
Authors: Sakurai D. , Zhao J. , Deng Y. , Kelly J.A. , Brown E.E. , Harley J.B. , Bae S.C. , Alarc¿n-Riquelme M.E. , BIOLUPUS and GENLES networks , Edberg J.C. , et al. .
Source: Plos Genetics, 2013; 9(10), p. e1003870.
PMID: 24130510
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Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries.
Authors: Kim K. , Brown E.E. , Choi C.B. , Alarcón-Riquelme M.E. , BIOLUPUS , Kelly J.A. , Glenn S.B. , Ojwang J.O. , Adler A. , Lee H.S. , et al. .
Source: Annals Of The Rheumatic Diseases, 2012 Nov; 71(11), p. 1809-14.
PMID: 22523428
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Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus.
Authors: Adrianto I. , Wang S. , Wiley G.B. , Lessard C.J. , Kelly J.A. , Adler A.J. , Glenn S.B. , Williams A.H. , Ziegler J.T. , Comeau M.E. , et al. .
Source: Arthritis And Rheumatism, 2012 Nov; 64(11), p. 3695-705.
PMID: 22833143
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A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.
Authors: Wang S. , Adrianto I. , Wiley G.B. , Lessard C.J. , Kelly J.A. , Adler A.J. , Glenn S.B. , Williams A.H. , Ziegler J.T. , Comeau M.E. , et al. .
Source: Genes And Immunity, 2012 Jul; 13(5), p. 380-7.
PMID: 22476155
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Evaluation of TRAF6 in a large multiancestral lupus cohort.
Authors: Namjou B. , Choi C.B. , Harley I.T. , Alarcón-Riquelme M.E. , BIOLUPUS Network , Kelly J.A. , Glenn S.B. , Ojwang J.O. , Adler A. , Kim K. , et al. .
Source: Arthritis And Rheumatism, 2012 Jun; 64(6), p. 1960-9.
PMID: 22231568
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Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.
Authors: Lessard C.J. , Adrianto I. , Ice J.A. , Wiley G.B. , Kelly J.A. , Glenn S.B. , Adler A.J. , Li H. , Rasmussen A. , Williams A.H. , et al. .
Source: American Journal Of Human Genetics, 2012-04-06 00:00:00.0; 90(4), p. 648-60.
EPub date: 2012-04-06 00:00:00.0.
PMID: 22464253
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Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.
Authors: Lin C.P. , Adrianto I. , Lessard C.J. , Kelly J.A. , Kaufman K.M. , Guthridge J.M. , Freedman B.I. , Anaya J.M. , Alarcón-Riquelme M.E. , BIOLUPUS and GENLES Networks , et al. .
Source: Genes And Immunity, 2012 Apr; 13(3), p. 232-8.
PMID: 22189356
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IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
Authors: Niewold T.B. , Kelly J.A. , Kariuki S.N. , Franek B.S. , Kumar A.A. , Kaufman K.M. , Thomas K. , Walker D. , Kamp S. , Frost J.M. , et al. .
Source: Annals Of The Rheumatic Diseases, 2012 Mar; 71(3), p. 463-8.
PMID: 22088620
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Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus.
Authors: Sanchez E. , Nadig A. , Richardson B.C. , Freedman B.I. , Kaufman K.M. , Kelly J.A. , Niewold T.B. , Kamen D.L. , Gilkeson G.S. , Ziegler J.T. , et al. .
Source: Annals Of The Rheumatic Diseases, 2011 Oct; 70(10), p. 1752-7.
PMID: 21719445
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Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups.
Authors: Tan W. , Sunahori K. , Zhao J. , Deng Y. , Kaufman K.M. , Kelly J.A. , Langefeld C.D. , Williams A.H. , Comeau M.E. , Ziegler J.T. , et al. .
Source: Arthritis And Rheumatism, 2011 Sep; 63(9), p. 2755-63.
PMID: 21590681
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Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus.
Authors: Ramos P.S. , Williams A.H. , Ziegler J.T. , Comeau M.E. , Guy R.T. , Lessard C.J. , Li H. , Edberg J.C. , Zidovetzki R. , Criswell L.A. , et al. .
Source: Arthritis And Rheumatism, 2011 Jul; 63(7), p. 2049-57.
PMID: 21437871
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Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.
Authors: Namjou B. , Kothari P.H. , Kelly J.A. , Glenn S.B. , Ojwang J.O. , Adler A. , Alarcón-Riquelme M.E. , Gallant C.J. , Boackle S.A. , Criswell L.A. , et al. .
Source: Genes And Immunity, 2011 Jun; 12(4), p. 270-9.
PMID: 21270825
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Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21.
Authors: Hughes T. , Kim-Howard X. , Kelly J.A. , Kaufman K.M. , Langefeld C.D. , Ziegler J. , Sanchez E. , Kimberly R.P. , Edberg J.C. , Ramsey-Goldman R. , et al. .
Source: Arthritis And Rheumatism, 2011 Jun; 63(6), p. 1689-97.
PMID: 21425124
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Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility.
Authors: Zhao J. , Wu H. , Khosravi M. , Cui H. , Qian X. , Kelly J.A. , Kaufman K.M. , Langefeld C.D. , Williams A.H. , Comeau M.E. , et al. .
Source: Plos Genetics, 2011 May; 7(5), p. e1002079.
PMID: 21637784
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Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus.
Authors: Adrianto I. , Wen F. , Templeton A. , Wiley G. , King J.B. , Lessard C.J. , Bates J.S. , Hu Y. , Kelly J.A. , Kaufman K.M. , et al. .
Source: Nature Genetics, 2011 Mar; 43(3), p. 253-8.
PMID: 21336280
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Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.
Authors: Chung S.A. , Taylor K.E. , Graham R.R. , Nititham J. , Lee A.T. , Ortmann W.A. , Jacob C.O. , Alarcón-Riquelme M.E. , Tsao B.P. , Harley J.B. , et al. .
Source: Plos Genetics, 2011 Mar; 7(3), p. e1001323.
PMID: 21408207
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Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes.
Authors: Taylor K.E. , Chung S.A. , Graham R.R. , Ortmann W.A. , Lee A.T. , Langefeld C.D. , Jacob C.O. , Kamboh M.I. , Alarcón-Riquelme M.E. , Tsao B.P. , et al. .
Source: Plos Genetics, 2011 Feb; 7(2), p. e1001311.
PMID: 21379322
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Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients.
Authors: Webb R. , Kelly J.A. , Somers E.C. , Hughes T. , Kaufman K.M. , Sanchez E. , Nath S.K. , Bruner G. , Alarcón-Riquelme M.E. , Gilkeson G.S. , et al. .
Source: Annals Of The Rheumatic Diseases, 2011 Jan; 70(1), p. 151-6.
PMID: 20881011
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Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus.
Authors: Sanchez E. , Webb R.D. , Rasmussen A. , Kelly J.A. , Riba L. , Kaufman K.M. , Garcia-de la Torre I. , Moctezuma J.F. , Maradiaga-Ceceña M.A. , Cardiel-Rios M.H. , et al. .
Source: Arthritis And Rheumatism, 2010 Dec; 62(12), p. 3722-9.
PMID: 20848568
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Recent findings on genetics of systemic autoimmune diseases.
Authors: Delgado-Vega A. , Sánchez E. , Löfgren S. , Castillejo-López C. , Alarcón-Riquelme M.E. .
Source: Current Opinion In Immunology, 2010 Dec; 22(6), p. 698-705.
PMID: 20933377
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Genetic associations in type I interferon related pathways with autoimmunity.
Authors: Delgado-Vega A.M. , Alarcón-Riquelme M.E. , Kozyrev S.V. .
Source: Arthritis Research & Therapy, 2010; 12 Suppl 1, p. S2.
PMID: 20392289
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The role of genetic variation near interferon-kappa in systemic lupus erythematosus.
Authors: Harley I.T. , Niewold T.B. , Stormont R.M. , Kaufman K.M. , Glenn S.B. , Franek B.S. , Kelly J.A. , Kilpatrick J.R. , Hutchings D. , Divers J. , et al. .
Source: Journal Of Biomedicine & Biotechnology, 2010; 2010, .
PMID: 20706608
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