RESUMO
Hysterectomy is one of the most common surgical procedures performed in United States, and currently, one in three women in United States has had a hysterectomy by the age of 60 years. Systemic lupus erythematosus (SLE) is a common autoimmune disease and especially targets women of childbearing age at least 10 times higher than men, which reflects the major role of female sex hormones. In this retrospective study, we evaluate the potential effects of previous hysterectomy in our lupus cohort. Data collected from study subject questionnaires were obtained from the Lupus Family Registry and Repository (LFRR) at the Oklahoma Medical Research Foundation. Hysterectomy data were available from 3389 subjects. SLE patients with a positive history of hysterectomy have been selected and compared with matched lupus patients with a negative history of hysterectomy and healthy controls. Association analyses were performed, and the P values and adjusted odds ratios (ORs) were calculated. SLE patients with a negative history of hysterectomy more likely had kidney nephritis or positive anti-dsDNA than age-matched SLE patients with a history of hysterectomy before disease onset. This effect was independent of ethnicity with an OR of 6.66 (95% CI = 3.09-14.38, P = 1.00 x 10(-8)) in European patients and 2.74 (95% CI = 1.43-5.25, P = 0.001) in African-Americans. SLE patients with a positive history of hysterectomy before disease onset also had a later age of disease onset (P = 0.0001) after adjustment for age and race. Our findings support the notion that the influence of female sex hormones in SLE and various clinical findings are tremendous and that surgical menopause such as this could significantly affect the outcome of disease and clinical manifestations.
Assuntos
Histerectomia , Lúpus Eritematoso Sistêmico/fisiopatologia , Adulto , Negro ou Afro-Americano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários , População BrancaRESUMO
Systemic lupus erythematosus (SLE) disproportionately affects women. Recent work demonstrates that men with Klinefelter's syndrome (47,XXY men) have a similar risk of developing SLE as do women. We present an unusual African-American family with two SLE-affected individuals in which one of the patients with SLE also has Turner's syndrome (46,X,del(X)(q13)). Although not definitive, this family raises interesting questions regarding the function of genes located on the X chromosome in the development of SLE. The paucity of case reports documenting the overlap of SLE with Turner's syndrome while there is an association of male SLE with Klinefelter's syndrome suggests a lower risk of SLE in women with Turner's syndrome. These observations are consistent with a gene dose effect at X with two X chromosomes (46,XX or 47,XXY) conferring higher risk and one X chromosome (46,XY or 45,XO) conferring lower risk of SLE.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Síndrome de Turner/genética , Adolescente , Cromossomos Humanos X , Feminino , HumanosRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Estudos de Casos e Controles , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Proteínas de Membrana/imunologia , População Branca/genéticaRESUMO
We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Quinases da Família src/genética , Fatores Etários , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologiaRESUMO
Few large, multi-ethnic studies have examined the clinical and serologic differences between familial and sporadic SLE patients. Understanding these similarities and differences is critical for interpreting genetic studies and developing therapeutic strategies. We compiled information on 1915 patients with SLE in a large multi-racial cohort, including general demographics, pedigree structure and the specific American College of Rheumatology (ACR) criteria met. One patient was randomly selected from each multiplex family for analysis, yielding 554 European-Americans (EA), 373 African-Americans (AA), 193 Hispanics (HI) and 237 patients of other of mixed races. When comparing familial and sporadic patients stratified by race, lupus erythematosus (LE) cells and arthritis were increased in white familial cases (P = 5.5 x 10(-6) and P = 0.028, respectively), but no other significant differences between familial and sporadic patients were found. We found that there were profound differences in clinical profiles between races. For example, photosensitivity and malar rash were decreased in AA (P = 1.3 x 10(-13) and 1.4 x 10(-7), respectively), whereas discoid rash was increased in AA (P = 5.5x10(-6)). EA had significantly less renal disease (P = 5.4x10(-13)), proteinuria (P = 4 x 10(-12)) and anti-Sm (P = 1.7 x 10(-12)) than AA or HI. We, therefore, conclude that familial and sporadic onset patients may be treated similarly with respect to clinical and genetic studies.
Assuntos
Negro ou Afro-Americano , Hispânico ou Latino , Lúpus Eritematoso Sistêmico/genética , População Branca , Adulto , Feminino , Humanos , MasculinoRESUMO
Increased expression of interferon (IFN)-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). One transcription factor responsible for regulating IFN, interferon regulatory factor-5 (IRF5), has been associated with SLE in genetic studies of Asian, Caucasian and Hispanic populations. We genotyped up to seven polymorphic loci in or near IRF5 in a total of 4870 African-American and Caucasian subjects (1829 SLE sporadic cases and 3041 controls) from two independent studies. Population-based case-control comparisons were performed using the Pearson's chi(2)-test statistics and haplotypes were inferred using HaploView. We observed significant novel associations with the IRF5 variants rs2004640 and rs3807306 in African Americans and replicated previously reported associations in Caucasians. While we identified risk haplotypes, the majority of haplotypic effects were accounted for by one SNP (rs3807306) in conditional analyses. We conclude that genetic variants of IRF5 associate with SLE in multiple populations, providing evidence that IRF5 is likely to be a crucial component in SLE pathogenesis among multiple ethnic groups.
Assuntos
Negro ou Afro-Americano/genética , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Frequência do Gene , Genética Populacional , Genótipo , Haplótipos/genética , Humanos , Fatores Reguladores de Interferon/metabolismo , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Previous reports suggest a protective role for anti-La autoantibody against the development of lupus nephritis. We studied the effect of anti-La on the prevalence of nephritis in a large cohort of lupus patients. In addition, we determined the association between anti-La and the presence of the various other lupus manifestations. We studied 1100 lupus patients enrolled in the Lupus Family Registry and Repository. Only one lupus patient per family was selected to exclude intrafamilial correlation. Since anti-La is present in patients who also have anti-Ro autoantibody, we compared anti-Ro positive lupus patients in the presence or absence of anti-La. Clinical data were obtained from medical records, interviews and participant questionnaires. Tests for autoantibodies against extractable nuclear antigens were performed using immunodiffussion assays. There is no difference in the age, sex or race between the anti-La positive and anti-La negative lupus patients. The presence of anti-La is associated with a significant reduced risk of lupus nephritis (proteinuria: 29.3% versus 46.3%, OR = 0.48, P = 0.023; cellular casts: 8.6% versus 20.6%, OR = 0.36, P = 0.038). In addition, lupus patients with anti-La have a reduced risk for seizures (0% versus 10.9%, P = 0.0096) and are more likely to have arthritis (79.3% versus 64.0%, OR = 2.16, P = 0.031). The presence of anti-nRNP autoantibody is significantly reduced in anti-La positive compared with anti-La negative lupus patients (10.3% versus 27.4%, OR = 0.31, P = 0.0075). In conclusion, anti-La autoantibody is associated with less severe lupus. Patients with anti-La have a lower risk of renal involvement and seizures compared with anti-La negative lupus patients.
Assuntos
Anticorpos Antinucleares/sangue , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/imunologia , Convulsões/imunologia , Negro ou Afro-Americano , Anticorpos Antinucleares/imunologia , Estudos de Coortes , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/fisiopatologia , Nefrite Lúpica/complicações , Razão de Chances , Fatores de Risco , Convulsões/complicações , População BrancaRESUMO
Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1,506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 x 10(-6)), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 x 10(-6)), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 x 10(-4)) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 x 10(-4)). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.
Assuntos
Autoanticorpos/genética , Ligação Genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Linhagem , Negro ou Afro-Americano , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Autoanticorpos/classificação , Doenças Autoimunes/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 4 , Feminino , Predisposição Genética para Doença , Humanos , Masculino , População BrancaRESUMO
Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22-24, 2q37, 4p16, 12p12-11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11-25, and 20q12 and greatly improved evidence for linkage at 1q22-24, 2q37, 12p12-11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.
Assuntos
Heterogeneidade Genética , Ligação Genética , Lúpus Eritematoso Sistêmico/genética , Análise de Variância , Feminino , Humanos , Escore Lod , Masculino , Modelos GenéticosRESUMO
Both systemic lupus erythematosus (SLE) and vitiligo are autoimmune disorders that have strong evidence of complex genetic contributions to their etiology, but, to date, efforts using genetic linkage to find the susceptibility genes for either phenotype have met with limited success. Since autoimmune diseases are thought to share at least some of their genetic origins, and since only a small minority (16 of 92) of the European-American pedigrees multiplex for SLE in our collection have one or more affected members with vitiligo, we hypothesized that these pedigrees might be more genetically homogeneous at loci important to both SLE and vitiligo and, hence, have increased power for detection of linkage. We therefore evaluated genomewide microsatellite-marker-scan data for markers at an average marker density of approximately 11 cM in these 16 European-American pedigrees and identified a significant linkage at 17p13, where the maximum multipoint parametric LOD score was 3.64 (P<4.3x10(-5)) and the nonparametric linkage score was 4.02 (P<2.8x10(-5)), respectively. The segregation behavior of this linkage suggests a recessive mode of inheritance with a virtually homogeneous genetic effect in these 16 pedigrees. These results support the hypotheses that SLE and vitiligo may share important genetic effects and that sampling on the basis of clinical covariates dramatically improves power to identify genetic effects.
Assuntos
Cromossomos Humanos Par 17/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Mutação/genética , Vitiligo/complicações , Vitiligo/genética , Mapeamento Cromossômico , Feminino , Genes , Humanos , Escore Lod , Masculino , Repetições de Microssatélites/genética , LinhagemRESUMO
OBJECTIVE: The possible molecular mimicry of the Epstein-Barr virus (EBV) peptide PPPGRRP by the peptide PPPGMRPP from Sm B'/B of the human spliceosome is consistent with the possibility that EBV infection is related to the origin of systemic lupus erythematosus (SLE) in some patients. Association of EBV exposure with SLE was therefore tested for and subsequently found in children and adolescents (odds ratio [OR] 49.9, 95% confidence interval [95% CI] 9.3-1,025, P < 10(-11)). These results were confirmed at the level of EBV DNA (OR > 10, 95% CI 2.53-infinity, P < 0.002). Much smaller seroconversion rate differences were found against 4 other herpes viruses. Herein, we extend these studies to adults and test the hypothesis that EBV infection is associated with adult SLE. METHODS: We selected 196 antinuclear antibody-positive adult SLE patients (age > or =20 years) and 2 age-, race-, and sex-matched controls per patient. SLE patients and matched controls were tested for evidence of previous infection with EBV, cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), or varicella-zoster virus (VZV) by standardized enzyme-linked immunosorbent assays. RESULTS: Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P = 0.014). No differences were observed between SLE patients and controls in the seroconversion rate against CMV, HSV-2, or VZV. CONCLUSION: These new data from adults, along with the many suggestive features of EBV infection, are consistent with the contribution of this infection to the etiology of SLE.
Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/virologia , Adulto , Anticorpos Antivirais/sangue , Capsídeo/imunologia , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Herpes Simples/epidemiologia , Herpes Simples/imunologia , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Estudos SoroepidemiológicosRESUMO
OBJECTIVE: To identify chromosomal regions containing genes involved in the susceptibility to human systemic lupus erythematosus (SLE)-related traits. METHODS: In the context of a genome scan, we analyzed 101 SLE-affected sibpairs with respect to dermatologic, renal, immunologic, hematologic, neurologic, cardiopulmonary, and arthritic characteristics. Phenotypes were redefined in terms of principal components, which are synthetic variables composed of linear combinations of the original traits. Using 9 principal components obtained from these 7 traits plus age at SLE onset and race, we analyzed genome scan data with the multivariate version of the new Haseman-Elston regression model. RESULTS: The largest linkage for an individual trait was on chromosome 2 at 228 cM (immunologic; P = 0.00048). The most significant linkage to an individual principal component was on chromosome 4 at 208 cM (P = 0.00007). The largest multivariate linkage was on chromosome 7 at 69 cM (P = 0.0001). Of the individual organ systems, dermatologic involvement had the largest effect (P = 0.0083) at this peak at 7p13 on chromosome 7. Further analyses revealed that malar rash, a subtype of dermatologic involvement, was linked significantly (P = 0.00458) to this location. CONCLUSION: These results provide evidence of the presence and locations of genes that are involved in the genetic susceptibility to SLE-related traits in humans.
Assuntos
Cromossomos Humanos Par 2 , Ligação Genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 7 , Feminino , Humanos , Masculino , Análise Multivariada , Fenótipo , Análise de RegressãoRESUMO
OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs. METHODS: Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32-1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests. RESULTS: A maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229. CONCLUSION: Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.
Assuntos
Cromossomos Humanos Par 1 , Lúpus Eritematoso Sistêmico/genética , População Negra/genética , Cromossomos Humanos Par 1/genética , Europa (Continente)/etnologia , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Repetições de Microssatélites/genética , Linhagem , Estados UnidosRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 10, purported linkage at 1q41-42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log10 of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14-23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26-27, and 12p12-11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcgammaRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.