title: Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage.
  
  
  METHODS
  We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
  
  
  RESULTS
  The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj  = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj  = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj  = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl  = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE.
  
  
  CONCLUSIONS
  Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
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authors.lastname: Alarcón-Riquelme
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Julie T
authors.initials: JT
authors.lastname: Ziegler
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Julio
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authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Timothy D
authors.initials: TD
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authors.affiliation: Stanford University School of Medicine, Stanford, California, and Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico.
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authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
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authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
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authors.affiliation: Stanford University School of Medicine, Stanford, California, and Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Mexico.
authors.forename: Patricia
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authors.lastname: Ortiz-Tello
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
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authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
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authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
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authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
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authors.affiliation: Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru.
authors.forename: Eduardo M
authors.initials: EM
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authors.affiliation: Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru.
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authors.forename: Ignacio
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authors.affiliation: Centro de Investigación Clínica de Morelia, Morelia, Mexico.
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authors.affiliation: Centro de Estudios Reumatológicos, Santiago, Chile.
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authors.affiliation: Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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authors.lastname: Catoggio
authors.affiliation: Hospital General de Culiacán, Culiacán, Mexico.
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authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
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authors.lastname: Gaffney
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authors.lastname: Vyse
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authors.initials: LA
authors.lastname: Criswell
authors.affiliation: University of California, Los Angeles.
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authors.lastname: Tsao
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Sivils
authors.affiliation: Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
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authors.affiliation: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
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authors.affiliation: University of Alabama at Birmingham.
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authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
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authors.initials: JA
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authors.affiliation: Hospital Interzonal General de Agudos General San Martin, La Plata, Argentina.
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authors.affiliation: Hospital Escuela Eva Perón, Granadero Baigorria, Argentina.
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authors.affiliation: Hospital Interzonal General de Agudos Oscar E. Alende, Mar del Plata, Argentina.
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authors.affiliation: Hospital Interzonal San Juan Bautista, San Fernando del Valle de Catamarca, Argentina.
authors.forename: Sergio
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authors.initials: SK
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authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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authors.lastname: Aguilar Salinas
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
authors.forename: Lorena
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authors.forename: Teresa
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authors.forename: Raphael
authors.initials: R
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authors.forename: Bernardo A
authors.initials: BA
authors.lastname: Pons-Estel
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
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mesh_terms: D044467:American Indian or Alaska Native / Q000235:genetics*; D001118:Argentina; D039481:CD11b Antigen / Q000235:genetics; D016022:Case-Control Studies; D002677:Chile; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008800:Mexico; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics; D016017:Odds Ratio; D010568:Peru; D025341:Principal Component Analysis; D050797:STAT4 Transcription Factor / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics; D028961:beta Karyopherins
chemical_list: C000606721:ATP5MK protein, human; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C103596:HLA-DQA2 antigen; C069051:HLA-DQB1 antigen; C431713:IRF5 protein, human; C509295:ITGAM protein, human; D050835:Interferon Regulatory Factors; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C117046:TNIP1 protein, human; C546476:TNPO3 protein, human; D028961:beta Karyopherins; D019255:NADPH Oxidases; C527764:NCF2 protein, human; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D025261:Mitochondrial Proton-Translocating ATPases