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Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.
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Sequência de Aminoácidos , Autoanticorpos/imunologia , Suscetibilidade a Doenças , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/imunologia , Lúpus Eritematoso Sistêmico/etiologia , Alelos , Substituição de Aminoácidos , Povo Asiático , Feminino , Predisposição Genética para Doença , Variação Genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Povo Asiático , Proteínas Relacionadas à Autofagia/genética , Quimiocina CCL22/genética , Proteínas de Ligação a DNA , Regulação da Expressão Gênica/genética , Genótipo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/patologia , Polimorfismo de Nucleotídeo Único/genética , Ribonuclease H/genética , Fatores de TranscriçãoRESUMO
Twenty-eight isolates of Sclerotinia homoeocarpa, causal agent of dollar spot disease in turf, were assessed for fungicide hormesis at sublethal concentrations of thiophanate-methyl (T-methyl). Each isolate was grown in corn meal agar amended with 11 concentrations of T-methyl (30,500 to 0.047 µg/liter), and the area of mycelial growth was determined relative to the control. Three replicates were used per concentration, and the experiment was repeated three to five times for each isolate. Reference isolates (EC50 > 20 µg/liter), with no prior history of T-methyl exposure, were highly sensitive and not stimulated by low doses. Likewise, no stimulation was observed in two highly sensitive isolates (EC50 > 30 µg/liter) that had been preconditioned by exposure to T-methyl, or in four T-methyl-tolerant isolates. Seventeen (81%) preconditioned T-methyl-tolerant isolates (EC50 = 294 to1,550 µg/liter) had statistically significant growth stimulation, in the range of 2.8 to 19.7% relative to the control. These results support that hormesis (low-dose stimulation, high-dose inhibition) is a common dose response in preconditioned S. homoeocarpa, particularly in response to subtoxic doses of T-methyl.
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Ascomicetos , Fungicidas Industriais , Farmacorresistência Fúngica , Hormese , TiofanatoRESUMO
Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P(EA) = 1.01 × 10(-54), PHS = 3.68 × 10(-10), P(AA) = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 × 10(-9)), and rs13306575 in HS and KR (P(HS) = 7.04 × 10(-7), P(KR) = 3.30 × 10(-3)). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 × 10(-7)), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE.
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Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , NADPH Oxidases/genética , Negro ou Afro-Americano/genética , Asiático/genética , Biologia Computacional , Heterogeneidade Genética , Variação Genética , Haplótipos , Hispânico ou Latino/genética , Humanos , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , População Branca/etnologia , População Branca/genéticaRESUMO
OBJECTIVE: To evaluate disease features and outcomes in two populations with significant Amerindian ancestry. METHODS: Hispanic patients (from Texas) from the Lupus in Minorities: Nature versus Nurture (LUMINA) cohort and Mestizo patients from the Grupo Latino Americano De Estudio del Lupus or Latin American Group for the Study of Lupus (GLADEL) cohort were included. Disease features and outcomes were evaluated at baseline and last visit. Admixture informative markers of Mestizo Genoma de Lupus Eritematoso Sistémico Network consortium (GENLES) patients and Hispanic LUMINA patients were compared. Univariable analyses were performed using Chi square or Student's t test as appropriate. Multivariable analyses adjusting for possible confounders were carried out using Poisson, logistic or Cox regression models as appropriate. RESULTS: A total of 114 LUMINA and 619 GLADEL patients were included. GLADEL patients had accrued more damage at baseline, but the opposite was the case at last visit. Being from LUMINA was a risk factor for damage accrual, even after adjusting for possible confounders [relative risk (RR) 1.33, 95% CI 1.12, 1.58]. Also, LUMINA patients have a higher risk of mortality than GLADEL patients [hazard ratio (HR) 2.37, 95% CI 1.10, 5.15], having 5-year survival of 85.6% and 94.5%, respectively. In addition, 79 LUMINA patients and 744 Mestizo GENLES patients were evaluated in order to compare genetic ancestry between the two groups; GENLES patients had a higher proportion of European ancestry (48.5% vs 43.3%, P = 0.003) and a lower proportion of Asian ancestry (3.7% vs 4.9%, P = 0.048), but the proportions of Amerindian and African ancestry were comparable in both. CONCLUSION: USA Hispanic patients seemed to have a poorer prognosis than their counterparts from Latin America, despite having a comparable genetic background. Socioeconomic factors may account for these observations.
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Predisposição Genética para Doença/etnologia , Hispânico ou Latino/genética , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Adulto , Fatores Etários , Análise de Variância , Estudos de Coortes , Bases de Dados Factuais , Feminino , Hispânico ou Latino/etnologia , Humanos , América Latina , Lúpus Eritematoso Sistêmico/mortalidade , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Análise Multivariada , Distribuição de Poisson , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Taxa de Sobrevida , Estados Unidos , Adulto JovemRESUMO
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
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Negro ou Afro-Americano/genética , RNA Helicases DEAD-box/genética , Lúpus Eritematoso Sistêmico/genética , Alelos , Antígenos Nucleares/genética , Antígenos Nucleares/imunologia , Apoptose/genética , Autoanticorpos/genética , Autoanticorpos/imunologia , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Predisposição Genética para Doença , Genoma Humano , Haplótipos , Humanos , Inflamação/genética , Helicase IFIH1 Induzida por Interferon , Autoantígeno Ku , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , População Branca/genéticaRESUMO
Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets.
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BACKGROUND: Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. METHODS: A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. RESULTS: Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10(-5), LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. CONCLUSION: These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
Assuntos
Albuminúria/genética , Nefropatias Diabéticas/genética , Estudo de Associação Genômica Ampla , Insuficiência Renal/genética , Idoso , Albuminúria/metabolismo , Mapeamento Cromossômico , Nefropatias Diabéticas/metabolismo , Etnicidade , Feminino , Ligação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Insuficiência Renal/metabolismo , Risco , Fatores de TempoRESUMO
The effect of sublethal doses of fungicides on fungicide-resistant Pythium isolates is unknown but potentially relevant to disease management. Occasional grower reports of Pythium disease increases after fungicide applications and our observations of greater radial growth in vitro on fungicide-amended media than on nonamended media suggests that Pythium isolates may be stimulated by sublethal doses of fungicides. The objectives of this study were to determine whether Pythium isolates were stimulated by sublethal doses of mefenoxam in vitro and whether this stimulation had any influence on Pythium damping-off of geranium seedlings. A mefenoxam-resistant isolate of Pythium aphanidermatum displayed 10% mean radial growth increase in vitro with mefenoxam at 1 × 10-10 µg/ml compared with growth on nonamended agar (nonsignificant). Geranium seedlings treated with one of eight mefenoxam concentrations were inoculated with 5-mm-diameter colonized agar plugs and evaluated for disease severity every 24 h. The area under the disease progress curve and the survival curve were estimated for each treatment and compared. Significant increases in damping-off were observed with mefenoxam at 1 × 10-6 and 1 × 10-10 µg/ml. Our data indicate that a Pythium isolate with resistance to mefenoxam can be stimulated by sublethal doses of the fungicide, and that this stimulation can result in significantly higher rates of Pythium damping-off of geranium seedlings.
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Bean pod mottle virus (BPMV) infection reduces yield and seed quality in soybean. To test the hypothesis that virus incidence and movement within plots would be reduced in soybean with resistance to feeding by the virus' bean leaf beetle (Cerotoma trifurcata) vector, BPMV spread was evaluated in five soybean genotypes at two inoculum levels over 2 years at two locations in Ohio. Soybean genotypes included two insect-feeding-susceptible genotypes (Williams 82 and Resnik), two insect-feeding-resistant, semidwarf genotypes (HC95-15 and HC95-24), and an insect-feeding-susceptible, semidwarf genotype (Troll). BPMV incidence was assessed in individual plants at growth stages R5/R6 and R7/R8 using enzyme-linked immunosorbent assay. Beetle feeding was visually assessed in 2004. Data for infection of individual plants were analyzed using a generalized linear mixed model, with a binomial distribution and logit-link. Within plots, BPMV incidence was highest in Resnik and Williams 82 and significantly lower in Troll. Incidence in HC95-15 was not significantly different than in Williams 82 and Resnik but incidence in HC95-24 was lower than in Resnik. BPMV incidence was also significantly (P < 0.05) affected by year, location, inoculum level and sampling date, with increasing incidence over time and higher incidence at the higher inoculum level. Beetle feeding damage was affected by the interaction of location-genotype. Significant spatial aggregation of infected plants was found for most plots but aggregation was independent of host genotype and inoculum level. Although the results indicate that BPMV infection varied by genotype, they do not support the hypothesis that insect-feeding resistance is sufficient to reduce the incidence and spread of BPMV.
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Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component. We recently identified a novel SLE susceptibility locus near RASGRP1, which governs the ERK/MAPK kinase cascade and B-/T-cell differentiation and development. However, precise causal RASGRP1 functional variant(s) and their mechanisms of action in SLE pathogenesis remain undefined. Our goal was to fine-map this locus, prioritize genetic variants likely to be functional, experimentally validate their biochemical mechanisms, and determine the contribution of these SNPs to SLE risk. We performed a meta-analysis across six Asian and European cohorts (9,529 cases; 22,462 controls), followed by in silico bioinformatic and epigenetic analyses to prioritize potentially functional SNPs. We experimentally validated the functional significance and mechanism of action of three SNPs in cultured T-cells. Meta-analysis identified 18 genome-wide significant (p < 5 × 10-8) SNPs, mostly concentrated in two haplotype blocks, one intronic and the other intergenic. Epigenetic fine-mapping, allelic, eQTL, and imbalance analyses predicted three transcriptional regulatory regions with four SNPs (rs7170151, rs11631591-rs7173565, and rs9920715) prioritized for functional validation. Luciferase reporter assays indicated significant allele-specific enhancer activity for intronic rs7170151 and rs11631591-rs7173565 in T-lymphoid (Jurkat) cells, but not in HEK293 cells. Following up with EMSA, mass spectrometry, and ChIP-qPCR, we detected allele-dependent interactions between heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and rs11631591. Furthermore, inhibition of hnRNP-K in Jurkat and primary T-cells downregulated RASGRP1 and ERK/MAPK signaling. Comprehensive association, bioinformatics, and epigenetic analyses yielded putative functional variants of RASGRP1, which were experimentally validated. Notably, intronic variant (rs11631591) is located in a cell type-specific enhancer sequence, where its risk allele binds to the hnRNP-K protein and modulates RASGRP1 expression in Jurkat and primary T-cells. As risk allele dosage of rs11631591 correlates with increased RASGRP1 expression and ERK activity, we suggest that this SNP may underlie SLE risk at this locus.
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Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/fisiologia , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/fisiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a DNA/análise , Humanos , Lúpus Eritematoso Sistêmico/etiologia , Locos de Características QuantitativasRESUMO
Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Povo Asiático/genética , Feminino , Expressão Gênica , Genótipo , Técnicas de Genotipagem , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
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.
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Indígena Americano ou Nativo do Alasca/genética , Lúpus Eritematoso Sistêmico/genética , Argentina , Antígeno CD11b/genética , Estudos de Casos e Controles , Chile , Cromossomos Humanos Par 10/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Haplótipos , Humanos , Fatores Reguladores de Interferon , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , México , ATPases Mitocondriais Próton-Translocadoras/genética , NADPH Oxidases/genética , Razão de Chances , Peru , Análise de Componente Principal , Fator de Transcrição STAT4/genética , Estados Unidos , População Branca/genética , beta CarioferinasRESUMO
Systemic Lupus Erythematosus (SLE) is a clinically heterogeneous autoimmune disease with strong genetic and environmental components. Our objective was to replicate 25 recently identified SLE susceptibility genes in two distinct populations (Chinese (CH) and Malays (MA)) from Malaysia. We genotyped 347 SLE cases and 356 controls (CH and MA) using the ImmunoChip array and performed an admixture corrected case-control association analysis. Associated genes were grouped into five immune-related pathways. While CH were largely homogenous, MA had three ancestry components (average 82.3% Asian, 14.5% European, and 3.2% African). Ancestry proportions were significantly different between cases and controls in MA. We identified 22 genes with at least one associated SNP (P < 0.05). The strongest signal was at HLA-DRA (P Meta = 9.96 × 10(-9); P CH = 6.57 × 10(-8), P MA = 6.73 × 10(-3)); the strongest non-HLA signal occurred at STAT4 (P Meta = 1.67 × 10(-7); P CH = 2.88 × 10(-6), P MA = 2.99 × 10(-3)). Most of these genes were associated with B- and T-cell function and signaling pathways. Our exploratory study using high-density fine-mapping suggests that most of the established SLE genes are also associated in the major ethnicities of Malaysia. However, these novel SNPs showed stronger association in these Asian populations than with the SNPs reported in previous studies.
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BACKGROUND: In Latin America, the medical attention directed to systemic autoimmune diseases competes with a budget designed to fight poverty, lack of education, etc. In this context, the access to treatments recommended internationally are expensive and limited; therefore, research of methods that make these treatments cheaper is of paramount importance. OBJECTIVE: Our objective was to describe the 24-month clinical outcome of patients with active systemic lupus erythematosus (SLE) who received low doses of rituximab (RTX), followed by hydroxychloroquine (HCQ), prednisone and low doses of mycophenolate mofetil (MMF). METHODS: Forty-six patients with active SLE received 500 mg of RTX (together with 500 mg of methylprednisolone as a premedication) administered on two occasions 2 weeks apart, followed by HCQ (200-400 mg/day), prednisone and MMF (500-1000 mg/day) during a 24-month follow-up period. Clinical outcome was assessed using the MEX-SLE Disease Activity Index (MEX-SLEDAI) and serial serologic measurements. Remission was defined as MEX-SLEDAI scores 0-1, mild disease activity 2-5, moderate disease activity 6-9, severe 10-13, and very severe 14 or more. RESULTS: Disease activity decreased over time with treatment. At baseline, 19 (41.3%) patients had very severe, 16 (34.8%) severe, and 9 (19.6%) moderate disease activity. Improvement on disease activity was detected at 3 months, since 9 (19.6%) patients reached disease remission after this period of time and remission increased to 16 (34.8%) patients at 6 months, 19 (41.3%) at 1 year, and 23 (50%) at 2 years of follow-up (p<0.0001). CONCLUSION: The administration of low doses of RTX followed by HCQ, prednisone and low doses of MMF is an effective therapy in Latin American patients with active SLE.
Assuntos
Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Hidroxicloroquina/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Prednisona/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Equador , Humanos , Hidroxicloroquina/uso terapêutico , América Latina , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Prednisona/uso terapêutico , Rituximab , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
PURPOSE: Diabetic retinopathy (DR) and diabetic nephropathy (DN) are serious microvascular complications of diabetes mellitus. Correlations between severity of DR and DN and computed heritability estimates for DR were determined in a large, multiethnic sample of diabetic families. The hypothesis was that (1) the severity of DR correlates with the presence and severity of nephropathy in individuals with diabetes mellitus, and (2) the severity of DR is under significant familial influence in members of multiplex diabetic families. METHODS: The Family Investigation of Nephropathy and Diabetes (FIND) was designed to evaluate the genetic basis of DN in American Indians, European Americans, African Americans, and Mexican Americans. FIND enrolled probands with advanced DN, along with their diabetic siblings who were concordant and discordant for nephropathy. These diabetic family members were invited to participate in the FIND-Eye study to determine whether inherited factors underlie susceptibility to DR and its severity. FIND-Eye participants underwent eye examinations and had fundus photographs taken. The severity of DR was graded by using the Early Treatment Diabetic Retinopathy Study Classification (ETDRS). Sib-sib correlations were calculated with the SAGE 5.0 program FCOR, to estimate heritability of retinopathy severity. RESULTS: This report summarizes the results for the first 2368 diabetic subjects from 767 families enrolled in FIND-Eye; nearly 50% were Mexican American, the largest single ethnicity within FIND. The overall prevalence of DR was high; 33.4% had proliferative DR; 7.5%, 22.8%, and 9.5% had severe, moderate, and mild nonproliferative DR, respectively; 26.6% had no DR. The severity of DR was significantly associated with severity of DN, both by phenotypic category and by increasing serum creatinine concentration (chi(2) = 658.14, df = 20; P < 0.0001). The sib-sib correlation for DR severity was 0.1358 in the total sample and 0.1224 when limited to the Mexican-American sample. Broad sense heritabilities for DR were 27% overall and 24% in Mexican-American families. The polygenic heritability of liability for proliferative DR approximated 25% in this FIND-Eye sample. CONCLUSIONS: These data confirm that the severity of DR parallels the presence and severity of nephropathy in individuals with diabetes mellitus. The severity of DR in members of multiplex diabetic families appears to have a significant familial connection.