Targeted Mutagenesis of the Multicopy Myrosinase Gene Family in Allotetraploid Brassica juncea Reduces Pungency in Fresh Leaves across Environments.

Recent breeding efforts in Brassica have focused on the development of new oilseed feedstock crop for biofuels (e.g., ethanol, biodiesel, bio-jet fuel), bio-industrial uses (e.g., bio-plastics, lubricants), specialty fatty acids (e.g., erucic acid), and producing low glucosinolates levels for oilseed and feed meal production for animal consumption. We identified a novel opportunity to enhance the availability of nutritious, fresh leafy greens for human consumption. Here, we demonstrated the efficacy of disarming the 'mustard bomb' reaction in reducing pungency upon the mastication of fresh tissue-a major source of unpleasant flavor and/or odor in leafy Brassica. Using gene-specific mutagenesis via CRISPR-Cas12a, we created knockouts of all functional copies of the type-I myrosinase multigene family in tetraploid Brassica juncea. Our greenhouse and field trials demonstrate, via sensory and biochemical analyses, a stable reduction in pungency in edited plants across multiple environments. Collectively, these efforts provide a compelling path toward boosting the human consumption of nutrient-dense, fresh, leafy green vegetables.

Metabolic syndrome predicts new damage in systemic lupus erythematosus patients: Data from the Almenara Lupus Cohort.

OBJECTIVES: This study aims to determine whether the MetS predicts damage accrual in SLE patients. METHODS: This longitudinal study was conducted in a cohort of consecutive SLE patients seen since 2012 at one single Peruvian institution. Patients had a baseline visit and then follow-up visits every 6 months. Patients with ≥ 2 visits were included. Evaluations included interview, medical records review, physical examination, and laboratory tests. Damage accrual was ascertained with the SLICC/ACR damage index (SDI) and disease activity with the SLEDAI-2K. Univariable and multivariable Cox-regression survival models were carried out to determine the risk of developing new damage. The multivariable model was adjusted for age at diagnosis; disease duration; socioeconomic status; SLEDAI; baseline SDI; the Charlson Comorbidity Index; daily dose; and time of exposure of prednisone (PDN), antimalarials, and immunosuppressive drugs. RESULTS: Two hundred and forty-nine patients were evaluated; 232 of them were women (93.2%). Their mean (SD) age at diagnosis was 35.8 (13.1) years; nearly all patients were Mestizo. Disease duration was 7.4 (6.6) years. The SLEDAI-2K was 5.2 (4.3) and the SDI, 0.9 (1.3). One hundred and eight patients (43.4%) had MetS at baseline. During follow-up, 116 (46.6%) patients accrued at least one new point in the SDI damage index. In multivariable analyses, the presence of MetS was a predictor of the development of new damage (HR: 1.54 (1.05-2.26); p < 0.029). CONCLUSIONS: The presence of MetS predicts the development of new damage in SLE patients, despite other well-known risk factors for such occurrence.

Factores asociados a infecciones serias en pacientes hospitalizados con lupus eritematoso sistémico / Factors associated with serious infections in patients hospitalized with systemic lupus erythematosus

RESUMEN Introducción. En pacientes con lupus eritematoso sistémico (LES) existe incremento de infecciones debido a la propia enfermedad, al uso de inmunosupresores y corticoides. Objetivo. Identificar los factores asociados a infecciones serias en pacientes lúpicos en un hospital de referencia nacional. Estudio retrospectivo, analítico, de casos y controles en el Servicio de Reumatología del Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú. Métodos. Se analizó el registro de pacientes hospitalizados en el periodo de estudio, los casos fueron pacientes en los que se demostró la etiología de la primera infección durante su hospitalización. Los controles fueron pacientes lúpicos hospitalizados sin infecciones en el mismo periodo de estudio. Se analizaron variables asociadas al desarrollo de infecciones. Resultados. 61 pacientes de 390 hospitalizados desarrollaron infecciones durante su hospitalización. 48 desarrollaron 1 solo evento infeccioso (en 40 se demostró etiología). Los casos tuvieron mayor actividad, daño y comorbilidad en comparación con los controles. En el análisis univariado, el salario (p=0,031), el uso de inmunosupresores a la admisión (previo: p=0,004 y actual: p=0,004), el uso de glucocorticoides (<30 días: p=0,015 y >30-360 días: p=0,028), la actividad (p=0,029) y el daño (p=0,026) producido por la enfermedad, y el tiempo de hospitalización (p=0,045) tuvieron asociación estadísticamente significativa. En el análisis multivariado, los días de hospitalización se asociaron al desarrollo de infecciones. Conclusiones. Existió asociación entre días de hospitalización y el desarrollo de infecciones serias en pacientes lúpicos durante el periodo de estudio.

ABSTRACT Introduction. Lupus patients have an increased risk of developing infections due to the disease, use of immunosuppressants and corticosteroids. Objective. To identify the associated factors for serious infections in lupus patients in a national referral hospital. Retrospective, analytical, case-control study in the Rheumatology Service of the Guillermo Almenara Irigoyen National Hospital, Lima, Peru. Methods. The registry of hospitalized patients in the study period was analyzed, the cases were patients in whom the etiology of the first infection developed their hospitalization. Controls were hospitalized lupus patients without infections in the same study period. Variables predisposing to the development of infections were analyzed. Results. 61 patients out of 390 hospitalized developed infections during their hospitalization. 48 developed 1 only infectious event (in 40 an etiology developed). The cases had higher damage, activity and comorbidity compared to the controls. In the univariate analysis, salary (p = 0.031), use of immunosuppressants upon admission (previous: p = 0.004 and current: p = 0.004), use of glucocorticoids (<30 days: p = 0.015 and> 30-360 days: p = 0.028), activity (p = 0.029) and damage (p = 0.026) produced by the disease and length of hospitalization (p = 0.045), had a statistically significant association. In the multivariate analysis, the days of hospitalization were associated with the development of infections. Conclusions. There is an association between days of hospitalization and the development of serious infections in lupus patients in the study period.

Performance of the 2017 American College of Rheumatology/European League Against Rheumatism Provisional Classification Criteria for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in a Peruvian Tertiary Care Center.

AIM: To validate the new classification criteria for antineutrophil cytoplasmic antibody-associated vasculitis in a real-life Peruvian cohort of antineutrophil cytoplasmic antibody-associated vasculitis patients. METHODS: We reviewed medical records from a Peruvian tertiary care center from January 1990 to December 2019. Antineutrophil cytoplasmic antibody-associated vasculitis was diagnosed based on the 1990 American College of Rheumatology (ACR) criteria, the 2012 Chapel Hill Consensus Conference definitions, the European Medicines Agency (EMEA) algorithm, and the clinical acumen of the treating rheumatologists. We classified all patients using the "former criteria" (the 1990 ACR criteria for granulomatosis with polyangiitis [GPA] and eosinophilic GPA [EGPA] and the 1994 Chapel Hill Consensus Conference definition for microscopic polyangiitis [MPA]), the EMEA algorithm, and the "new criteria" (the 2017 ACR/European League Against Rheumatism Provisional Criteria). The level of agreement (using Cohen κ) was calculated using the clinical diagnosis as the criterion standard. RESULTS: We identified 212 patients, 12 of whom were excluded. One hundred fifty-four (77%) had MPA, 41 (20.5%) GPA, and 5 (2.5%) EGPA. The new criteria performed well for MPA (κ = 0.713) and EGPA (κ = 0.659), whereas the EMEA algorithm performed well for GPA (κ = 0.938). In the overall population, the new criteria showed better agreement (κ = 0.653) than the EMEA algorithm (κ = 0.506) and the former criteria (κ = 0.305). CONCLUSIONS: The 2017 ACR/European League Against Rheumatism Provisional Criteria showed better agreement for the clinical diagnosis of all the patients overall and had the best performance for MPA and EGPA. The EMEA algorithm had the best performance for GPA.

Survival in ANCA-Associated Vasculitides in a Peruvian Center: 28 Years of Experience.

AIM: The aim of this study was to identify demographic and clinical risk factors for mortality in patients with antineutrophil cytoplasmic antibodies-associated vasculitides (AAVs) in a Peruvian tertiary referral hospital. METHODS: Medical records of patients with AAV according to classification criteria or diagnosed by an experienced rheumatologist, covering the period between January 1990 and December 2018, were reviewed. Granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis were included. Potential predictors of mortality were demographic factors, clinical manifestations, antineutrophil cytoplasmic antibodies status, diagnosis, disease categorization, the 2009 Five Factor Score (FFS), and treatment. Cox regression models were used to determine the risk factors for mortality. Univariable and multivariable analyses using a backward selection method were performed. RESULTS: One hundred ninety-six patients were included; female-to-male ratio was 2:1. The median (interquartile range) age at diagnosis and follow-up were 60.0 (51.0-68.0) and 4.8 (1.3-11.6) years, respectively. One hundred forty-eight patients (75.5%) had microscopic polyangiitis, 37 (18.9%) granulomatosis with polyangiitis, 5 (2.6%) eosinophilic granulomatosis with polyangiitis, and 6 (3.0%) renal-limited vasculitis. Overall survival rates at 1, 5, and 10 years were 83.4%, 68.2%, and 51.7%, respectively. Ocular involvement was protective (hazards ratio [HR], 0.36; 95% confidence interval [CI], 0.17-0.74; p = 0.006), whereas renal (HR, 2.09; 95% CI, 1.33-3.28; p = 0.001) and lung involvement (HR, 2.07; 95% CI, 1.31-3.28; p = 0.002) and the 2009 FFSs were predictive of mortality (2009 FFS = 1: HR, 2.46; 95% CI, 1.50-4.04; p < 0.001; 2009 FFS = 2: HR, 3.07; 95% CI, 1.54-6.10; p = 0.001; 2009 FFS = 3: HR, 13.29; 95% CI, 3.69-47.88; p < 0.001). CONCLUSIONS: Ocular involvement was protective, whereas 2009 FFS ≥ 1 and renal and lung involvement were predictive factors of mortality in Peruvian AAV patients.

Demographic and Clinical Features of ANCA-Associated Vasculitides in a Peruvian Tertiary Center.

AIM: The aim of this study was to identify the demographic and clinical features of patients with ANCA-associated vasculitides (AAVs) in a Peruvian tertiary referral hospital. METHODS: Medical records of patients with AAV according to classification criteria or diagnosed by an experienced rheumatologist, and covering the period between January 1990 and December 2019, were reviewed. Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and renal-limited vasculitis (RLV) were included. Demographic factors (age at diagnosis, sex), disease duration, clinical manifestations (per organ involvement), creatinine level at diagnosis (milligram per deciliter), ANCA status, diagnosis, 2009 Five Factor Score, disease categorization, and treatment were recorded. RESULTS: Two hundred twelve patients were included. Their female-to-male ratio was 1.9:1 (139 [65.6%]/73 [34.4%]), and their mean (SD) age at diagnosis was 59.2 (12.5) years. One hundred fifty-eight patients (74.5%) had MPA, 42 (19.8%) GPA, 7 (3.3%) RLV, and 5 (2.4%) EGPA. Neurological, lung, and renal involvements were the most frequently affected systems. Myeloperoxidase preferentially occurred in MPA (82.5%), whereas proteinase 3 did occur in GPA (79.5%). Microscopic polyangiitis patients were older (61.1 [11.5] years). Female sex predominated in MPA and RLV (2.4:1 and 6:1, respectively), but the opposite was the case for EGPA (1:4). Ear-nose-throat and ocular involvement were more frequent in GPA (both p's < 0.001), and neurological and cardiovascular involvement were more frequent in EGPA (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: This is one of the largest series of AAV patients in Latin America. Overall, female sex predominated. Microscopic polyangiitis was the most frequent AAV, and myeloperoxidase-ANCA was the most frequent antibody in Peruvian AAV population.

Serum uric acid is associated with damage in patients with systemic lupus erythematosus.

Introduction: Serum uric acid levels have been reported as predictors of cardiovascular, pulmonary, neurological and renal morbidity in patients with SLE. However, their role in cumulative global damage in these patients has not yet been determined. Objective: To determine whether serum uric acid levels are associated with new damage in patients with SLE. Methods: This is a longitudinal study of patients with SLE from the Almenara Lupus Cohort, which began in 2012. At each visit, demographic and clinical characteristics were evaluated, such as activity (Systemic Lupus Erythematosus Disease Activity Index-2K or SLEDAI-2K) and cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index or SDI). Treatment (glucocorticoids, immunosuppressive drugs and antimalarials) was also recorded. Univariable and multivariable Cox regression models were used to determine the impact of serum uric acid levels on the risk of new damage. Results: We evaluated 237 patients, with a mean age (SD) at diagnosis of 35.9 (13.1) years; 220 patients (92.8%) were women, and the duration of the disease was 7.3 (6.6) years. The mean SLEDAI-2K and SDI scores were 5.1 (4.2) and 0.9 (1.3), respectively. Serum uric acid level was 4.5 (1.4) mg/dL. Follow-up time was 3.1 (1.3) years, and 112 (47.3%) patients accrued damage during follow-up. In univariable and multivariable analyses, serum uric acid levels were associated with new damage (HR=1.141 (95% CI 1.016 to 1.282), p=0.026; HR=1.189 (95% CI 1.025 to 1.378), p=0.022, respectively). Conclusion: Higher serum uric acid levels are associated with global damage in patients with SLE.

Better Health-Related Quality of Life in Systemic Lupus Erythematosus Predicted by Low Disease Activity State/Remission: Data From the Peruvian Almenara Lupus Cohort.

OBJECTIVE: To determine if low disease activity state (LDAS)/remission predicts a better health-related quality of life (HRQoL). METHODS: Patients with systemic lupus erythematosus from a single center and having completed at least 2 visits were included. Visits were performed every 6 months. HRQoL was measured with the LupusQoL questionnaire. The definition of remission included a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 0, prednisone daily dosage of ≤5 mg/day, and immunosuppressive drugs on maintenance dose. LDAS was defined as a SLEDAI-2K score of ≤4, prednisone daily dosage of ≤7.5 mg/day, and immunosuppressive drugs as maintenance therapy. For these analyses, remission and LDAS were combined as one variable. Generalized estimating equations were calculated, using as the outcome 1 of each of the 8 components of the LupusQoL questionnaire in the subsequent visit and the activity state in the previous visit. Multivariable models were adjusted for possible confounders. RESULTS: A total of 243 patients were included. During the follow-up, 590 visits (61.6%) were categorized as LDAS/remission. LDAS/remission predicted a better HRQoL in the components of physical health (B = 4.17 [95% confidence interval (95% CI) 1.20, 7.14]; P = 0.006), pain (B = 6.47 [95% CI 3.18, 9.76]; P < 0.001), planning (B = 4.97 [95% CI 1.43, 8.52]; P = 0.006), burden to others (B = 4.12 [95% CI 0.24, 8.01]; P = 0.037], emotional health (B = 4.50 [95% CI 1.56, 7.44]; P = 0.003), and fatigue (B = 3.25 [95% CI 0.04, 6.47]; P = 0.048). CONCLUSION: Being in LDAS/remission predicts a better HRQoL, especially in the components of physical health, pain, planning, burden to others, emotional health, and fatigue.

Correction to: Homocysteine levels are independently associated with damage accrual in systemic lupus erythematosus patients from a Latin-American cohort.

The affiliations of Manuel F. Ugarte-Gil, one of the author of the above article has a discrepancy between the online version of the publisher's internet portal ( Springerlink.com ) and the online pdf version.

Homocysteine levels are independently associated with damage accrual in systemic lupus erythematosus patients from a Latin-American cohort.

OBJECTIVE: To determine the impact of homocysteine levels on damage accrual in systemic lupus erythematosus (SLE) patients. METHODS: This longitudinal study was conducted in consecutive patients seen every 6 months at our Rheumatology Department since 2012. Patients with available homocysteine levels and who had at least one subsequent visit were included. Univariable and multivariable Cox regression models were done to determine if homocysteine levels were predictive of damage accrual as per the SLICC Damage Index (SDI). The multivariable model was adjusted for pertinent variables (age at diagnosis, gender, socioeconomic status, disease duration, disease activity (SLEDAI), Framingham score, antimalarial and immunosuppressive drug use, average daily dose, and exposure time to prednisone (PDN)). RESULTS: One hundred forty-five patients were included; their mean (SD) age at diagnosis was 43.70 (12.09) years, 136 (93.8%) were female, and nearly all were Mestizo. At baseline, disease duration was 7.55 (6.73) years; patients were followed for 3.54 (1.27) years. The SLEDAI was 5.60 (4.34), and the SDI 0.97 (1.35). The average daily PDN dose was 7.30 (5.78) mg/day and the time of PDN exposure was 7.36 (6.73) years. Mean homocysteine levels were 10.07 (3.71) µmol/L. The highest tertile of homocysteine levels predicted new damage accrual in the univariable and multivariable models [HR 1.78 (95% CI, 1.042-3.039); p = 0.035 and HR 2.045 (95% CI, 1.077-3.883); p = 0.029, respectively]. Increased levels (> 15 µmol/L) were found in 12 (8.3%) patients; 75 (51.7%) patients increased ≥ 1 SDI point. CONCLUSION: In SLE patients, homocysteine levels predicted damage accrual independently of other well-known risk factors for such occurrence.

Astaxanthin-Loaded Nanostructured Lipid Carriers for Preservation of Antioxidant Activity.

Astaxanthin is a xanthophyll carotenoid showing efficient scavenging ability and represents an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies. However, its high lipophilicity and thermolability often limits its antioxidant efficacy in human applications. Here, we developed a formulation of lipid carriers to protect astaxanthin's antioxidant activity. The synthesis of natural astaxanthin-loaded nanostructured lipid carriers using a green process with sunflower oil as liquid lipid is presented. Their antioxidant activity was measured by α-Tocopherol Equivalent Antioxidant Capacity assay and was compared to those of both natural astaxanthin and α-tocopherol. Characterizations by dynamic light scattering, atomic force microscopy, and scattering electron microscopy techniques were carried out and showed spherical and surface negative charged particles with z-average and polydispersity values of ~60 nm and ~0.3, respectively. Astaxanthin loading was also investigated showing an astaxanthin recovery of more than 90% after synthesis of nanostructured lipid carriers. These results demonstrate the capability of the formulation to stabilize astaxanthin molecule and preserve and enhance the antioxidant activity.

Peripheral CD4+CD28null T-cells as predictors of damage in systemic lupus erythematosus patients.

OBJECTIVES: To determine whether the CD4+CD28null T-cells subpopulation predicts the occurrence of damage in SLE. METHODS: This longitudinal study was conducted in consecutive SLE patients seen every six months in our Rheumatology Department since 2012. Patients in whom CD4+CD28null T-cells had been measured and who had at least one subsequent visit were included in the study. Survival analyses (univariable and multivariable Cox-regression models) were performed to determine the risk of overall and domain damage (as per the SLICC Damage Index - SDI) as a function of the frequency of this T-cell subpopulation. The multivariable model was adjusted for pertinent confounders. All analyses were performed using SPSS 21.0. RESULTS: One hundred and nineteen patients were evaluated; their mean (SD) age was 43.5 (11.9) years, 113 (95.0%) were female. Disease duration was 7.8 (7.0) years, the SLEDAI 5.3 (4.1) and the SDI 1.0 (1.4). The percentage of CD4+CD28null T-cells was 17.4 (14.0). The mean follow-up was 2.1 (0.8) years, and the mean number of visits per patient 3.5 (1.1). Forty-six (38.7%) patients increase at least one SDI point. In the univariable and multivariable analyses, the percentage of CD4+CD28null predicted the occurrence of lung damage [HR: 1.042 (CI95%: 1.001-1.085); p=0.047 and HR: 1.099 (CI95%1.020-1.184); p=0.013, respectively] but neither the total SDI score nor all other SDI domain scores were predicted by the percentage of CD4+CD28null cells. CONCLUSIONS: In SLE patients, CD4+CD28null T-cells predict the occurrence of new lung damage, independently of other risk factors but not of overall damage or damage on other domains.

Genotyping-by-Sequencing Derived High-Density Linkage Map and its Application to QTL Mapping of Flag Leaf Traits in Bread Wheat.

Winter wheat parents 'Harry' (drought tolerant) and 'Wesley' (drought susceptible) were used to develop a recombinant inbred population with future goals of identifying genomic regions associated with drought tolerance. To precisely map genomic regions, high-density linkage maps are a prerequisite. In this study genotyping-by- sequencing (GBS) was used to construct the high-density linkage map. The map contained 3,641 markers distributed on 21 chromosomes and spanned 1,959 cM with an average distance of 1.8 cM between markers. The constructed linkage map revealed strong collinearity in marker order across 21 chromosomes with POPSEQ-v2.0, which was based on a high-density linkage map. The reliability of the linkage map for QTL mapping was demonstrated by co-localizing the genes to previously mapped genomic regions for two highly heritable traits, chaff color, and leaf cuticular wax. Applicability of linkage map for QTL mapping of three quantitative traits, flag leaf length, width, and area, identified 21 QTLs in four environments, and QTL expression varied across the environments. Two major stable QTLs, one each for flag leaf length (Qfll.hww-7A) and flag leaf width (Qflw.hww-5A) were identified. The map constructed will facilitate QTL and fine mapping of quantitative traits, map-based cloning, comparative mapping, and in marker-assisted wheat breeding endeavors.

Transancestral mapping and genetic load in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Serum uric acid levels contribute to new renal damage in systemic lupus erythematosus patients.

This study aims to determine whether uric acid levels contribute to new renal damage in systemic lupus erythematosus (SLE) patients. This prospective study was conducted in consecutive patients seen since 2012. Patients had a baseline visit and follow-up visits every 6 months. Patients with ≥2 visits were included; those with end-stage renal disease (regardless of dialysis or transplantation) were excluded. Renal damage was ascertained using the SLICC/ACR damage index (SDI). Univariable and multivariable Cox-regression models were performed to determine the risk of new renal damage. Uric acid was included as a continuous and dichotomous (per receiving operating characteristic curve) variable. Multivariable models were adjusted for age at diagnosis, disease duration, socioeconomic status, SLEDAI, SDI, serum creatinine, baseline use of prednisone, antimalarials, and immunosuppressive drugs. One hundred and eighty-six patients were evaluated; their mean (SD) age at diagnosis was 36.8 (13.7) years; nearly all patients were mestizo. Disease duration was 7.7 (6.8) years. Follow-up time was 2.3 (1.1) years. The SLEDAI was 5.2 (4.3) and the SDI 0.8 (1.1). Uric acid levels were 4.5 (1.3) mg/dl. During follow-up, 16 (8.6%) patients developed at least one new point in the renal domain of the SDI. In multivariable analyses, uric acid levels (continuous and dichotomous) at baseline predicted the development of new renal damage (HR 3.21 (1.39-7.42), p 0.006; HR 18.28 (2.80-119.48), p 0.002; respectively). Higher uric acid levels contribute to the development of new renal damage in SLE patients independent of other well-known risk factors for such occurrence.

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.

Circulating naive and memory CD4+ T cells and metabolic syndrome in patients with systemic lupus erythematosus: data from a primarily Mestizo population.

OBJECTIVE: The aim of this study was to determine whether the proportions of naive and memory CD4(+) T cell are independently associated with the metabolic syndrome (MetS) in patients with SLE. METHODS: This cross-sectional study was conducted in SLE patients seen at our rheumatology department between September 2013 and April 2014. CD4(+) T cell subpopulations were examined by flow cytometry. The association of MetS and CD4(+) T cell subpopulations was examined by Mann-Whitney U-test and by multivariable analysis, adjusting for all possible confounding variables. RESULTS: One hundred and seventeen patients were evaluated. Their mean age was 44.6 years (S.D. 12.6), 109 (93.2%) were female and all patients were Mestizo (mixed Caucasian and Amerindian ancestry). Fifty-two patients (44.4%) presented with MetS. Disease duration was 7.6 years (S.D. 6.8). The percentage of naive CD4(+) T cells was 25.0 (S.D. 12.7) and memory CD4(+) T cells was 66.7 (S.D. 13.2) and the memory:naive CD4(+) T cell ratio was 4.3 (S.D. 5.6). In multivariable analysis, the percentage of naive CD4(+) T cells was negatively associated with the presence of MetS [odds ratio (OR) 0.959 (95% CI 0.923, 0.997), P = 0.033], whereas the percentage of memory CD4(+)T cells and the memory:naive CD4(+) T cell ratio were positively associated with its presence [OR 1.040 (95% CI 1.003, 1.078), P = 0.031 and OR 1.238 (95% CI 1.041, 1.472), P = 0.016, respectively]. CONCLUSION: In the SLE patients studied, a lower percentage of naive CD4(+) T cells, a higher percentage of memory CD4(+) T cells and the memory:naive CD4(+) T cell ratio were independently associated with the presence of MetS. This association could reflect the impact of immunosenescence among SLE patients with cardiovascular morbidity.

The number of flares patients experience impacts on damage accrual in systemic lupus erythematosus: data from a multiethnic Latin American cohort.

PURPOSE: To determine the association between the number of flares systemic lupus erythematosus (SLE) patients experience and damage accrual, independently of other known risk factors. METHODS: SLE patients (34 centres, nine Latin American countries) with a recent diagnosis (≤2 years) and ≥3 evaluations were studied. Disease activity was ascertained with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and damage with the SLICC/ACR Damage Index (SDI). Flare was defined as an increase ≥4 points in the SLEDAI between two study visits. An ambidirectional case- crossover design was used to determine the association between the number of flares and damage accrual. RESULTS: 901 patients were eligible for the study; 500 of them (55.5%) experienced at least one flare, being the mean number of flares 0.9 (SD: 1.0). 574 intervals from 251 patients were included in the case-crossover design since they have case and control intervals, whereas, the remaining patients did not. Their mean age at diagnosis was 27.9 years (SD: 11.1), 213 (84.9%) were women. The mean baseline SDI and SLEDAI were 1.3 (1.3) and 13.6 (8.1), respectively. Other features were comparable to those of the entire sample. After adjusting for possible confounding variables, the number of flares, regardless of their severity, was associated with damage accrual (SDI) OR 2.05, 95% CI 1.43 to 2.94, p<0.001 (OR 2.62, 95% CI 1.31 to 5.24, p=0.006 for severe and OR 1.91, 95% CI 1.28 to 2.83, p=0.001 for mild-moderate). CONCLUSIONS: The number of flares patients experience, regardless of their severity, increases the risk of damage accrual, independently of other known risk factors.

Primary cardiac disease in systemic lupus erythematosus patients: protective and risk factors--data from a multi-ethnic Latin American cohort.

OBJECTIVES: The aim of this study was to assess the cumulative incidence, risk and protective factors and impact on mortality of primary cardiac disease in SLE patients (disease duration ≤2 years) from a multi-ethnic, international, longitudinal inception cohort (34 centres, 9 Latin American countries). METHODS: Risk and protective factors of primary cardiac disease (pericarditis, myocarditis, endocarditis, arrhythmias and/or valvular abnormalities) were evaluated. RESULTS: Of 1437 patients, 202 (14.1%) developed one or more manifestations: 164 pericarditis, 35 valvulopathy, 23 arrhythmias, 7 myocarditis and 1 endocarditis at follow-up; 77 of these patients also had an episode of primary cardiac disease at or before recruitment. In the multivariable parsimonious model, African/Latin American ethnicity [odds ratio (OR) 1.80, 95% CI 1.13, 2.86], primary cardiac disease at or before recruitment (OR 6.56, 95% CI 4.56, 9.43) and first SLICC/ACR Damage Index for SLE assessment (OR 1.31, 95% CI 1.14, 1.50) were risk factors for the subsequent occurrence of primary cardiac disease. CNS involvement (OR 0.44, 95% CI 0.25, 0.75) and antimalarial treatment (OR 0.62, 95% CI 0.44, 0.89) at or before recruitment were negatively associated with the occurrence of primary cardiac disease risk. Primary cardiac disease was not independently associated with mortality. CONCLUSION: Primary cardiac disease occurred in 14.1% of SLE patients of the Grupo Latino Americano de Estudio de Lupus cohort and pericarditis was its most frequent manifestation. African origin and lupus damage were found to be risk factors, while CNS involvement at or before recruitment and antimalarial treatment were protective. Primary cardiac disease had no impact on mortality.