RESUMEN
BACKGROUND: Henoch-Schönlein purpura (HSP) is a multisystem, small vessel, leucocytoclastic vasculitis. It is predominantly a childhood vasculitis, rarely reported in adults. Studies have shown that several different genetic factors such as genes involved in inflammatory system and renin-angiotensin system (RAS) are important in the pathogenesis of Henoch-Schönlein purpura. OBJECTIVES: The purpose of this study was to evaluate the independent effect of 3 gene polymorphisms including CCL2-2518 C/T, VEGF-634G/C and ACE(I/D) with HSP disease and their possible joint interactions in developing the disease. MATERIAL AND METHODS: In this case-control study 47 HSP cases and 74 unrelated healthy controls were enrolled for evaluation. All individuals were genotyped for CCL2-2518C/T, VEGF-634G/C and ACE(I/D) gene polymorphisms. The possible association of these polymorphisms with susceptibility to develop HSP disease independently and in different joint combinations was evaluated. RESULTS: The frequencies of TT genotype and T allele of CCL2-2518C/T gene polymorphism and CC genotype and C allele of VEGF-634G/C gene polymorphism were significantly high in HSP children (p-values = 0.005 and = 0.007 respectively). Interestingly, studying the joint interaction of these 2 genotypes (CC genotype of VEGF G-634C and TT genotype of CCL2 C-2518T) in this cohort showed a more significant effect in the development of the disease (p < 0.000, OR = 6.009). The frequency of TT genotype of CCL2 gene when combined with II genotype of ACE gene in HSP children was significantly higher (p < 0.000, OR = 4.213). CONCLUSIONS: The results of this pilot study provide evidence of the possible gene-gene interaction effects of CCL2, VEGF and ACE genes in developing HSP disease.
Asunto(s)
Quimiocina CCL2/genética , Epistasis Genética , Vasculitis por IgA/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo de Nucleótido Simple , Factor A de Crecimiento Endotelial Vascular/genética , Estudios de Casos y Controles , Niño , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , MasculinoRESUMEN
BACKGROUND: To determine the joint effect of complement component 3(C3 R102G) with CC-cytokine ligand2 (CCL2-2518) or complement factor H (CFH) Y402H polymorphisms on advanced age-related macular degeneration (AMD). METHODS: In this case-control study, 233 patients with advanced AMD and 159 unrelated healthy controls enrolled for evaluation. Selected polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: A combination of AA CCL2 (rs1024611) and GG C3 (R102G) genotypes resulted in a super-additivity of the risks: OR = 10.13, 95% CI 1.04-98.49, p = 0.04, adjusted OR = 7.74, 95% CI 0.71-84.75, p < 0.1, adjusted synergy indices: relative excess risk due to interaction (RERI) = 1.38, the attributable proportion due to interaction (AP) = 24.7% and the synergy index (S) = 1.43. Combination of at-risk genotypes of CFH Y402H and C3 R102G resulted in a strong super-additive risk: adjusted OR = 22.65, 95% CI 2.32-220.91, p = 0.007, adjusted AP = 90.4% and the S = 12.86. Attributable proportion of risk owing to C3-CCL2 and C3-CFH interaction calculated at 25% and 90% for advanced AMD. CONCLUSION: We have previously shown a strong association of C3 (R102G) and CFH Y402H with AMD whereas no association was found for CCL2-2518. This study enclosed strong synergistic association of risk genotypes of C3 and CFH Y402H with AMD. We also revealed synergistic influence of CCL2-2518 and the at-risk genotype of the C3 in AMD with an estimated AP = 50.9% (adjusted AP = 24.7%). Present findings show that CCL2-2518 polymorphism is not an innocent bystander in AMD susceptibility when combined with the at-risk genotype of C3 (R102G).
Asunto(s)
Quimiocina CCL2/genética , Complemento C3/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Factor H de Complemento/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Degeneración Macular/diagnóstico , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
BACKGROUND: Age related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population. Inflammatory mediators play an important role in AMD pathogenesis and immune-related gene polymorphisms are shown to increase the risk. Complement system is an important mediator of the immunity system and several genes encoding proteins involved in this system are associated with susceptibility to AMD. The central element of the complement cascade, C3 has been a plausible candidate since its cleavage product C3a was found in drusen. This study was planned to evaluate the association of C3-rs2230199 (R102G) variants with advanced type AMD in this cohort. MATERIALS AND METHODS: In this case-control study, 494 participants consisting of 266 AMD patients (187 wet AMD and 79 advanced dry AMD) and 228 samples from unrelated healthy controls were enrolled for evaluation. Extracted-DNA samples were amplified to obtain fragments including the polymorphic region. RESULTS: The distribution of the R102G genotypes was significantly different in the AMD patients compared to controls (p = 0.001).The Odds Ratio compared to CC individuals was 1.69 (95% CI 1.15-2.49) for GC individuals and 6.48 (95% CI1.87-22.43) for GG individuals. The Odds Ratio compared to the C allele was 2.31 (95% CI 0.48-11) for the G allele. GG and GC genotypes and G allele were significantly associated with both types of advanced-AMD. Individuals carrying GG genotype have over a six-fold risk of developing AMD in comparison to those carrying the CC genotype in this cohort. Our meta-analysis pooled data showed that our homozygous individuals for GG have a higher risk of AMD compared to previous publications in different nations (p = 0.017). CONCLUSIONS: Our study shows C3 to be a relatively strong susceptibility gene for advanced-type-AMD (exudative-and-geographic-atrophy) in an Iranian population.
Asunto(s)
Complemento C3/genética , Atrofia Geográfica/genética , Polimorfismo de Nucleótido Simple , Degeneración Macular Húmeda/genética , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Colorantes/administración & dosificación , Femenino , Angiografía con Fluoresceína , Frecuencia de los Genes , Genotipo , Atrofia Geográfica/diagnóstico , Humanos , Verde de Indocianina/administración & dosificación , Irán , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Tomografía de Coherencia Óptica , Degeneración Macular Húmeda/diagnósticoRESUMEN
PURPOSE: To evaluate the association of CC-cytokine ligand 2 CCL2-2518 (rs1024611) single nucleotide polymorphism, complement factor H (CFH Y402H) and their possible interaction in developing advanced age-related macular degeneration (AMD). METHODS: In this case-control study, DNA samples from 266 patients with advanced AMD and 229 healthy controls were genotyped for CCL2 polymorphism and also 254 patients and 164 healthy controls were genotyped for CFH polymorphism. The possible associations of these polymorphisms with susceptibility to AMD independently and in different joint combinations were evaluated. RESULTS: The genotype frequency for CFH was found to be significantly different between AMD and normal controls (31.5% versus 20.7%, OR = 3.56, p < 0.001 for CC and 52.4% versus 41.5%, OR = 2.96, p < 0.001 for CT genotype). However, no significant association between CCL2 polymorphism and AMD was observed in this cohort (OR = 1.15 and OR = 0.8, p = 0.172). Interestingly, studying the joint effects of two genotypes (TT genotype of CFH Y402H and AG genotype of CCL2-2518) showed more significant protective effect against AMD (p = 0.0001), while the risk effect of CC and CT genotypes of CFH was only visible in the presence of AA genotype of CCL2-2518 (p = 0.044 and p = 0.05). CONCLUSION: Complement factor H Y402H polymorphism is strongly associated with advanced type AMD. Although this study revealed no association of CCL2-2518 with AMD, the risk effect of CFH genotypes was only visible in the presence of AA genotype of CCL2-2518. AG genotype of CCL2-2518 in combination with TT genotype of CFH Y402H showed significant protective effect against AMD.
Asunto(s)
Quimiocina CCL2/genética , Atrofia Geográfica/genética , Polimorfismo de Nucleótido Simple , Degeneración Macular Húmeda/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Factor H de Complemento/genética , Análisis Mutacional de ADN , Femenino , Angiografía con Fluoresceína , Frecuencia de los Genes , Técnicas de Genotipaje , Atrofia Geográfica/diagnóstico , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Tomografía de Coherencia Óptica , Degeneración Macular Húmeda/diagnósticoAsunto(s)
Proteína C-Reactiva/metabolismo , Quimiocina CCL2/genética , Polimorfismo de Nucleótido Simple , Degeneración Macular Húmeda/genética , Anciano , Estudios de Casos y Controles , Colorantes/administración & dosificación , Femenino , Angiografía con Fluoresceína , Frecuencia de los Genes , Humanos , Verde de Indocianina/administración & dosificación , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Degeneración Macular Húmeda/sangre , Degeneración Macular Húmeda/diagnósticoRESUMEN
BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common small-vessel vasculitis and mainly affects children. Although its pathophysiology is unknown, several studies have indicated the possible involvement of infections and genetic factors in the development of HSP. The human leukocyte antigen (HLA) gene family and several other genes involved in the inflammatory system have been studied. The CCL2 gene, encoding chemokine monocyte chemo-attractant protein 1 (MCP-1/CCL2), is one of several cytokine genes clustered on chromosome 17. The encoded protein displays chemotactic activity for monocytes. METHODS: This is a case-control study comparing 36 children diagnosed with HSP within the Iranian Azeri-Turkish ethnic population and 50 healthy adults from the same ethnic group. CCL2, C-2518T polymorphism genotypes were determined by polymerase chain reaction and by PVUII restriction enzyme analysis and subsequent agarose gel electrophoresis. RESULTS: Our results showed a significant association between the allelic and genotypic frequency of this gene and HSP disease in this cohort. The results of this study indicate that frequencies of the T allele of CCL2 (P = 0.015) and the TT genotype (P = 0.004) are significantly higher in HSP patients. A comparison of clinical symptoms and laboratory data with CCL2 C-2518T polymorphism showed that patients with the TT genotype presented a higher clinical score and more severe clinical features. CONCLUSIONS: MCP1/CCL2 C-2518T gene polymorphism is associated with susceptibility to HSP. This is the first study to report a significant association between MCP1/CCL2 C-2518T and a susceptibility to HSP in this population.