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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78480/1/27753_ftp.pd

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 (B50% of these regions have multiple independent associations); these include 24 novel SLE regions (Po5 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 SL

Caracterización clínica y epidemiológica de los casos de dengue: experiencia del Hospital General de Culiacán, Sinaloa, México Clinical and epidemiologic characteristics of dengue cases: the experience of a general hospital in Culiacan, Sinaloa, Mexico

OBJETIVO: Documentar las características clínicas y epidemiológicas de los pacientes con dengue atendidos en un hospital de Culiacán, Sinaloa, México. MÉTODOS: Estudio transversal, observacional y analítico realizado en el Hospital General Dr. Bernardo J. Gastélum de Culiacán entre el 1 de octubre y el 2 de diciembre de 2003. Se evaluó la asociación entre las variables independientes (las características clínicas y epidemiológicas de los pacientes) y la variable dependiente (diagnóstico confirmado de dengue hemorrágico) mediante el análisis de regresión simple. Las variables que mostraron una relación significativa (P < 0,05) se incluyeron en el análisis de regresión logística multifactorial. RESULTADOS: En los 241 casos que cumplieron los criterios de inclusión para este estudio (207 de dengue y 34 de dengue hemorrágico), la edad promedio fue de 34,7 ± 15,1 años. Según los resultados del análisis multifactorial ajustado por la edad, el sexo y la presencia de casos de dengue en la localidad, las variables con valor predictivo de una mayor gravedad de la enfermedad fueron: la presencia de ascitis (OR = 22,12; IC95%: 5,00 a 97,87), la gingivorragia (OR = 7,35; IC95%: 2,11 a 25,61), la hematemesis (OR = 7,40; IC95%: 1,04 a 52,42), la trombocitopenia (plaquetas entre 40 001/mm³ y 60 000/mm³) (OR = 5,43; IC95%: 1,58 a 18,72), la hiperemia conjuntival (OR = 4,27; IC95%: 1,37 a 13,28), los vómitos persistentes (OR = 3,04; IC95%: 1,05 a 8,80) y la ausencia de congestión nasal (OR = 0,015; IC95%: 0,0004 a 0,473). CONCLUSIONES: Se confirmó el valor de la presencia de ascitis, gingivorragia, hematemesis, trombocitopenia (con valores de plaquetas entre 40 001/mm³ y 60 000/mm³) y vómitos persistentes como signos de alarma que anuncian la inminencia del choque por dengue. Se observaron conteos plaquetarios > 100 000/mm3 en casos con cuadros clínicos graves (fuga capilar) que no se clasificaron como dengue hemorrágico por no cumplir todos los criterios establecidos por la OMS.<br>OBJECTIVES: To document the clinical and epidemiological characteristics present in dengue patients served by a hospital in Culiacan, Sinaloa, Mexico. METHODS: A cross-sectional, observational, and analytical study was carried out at the Hospital General Dr. Bernardo J. Gastélum de Culiacan from 1 October to 2 December 2003. Associations between the independent variables (the patients' clinical and epidemiological characteristics) and the dependent variable (confirmed hemorrhagic dengue) were determined through simple regression analysis. The variables that were significantly associated (P < 0.05) were submitted to multifactorial logistic regression analysis. RESULTS: Of the only 241 cases that met the study's inclusion criteria (207 dengue and 34 hemorrhagic dengue), the mean age was 34.7 ± 15.1 years. According to the results of the multifactorial analysis (adjusted by age, sex, and the presence of dengue cases at the geographic location), the variables predictive of major complications of the disease were: the presence of ascites (odds ration [OR] = 22.12; 95% confidence interval [95%CI]: 5.00-97.87), gingivorrhagia (OR = 7.35; 95%CI: 2.11-25.61), hematemesis (OR = 7.40; 95%CI: 1.04-52.42), thrombocytopenia (platelets from 40001/mm³- 60000/mm³) (OR = 5.43; 95%CI: 1.58-18.72), conjunctival hyperemia (OR = 4.27; 95%CI: 1.37-13.28), persistent vomiting (OR = 3.04; 95%CI: 1.05-8.80), and the absence of nasal congestion (OR = 0.015; 95%CI: 0.0004-0.473). CONCLUSIONS: The presence of ascites, gingivorrhagia, hematemesis, thrombocytopenia (with platelet values from 40001/mm³-60000/mm³), and persistent vomiting were confirmed as warning signs of an imminent dengue attack. Platelet counts of > 100000/mm3 were confirmed in cases with acute clinical symptoms (capillary leak) that were not classified as hemorrhagic dengue due to falling short of the criteria established by WHO

Effects of Amerindian Genetic Ancestry on Clinical Variables and Therapy in Patients with Rheumatoid Arthritis.

To define whether Amerindian genetic ancestry correlates with clinical and therapeutic variables in admixed individuals with rheumatoid arthritis (RA) from Latin America. Patients with RA (n = 1347) and healthy controls (n = 1012) from Argentina, Mexico, Chile, and Peru were included. Samples were genotyped for the Immunochip v1 using the Illumina platform. Clinical data were obtained through interviews or the clinical history. Percentage of Amerindian ancestry was comparable between cases and controls. Morning stiffness (p Amerindian ancestry protects against most major clinical criteria of RA, but regarding the association of RF with increased European ancestry, age, sex, and smoking are modifiers. Ancestry also correlates with the therapeutic profiles

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

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage. MATERIALS AND METHODS: We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles. RESULTS: The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, P(gcadj) = 2.61×10(−29), OR = 2.12, 95% CI: 1.88–2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, P(gcadj) = 1.11 × 10(−16), OR = 1.62, 95% CI: 1.46–1.80; rs9271366, P(gcadj)=6.46 × 10(−12), OR = 2.06, 95% CI: 1.71–2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, P(gcadj) =1.4×10(−8)) with a eQTL effect (P(eqtl)=8.0 × 10(−37) at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection. CONCLUSIONS: Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases

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

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage. MATERIALS AND METHODS: We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles. RESULTS: The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, P(gcadj) = 2.61×10(−29), OR = 2.12, 95% CI: 1.88–2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, P(gcadj) = 1.11 × 10(−16), OR = 1.62, 95% CI: 1.46–1.80; rs9271366, P(gcadj)=6.46 × 10(−12), OR = 2.06, 95% CI: 1.71–2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, P(gcadj) =1.4×10(−8)) with a eQTL effect (P(eqtl)=8.0 × 10(−37) at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection. CONCLUSIONS: Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases

Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations

Objective American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. Methods A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P less than 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P less than 0.0001). American Indian ancestry protected against photosensitivity (P less than 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P less than 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P less than 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. Conclusion In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age. Copyright © 2012 by the American College of Rheumatology

Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations

Objective American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. Methods A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). Results The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P less than 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P less than 0.0001). American Indian ancestry protected against photosensitivity (P less than 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P less than 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P less than 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. Conclusion In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age. Copyright © 2012 by the American College of Rheumatology

Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE