Genome‐Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture

Arthritis and Rheumatology - Tập 68 Số 4 - Trang 932-943 - 2016
Marta E. Alarcón‐Riquelme1, Julie T. Ziegler2, Julio E. Molineros1, Timothy D. Howard2, Andrés Moreno‐Estrada3, Elena Sánchez4, Hannah C. Ainsworth2, Patricia A. Ortiz-Tello3, Mary E. Comeau2, Astrid Rasmussen1, Jennifer A. Kelly1, Adam Adler1, Eduardo Acevedo5, Jorge M. Cucho‐Venegas5, Ignacio García‐De La Torre6, Mario H. Cardiel7, Pedro C. Miranda8, Luís J. Catoggio9, Marco A. Maradiaga‐Ceceña10, Patrick M. Gaffney1, Timothy J. Vyse11, Lindsey A. Criswell12, Betty P. Tsao13, Kathy L. Sivils1, Sang‐Cheol Bae14, Judith A. James15, Robert P. Kimberly16, Kenneth M. Kaufman17, Joel M. Guthridge17, Andrew Whelton18, J. F. Moctezuma19, Mercedes García20, Guillermo Berbotto21, Alejandra Babini22, Hugo R Scherbarth23, Sergio Toloza24, Vicente Baca25, Swapan K. Nath1, Carlos A. Aguilar‐Salinas26, Lorena Orozco27, Teresa Tusié‐Luna28, Raphael Zidovetzki29, Bernardo A. Pons‐Estel30, Carl D. Langefeld2, Chaim O. Jacob31
1Oklahoma Medical Research Foundation, Oklahoma City;
2Wake Forest School of Medicine, Winston–Salem, North Carolina
3Stanford 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
4Icahn School of Medicine at Mount Sinai, New York, New York
5Hospital Nacional Guillermo Almenara Irigoyen, Lima, Peru
6Hospital General de Occidente Zapopan Mexico
7Centro de Investigación Clínica de Morelia, Morelia, Mexico
8Centro de Estudios Reumatológicos, Santiago, Chile
9Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
10Hospital General de Culiacán Culiacán Mexico
11King's College London, London, UK
12University of California San Francisco
13University of California, Los Angeles
14Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
15Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
16University of Alabama at Birmingham
17Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
18Hospital Universitario Dr. José Eleuterio González Universidad Autonoma de Nuevo León Monterrey Mexico
19Hospital General de México, Mexico City, Mexico
20Hospital Interzonal General de Agudos General San Martin La Plata Argentina
21Hospital Escuela Eva Perón, Granadero Baigorria, Argentina
22Hospital Italiano de Córdoba, Córdoba, Argentina
23Hospital Interzonal General de Agudos Oscar E. Alende Mar del Plata Argentina
24Hospital Interzonal San Juan Bautista San Fernando del Valle de Catamarca Argentina
25Hospital de Peditaria, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social Mexico City Mexico
26Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
27Instituto Nacional de Medicina Genómica, Mexico city, Mexico
28Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México Mexico City Mexico
29University of California, Riverside
30Sanatorio Parque, Rosario, Argentina
31University of Southern California School of Medicine, Los Angeles

Tóm tắt

ObjectiveSystemic 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.MethodsWe 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.ResultsThe 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.ConclusionOur results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.

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Arthritis and Rheumatology

Tập 68 Số 4

932-943

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