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

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. CONCLUSION: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.

In vivo peripheral blood proinflammatory T cells in patients with ankylosing spondylitis.

OBJECTIVE: Previous reports have shown an increase in peripheral blood mononuclear cells' (PBMC) Th17 cell subpopulation and tumor necrosis factor-α (TNF-α) secretion after in vitro stimulation with anti-CD3/CD28 or phorbol myristate acetate/ionomycin in ankylosing spondylitis (AS). The aim of our study was to determine whether there is a Th17 polarization not subjected to in vitro stimulation in patients with AS. METHODS: Nonstimulated PBMC were analyzed from 46 patients with AS, including 7 (15.2%) receiving tumor necrosis factor-α (TNF-α) inhibitors, 20 patients with rheumatoid arthritis, and 25 healthy controls. The surface phenotype of freshly isolated PBMC was determined by flow cytometry. Th1, Th2, Th17, and Treg subsets were defined as CD3+CD4+IFN-γ+, CD3+CD4+IL-4+, CD3+CD4+IL-17A+, and CD3+CD4+FoxP3+, respectively. Serum cytokines and interleukin 8 (IL-8) levels were quantified by Luminex technology. RESULTS: The percentages of Th17 and Th1 cells in AS were higher than in healthy controls (7.4% ± 1.8% vs 0.7% ± 0.2% and 4.0% ± 1.3% vs 1.1% ± 0.3%, respectively; p < 0.0001). Th17 and Th1 cell subsets in patients taking TNF-α inhibitors were lower than in those naive to such therapeutics and similar to healthy controls. Serum levels of IL-6, IL-17A, TNF-α, and IL-8 were significantly higher in patients with AS compared to controls. CONCLUSION: The percentages of Th17 and Th1 cells in PBMC without in vitro stimulation, as well as cytokine and IL-8 levels, were significantly increased in patients with AS compared with healthy controls. These T cell subsets and cytokine profiles of patients with AS taking TNF-α inhibitors were similar to those of healthy controls.

Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus.

OBJECTIVE: To assess whether genetically determined Amerindian ancestry predicts increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus (SLE). METHODS: Single-nucleotide polymorphisms (SNPs) within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation between ancestry and the presence of risk alleles was analyzed using linear regression. RESULTS: A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, ITGAM, and IRF5 were associated with lupus in a Hispanic Mestizo cohort enriched for European and Amerindian ancestry. In addition, 2 SNPs within the major histocompatibility complex region, previously shown to be associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression, we predicted an average increase of 2.34 risk alleles when comparing an SLE patient with 100% Amerindian ancestry versus an SLE patient with 0% Amerindian ancestry (P < 0.0001). SLE patients with 43% more Amerindian ancestry were predicted to carry 1 additional risk allele. CONCLUSION: Our results demonstrate that Amerindian ancestry is associated with an increased number of risk alleles for SLE.