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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
Author(s) -
AlarcónRiquelme Marta E.,
Ziegler Julie T.,
Molineros Julio,
Howard Timothy D.,
MorenoEstrada Andrés,
SánchezRodríguez Elena,
Ainsworth Hannah C.,
OrtizTello Patricia,
Comeau Mary E.,
Rasmussen Astrid,
Kelly Jennifer A.,
Adler Adam,
AcevedoVázquez Eduardo M.,
Mariano Cucho-Venegas Jorge,
GarcíaDe la Torre Ignacio,
Cardiel Mario H.,
Miranda Pedro,
Catoggio Luis J.,
MaradiagaCeceña Marco,
Gaffney Patrick M.,
Vyse Timothy J.,
Criswell Lindsey A.,
Tsao Betty P.,
Sivils Kathy L.,
Bae SangCheol,
James Judith A.,
Kimberly Robert P.,
Kaufman Kenneth M.,
Harley John B.,
EsquivelValerio Jorge A.,
Moctezuma José F.,
García Mercedes A.,
Berbotto Guillermo A.,
Babini Alejandra M.,
Scherbarth Hugo,
Toloza Sergio,
Baca Vicente,
Nath Swapan K.,
Aguilar Salinas Carlos,
Orozco Lorena,
TusiéLuna Teresa,
Zidovetzki Raphael,
PonsEstel Bernardo A.,
Langefeld Carl D.,
Jacob Chaim O.
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39504
Subject(s) - genome wide association study , expression quantitative trait loci , imputation (statistics) , odds ratio , genetic association , locus (genetics) , allele , population , genetics , human leukocyte antigen , case control study , biology , medicine , immunology , single nucleotide polymorphism , genotype , gene , environmental health , machine learning , antigen , missing data , computer science
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 [ P gcadj ] = 2.61 × 10 −29 , OR 2.12 [95% CI 1.88–2.39]), followed by HLA class II on the DQA2–DQB1 loci (rs9275572: P gcadj = 1.11 × 10 −16 , OR 1.62 [95% CI 1.46–1.80] and rs9271366: P gcadj = 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: P gcadj = 1.39 × 10 −8 ) with an expression quantitative trait locus (eQTL) effect ( P eqtl = 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. Conclusion Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.