RESUMEN
Systemic lupus erythematosus (SLE) is an autoimmune disease influenced by genetic and environmental factors. We carried out a genome-wide association scan and replication study and found an association between SLE and a variant in TNFAIP3 (rs5029939, meta-analysis P = 2.89 x 10(-12), OR = 2.29). We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis (RA). These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA.
Asunto(s)
Cromosomas Humanos Par 6 , Péptidos y Proteínas de Señalización Intracelular/genética , Lupus Eritematoso Sistémico/genética , Proteínas Nucleares/genética , Artritis Reumatoide/genética , Proteínas de Unión al ADN , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
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.
Asunto(s)
Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/genética , NADPH Oxidasas/genética , Negro o Afroamericano/genética , Asiático/genética , Biología Computacional , Heterogeneidad Genética , Variación Genética , Haplotipos , Hispánicos o Latinos/genética , Humanos , Modelos Moleculares , Polimorfismo de Nucleótido Simple , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
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.
Asunto(s)
Negro o Afroamericano/genética , ARN Helicasas DEAD-box/genética , Lupus Eritematoso Sistémico/genética , Alelos , Antígenos Nucleares/genética , Antígenos Nucleares/inmunología , Apoptosis/genética , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Mapeo Cromosómico , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Predisposición Genética a la Enfermedad , Genoma Humano , Haplotipos , Humanos , Inflamación/genética , Helicasa Inducida por Interferón IFIH1 , Autoantígeno Ku , Lupus Eritematoso Sistémico/inmunología , Polimorfismo de Nucleótido Simple , Unión Proteica , Población Blanca/genéticaRESUMEN
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Ligando OX40/genética , Negro o Afroamericano/genética , Alelos , Pueblo Asiatico/genética , Mapeo Cromosómico , Femenino , Genotipo , Haplotipos , Hispánicos o Latinos/genética , Humanos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico/patología , Linfocitos/patología , Masculino , FN-kappa B/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética , Lupus Eritematoso Sistémico/genética , Modelos Moleculares , Complejos Multiproteicos/genética , NADPH Oxidasas/metabolismo , Secuencia de Aminoácidos , California , Genotipo , Humanos , Datos de Secuencia Molecular , Complejos Multiproteicos/química , Mutación Missense/genética , NADPH Oxidasas/química , NADPH Oxidasas/genética , Plásmidos/genética , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Unión Proteica , Proteínas Proto-Oncogénicas c-vav/química , Proteínas Proto-Oncogénicas c-vav/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína de Unión al GTP rac1/químicaRESUMEN
Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.
Asunto(s)
Cromosomas Humanos Par 11/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Receptores de Hialuranos/genética , Lupus Eritematoso Sistémico/genética , Complejo Piruvato Deshidrogenasa/genética , Negro o Afroamericano/genética , Indio Americano o Nativo de Alaska/genética , Pueblo Asiatico/genética , Estudios de Cohortes , Femenino , Haplotipos , Hispánicos o Latinos/genética , Humanos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico/etnología , Masculino , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, nâ=â811) and anti-dsDNA autoantibody negative (anti-dsDNA -, nâ=â906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, pâ=â2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, pâ=â2.4E-04), with p(heterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
Asunto(s)
Autoanticuerpos , ADN/inmunología , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Antígeno CD11b/genética , Estudios de Casos y Controles , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Complejo Mayor de Histocompatibilidad/genética , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT4/genéticaRESUMEN
In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, Pâ=â2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/genética , Diabetes Mellitus Tipo 1/genética , Lupus Eritematoso Sistémico/genética , Receptores de Interleucina/genética , Inhibidor 1 de la Activación de Células T con Dominio V-Set/genética , Artritis Reumatoide/genética , Estudios de Casos y Controles , Estudios de Cohortes , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Pleiotropía Genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Ligando OX40/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p < 5 x 10⻹²8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend pâ=â4 x 10â»8. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR(high-low)â=â2.36, pâ=â9e-9), the immunologic criterion (OR(high-low)â=â2.23, pâ=â3e-7), and age at diagnosis (OR(high-low)â=â1.45, pâ=â0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, ORâ=â1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, ORâ=â0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.
Asunto(s)
Alelos , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Anticuerpos Antinucleares/inmunología , Área Bajo la Curva , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Lupus Eritematoso Sistémico/inmunología , Masculino , Modelos Genéticos , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta)â=â6.6×10(-8), ORâ=â1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta)â=â2.9×10(-7), ORâ=â1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta)â=â3.2×10(-7), ORâ=â1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta)â=â3.5×10(-4), ORâ=â1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.
Asunto(s)
Antígenos de Neoplasias/genética , Biomarcadores de Tumor/genética , Factor H de Complemento/genética , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Negro o Afroamericano/genética , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 1/genética , Eliminación de Gen , Frecuencia de los Genes , Genotipo , Hispánicos o Latinos/genética , Humanos , Intrones , Lupus Eritematoso Sistémico/etnología , Población Blanca/genéticaRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon-α (IFNα) levels in a large multiancestral SLE cohort. METHODS: We studied serum TNFα levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFα was measured using an enzyme-linked immunosorbent assay, and IFNα was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. RESULTS: Serum TNFα levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNFα levels were positively correlated with high serum IFNα levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNFα levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFα and IFNα was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNFα levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. CONCLUSION: Serum TNFα levels are high in many SLE patients, and we observed a positive correlation between serum TNFα and IFNα levels. These data support a role for TNFα in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease.
Asunto(s)
Lupus Eritematoso Sistémico/sangre , Factor de Necrosis Tumoral alfa/sangre , Adulto , Negro o Afroamericano , Autoanticuerpos/sangre , Femenino , Hispánicos o Latinos , Humanos , Interferón-alfa/sangre , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Población BlancaRESUMEN
OBJECTIVE: Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene-gene interactions in a number of known lupus susceptibility loci. METHODS: Eighteen single-nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2-step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. RESULTS: We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10(-5) [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10(-45)). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively). CONCLUSION: We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
Asunto(s)
Epistasis Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Adulto , Alelos , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. METHODS: Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. CONCLUSION: Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
Asunto(s)
Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Factor 6 Asociado a Receptor de TNF/genética , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , MasculinoRESUMEN
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 < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian ancestry protected against photosensitivity (P < 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P < 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P < 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.
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Indígenas Norteamericanos/genética , Indígenas Sudamericanos/genética , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/genética , Población Blanca/genética , Adolescente , Adulto , Niño , Femenino , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Indígenas Sudamericanos/estadística & datos numéricos , Nefritis Lúpica/etnología , Nefritis Lúpica/genética , Masculino , Persona de Mediana Edad , Morbilidad , Prevalencia , Factores de Riesgo , Factores Socioeconómicos , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. METHODS: We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. CONCLUSION: Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
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Proteínas de Unión al ADN/genética , Haplotipos/genética , Lupus Eritematoso Sistémico/etnología , Lupus Eritematoso Sistémico/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Negro o Afroamericano/genética , Negro o Afroamericano/estadística & datos numéricos , Asiático/genética , Asiático/estadística & datos numéricos , Linfocitos B/citología , Línea Celular Transformada , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Hispánicos o Latinos/genética , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Estados Unidos/epidemiología , Población Blanca/genética , Población Blanca/estadística & datos numéricosRESUMEN
OBJECTIVES: Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis. METHODS: The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK. RESULTS: Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies. CONCLUSION: This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.
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Proteínas Adaptadoras Transductoras de Señales/genética , Linfocitos B/inmunología , Lupus Eritematoso Sistémico/genética , Proteínas de la Membrana/genética , Familia-src Quinasas/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Estudios de Casos y Controles , Epistasis Genética/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Proteínas de la Membrana/metabolismo , Polimorfismo de Nucleótido Simple , Unión Proteica/genética , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
OBJECTIVE: High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease. METHODS: 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African-American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay. RESULTS: In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9×10(-14) for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African-American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African-American subjects and absent in African patients with SLE. CONCLUSIONS: The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population. These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness and are likely pathogenic in SLE.
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Factores Reguladores del Interferón/genética , Interferón-alfa/sangre , Lupus Eritematoso Sistémico/genética , Negro o Afroamericano/genética , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Estudios de Casos y Controles , ADN/inmunología , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Lupus Eritematoso Sistémico/inmunología , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
OBJECTIVES: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. METHODS: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. RESULTS: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10-8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. CONCLUSIONS: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
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Ligamiento Genético , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Sitios de Carácter Cuantitativo , Factores de Riesgo , Factores SexualesRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M) (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. METHODS: The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. RESULTS: The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88×10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32×10(-46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10(-5)). CONCLUSION: These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE.
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Moléculas de Adhesión Celular/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Grupos Raciales/genética , Marcadores Genéticos , Genética de Población , Humanos , Molécula 1 de Adhesión Intercelular/genética , Lupus Eritematoso Sistémico/epidemiología , Proteínas del Tejido Nervioso/genética , Grupos Raciales/etnologíaRESUMEN
While Sjögren's syndrome (SS) is more common than related autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), scientific and medical research in SS has lagged behind significantly. This is especially true in the field of SS genetics, where efforts to date have relied heavily on candidate gene approaches. Within the last decade, the advent of the genome-wide association (GWA) scan has altered our understanding of disease pathogenesis in hundreds of disorders through the successful identification of novel risk loci. With strong evidence for a genetic component in SS as evidenced by familial aggregation of SS as well as similarities between SS and SLE and RA, the application of GWA approaches would likely yield numerous novel risk loci in SS. Here we review the fundamental scientific principles employed in GWA scans as well as the limitations of this tool, and we discuss the application of GWA scans in determining genetic variants at play in complex disease. We also examine the successful application of GWA scans in SLE, which now has more than 40 confirmed risk loci, and consider the possibility for a similar trajectory of SS genetic discovery in the era of GWA scans. Ultimately, the GWA studies that will be performed in SS have the potential to identify a myriad of novel genetic loci that will allow scientists to begin filling in the gaps in our understanding of the SS pathogenesis.