RESUMEN
BACKGROUND: Interferon (IFN) gamma (IFNG) allelic variants are associated with susceptibility to multiple sclerosis (MS) in men but not in women. OBJECTIVES: To conduct a high-density linkage disequilibrium association study of IFNG and the surrounding region for sex-associated MS susceptibility bias and to evaluate whether IFNG allelic variants associated with MS susceptibility are associated with expression. DESIGN: Genotype case-control study, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay expression analyses for IFN gamma. SETTING: Three independently ascertained populations from the Mayo Clinic, Rochester, Minnesota, Queen's University of Belfast, Belfast, Ireland, and University of Leuven, Leuven, Belgium. PATIENTS: For linkage disequilibrium, 861 patients with MS (293 men and 568 women) and 843 controls (340 men and 503 women) derived from the US (population-based) and the Northern Ireland and Belgium (clinic-based) cohorts were studied. For expression analyses, 50 US patients were selected to enrich for homozygotes and to achieve a balance between men and women. INTERVENTIONS: Twenty markers were genotyped over the 120-kilobase region harboring IFNG and the interleukin 26 gene (IL26). MAIN OUTCOME MEASURES: Expression of IFN gamma was evaluated by qPCR and enzyme-linked immunosorbent assay in stimulated peripheral blood mononuclear cells. RESULTS: Multiple markers were associated with MS susceptibility in men but not in women. The sex-specific susceptibility markers, of which rs2069727 was the strongest, were confined to IFNG. Carriers of rs2069727*G had higher expression than noncarriers. The effect of genotype in the qPCR experiments was also evident in men but not in women. CONCLUSIONS: IFNG is associated with sex bias in MS susceptibility and with expression of IFN gamma in MS. These observations add to a growing body of literature that implicates an interaction between sex and IFN gamma expression in a variety of disease states.
Asunto(s)
Expresión Génica/genética , Predisposición Genética a la Enfermedad , Interferón gamma/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Caracteres Sexuales , Alelos , Bélgica/epidemiología , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Frecuencia de los Genes , Humanos , Interferón gamma/metabolismo , Irlanda/epidemiología , Desequilibrio de Ligamiento , Masculino , Estados Unidos/epidemiologíaRESUMEN
Four distinct patterns of tissue injury have been described in multiple sclerosis (MS) lesions. Infiltrating monocytes in lesions of all patterns co-express CCR1 and CCR5. However, in pattern II lesions, the number of CCR1 cells is decreased, while the number of CCR5 expressing cells is increased in late active versus early active regions. In contrast, CCR1 and CCR5 cells were equal in all regions of pattern III lesions. These suggest distinct inflammatory microenvironments in pattern II and III lesions and support MS pathological heterogeneity. A deletion in CCR5 (CCR5*Delta32), which encodes a truncated, non-functional protein, has been associated with late onset of MS and a favorable prognosis. We studied the association of CCR5*Delta32 with the course and severity of MS in 221 patients from a population-based cohort in Olmsted County, MN, and with patterns of immunopathology in 94 patients with biopsy-derived, pathologically confirmed demyelinating disease participating in the MS Lesion Project. The frequency of the genotypes in 221 patients from Olmsted County, MN, was 167 (75.6%) wild type, 52 (23.5%) heterozygotes, and 2 (0.9%) homozygotes. There was no association of carrier status for the CCR5*Delta32 mutation with disease severity as analyzed using the disease severity score (ranking of EDSS/duration stratified by duration), age of onset, gender or disease course (bout onset versus primary progressive). Due to low frequency of homozygotes no conclusion can be made regarding their relation to heterozygosity or wild-type status. The frequency of genotypes in the 94 biopsies was 77 (81.9%) wild type, 15 (16.0%) heterozygotes and 2 (2.1%) homozygotes. Carrier status for the CCR5*Delta32 mutation was not associated with patterns of immunopathology in MS. Despite similar numbers of T-lymphocytes, there were no CCR5+ T-cells nor was CCR5 expressed in the CNS of a homozygous CCR5*Delta32 MS patient, and heterozygous patients had reduced CCR5 expression compared to wild type patients. CCR5*Delta32 has a dose effect on CCR5 expression in the CNS, but is neither necessary for development of MS, nor CD3+ T cell recruitment into the CNS. Furthermore it does not segregate with patterns of immunopathology in MS. We did not find an association between CCR5*Delta32 mutation and disease severity and age of onset in MS.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Polimorfismo Genético , Receptores CCR5/genética , Adulto , Northern Blotting/métodos , Recuento de Células , Progresión de la Enfermedad , Femenino , Eliminación de Gen , Genotipo , Humanos , Macrófagos/fisiología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/clasificación , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , ARN Mensajero/biosíntesis , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Linfocitos T/fisiologíaRESUMEN
CD95/CD95L interaction results in activation-induced apoptosis thereby regulating clonal expansion of T cells outside the thymus. Genetic defects in this system result in autoimmune lymphoproliferation in mice and men. CD95-induced cell death may be defective in MS. We studied the association of CD95 and CD95L polymorphisms with MS in 221 unique patients representing 79% ascertainment in Olmsted County, MN, and 442 gender-, age- and ethnicity-matched controls. Being a homozygote for the G allele of CD95 5'(-670)*A-->G SNP (p=0.034; OR: 1.59, 95% CI: 1.06-2.38) and for the C allele of CD95 E7(74)*C-->T SNP (p=0.007; OR: 1.73, 95% CI: 1.17-2.56) increased susceptibility to MS exclusively in women. There was strong but incomplete linkage disequilibrium between the two markers (p<0.001; D'=0.546). Homozygosity for 5'(-670)*A or E7(74)*C explained 28% of risk of MS in women but 0% of the risk in men in Olmsted County, MN. Our results agree with the previously published studies and highlight that the association of the polymorphisms is restricted to women with MS. We did not find an association between CD95L and susceptibility to MS nor CD95 or CD95L and age of onset, disease course and disease severity.
Asunto(s)
Glicoproteínas de Membrana/genética , Esclerosis Múltiple/genética , Polimorfismo Genético/genética , Receptor fas/genética , Estudios de Cohortes , Intervalos de Confianza , Proteína Ligando Fas , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Oportunidad RelativaRESUMEN
Previous studies have suggested a role for interleukin-4 gene (IL4) in susceptibility to multiple sclerosis (MS) as well as other autoimmune diseases. We screened the promoter region, exons 1-4 and their splice sites for polymorphisms and tested the association between novel polymorphisms E1(33)*C-->T and I3(2580)*C-->A, and the established 5'(-523)*C-->T and I3(709)*VNTR polymorphisms with susceptibility to, age of onset in, and course and severity of MS in sporadic cases. I3(709)*VNTR was associated with susceptibility to MS (p=0.004) due to a dearth of heterozygotes in patients (29/122; 23.8%) compared to controls (91/244; 37.3%). Homozygotes for the uncommon I3(709)*allele-2 may have increased susceptibility (p=0.044; OR=5.17, 95% CI: 0.83-54.95) as might carriers for the extended haplotypes 5'(-523)*T/E1(33)*T/I3(709)*allele-2/I3(2580)*C (p=0.003; OR: 3.75, 95% CI: 1.18-11.93) or 5'(-523)*C/E1(33)*C/I3(709)*allele-1/I3(2580)*A (p=0.004; OR: 4.22, 95% CI: 1.22-14.54). We could not confirm the previously reported association between carriage of I3(709)*allele-2 and older age of onset. However, we found a trend for association between the homozygous state for this allele and older age of onset.
Asunto(s)
Interleucina-4/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Polimorfismo Genético/genética , Adulto , Edad de Inicio , Análisis de Varianza , Estudios de Casos y Controles , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 5/inmunología , Intervalos de Confianza , Haplotipos/inmunología , Humanos , Minnesota/epidemiología , Datos de Secuencia Molecular , Esclerosis Múltiple/epidemiología , Oportunidad Relativa , Prevalencia , Índice de Severidad de la Enfermedad , Estadísticas no ParamétricasRESUMEN
We comprehensively screened CTLA4 for novel genetic variations in patients with MS. We studied genetic variations by association methods in a population-based sample of 122 sporadic patients with MS and 244 age-, gender- and ethnicity-matched controls, and by linkage and family-based association methods in 395 individuals from 59 American multiplex pedigrees with 141 affected individuals. Being homozygous for AT(8) (common) allele of the 3'(514) microsatellite (OR: 1.69; CI: 0.99-2.86) and for the common 5'(318)*C/E1(49)*A/3'(514*AT(8) haplotype (OR: 1.96; CI: 1.13-3.39) was associated with increased susceptibility to MS in Olmsted County. The genotype frequencies of other individual polymorphisms were not significantly different between cases and controls. A pooled analysis of association studies revealed an odds ratio of 1.28 (95% CI: 1.01-1.63; p=0.043) for 5'(-318)*C homozygotes and 1.28 (95% CI: 1.08-1.51; p=0.005) for the 3'(514)*AT(8) allele. We did not detect linkage with MS susceptibility in multiplex families. We did not find a strong association with age at onset, disease course or severity. CTLA-4 is associated with susceptibility to MS.
Asunto(s)
Antígenos de Diferenciación/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Inmunoconjugados , Esclerosis Múltiple/genética , Polimorfismo Genético/genética , Abatacept , Edad de Inicio , Empalme Alternativo/genética , Antígenos CD , Antígenos de Diferenciación/inmunología , Boston , Antígeno CTLA-4 , Análisis Mutacional de ADN , Progresión de la Enfermedad , Exones/genética , Femenino , Ligamiento Genético/genética , Pruebas Genéticas , Genotipo , Haplotipos/genética , Humanos , Masculino , Repeticiones de Microsatélite/genética , Minnesota , Esclerosis Múltiple/inmunologíaRESUMEN
OBJECTIVE: To study the association of the myeloperoxidase (MPO) -463 (G-->A) polymorphism with lung cancer risk. PATIENTS AND METHODS: We performed a paired case-control analysis of 307 patients with primary lung cancer and an equal number of age-, sex-, and ethnicity-matched controls to evaluate the effect of the MPO -463 (G-->4A) polymorphism on disease susceptibility. We also performed conditional logistic regression analyses to evaluate the effect of the polymorphism adjusted for smoking status and chronic obstructive pulmonary disease, 2 established risk factors. We used 2 models for these analyses: one to compare homozygous (AA) genotypes with wild type (GG) and heterozygous (GA) genotypes and one to compare carriers (heterozygotes and AA homozygotes) with GG genotypes. Finally, we combined the results from the published studies of this putative association and performed a stratified analysis. RESULTS: The AA genotype was inversely associated with susceptibility to lung cancer (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.15-1.00). There was no association in heterozygotes. However, in the stratified analysis, we found an association between patients with the AA (OR, 0.44; 95% CI, 0.27-0.68) and GA (OR, 0.77; 95% CI, 0.64-0.93) genotypes vs the GG genotype. CONCLUSION: Our results are consistent with previous reports and show that homozygotes of the less common A allele of MPO -463 polymorphism have a 2.6-fold lower risk of lung cancer.