RESUMO
The data presented in this article are related to the research article entitled "The autoimmune risk gene ZMIZ1 is a vitamin D responsived marker of a molecular phenotype of multiple sclerosis" Fewings et al. (2017) [1]. Here we identify the set of genes correlated with ZMIZ1 in multiple cohorts, provide phenotypic details on those cohorts, and identify the genes negatively correlated with ZMIZ1 and the cells predominantly expressing those genes. We identify the metabolic pathways in which the molecular phenotype genes are over-represented. Finally, we present the flow cytometry gating strategy we have used to identify the immune cells from blood which are producing ZMIZ1 and RPS6.
RESUMO
Multiple Sclerosis (MS) is a neurological condition driven in part by immune cells from the peripheral circulation, the targets for current successful therapies. The autoimmune and MS risk gene ZMIZ1 is underexpressed in blood in people with MS. We show that, from three independent sets of transcriptomic data, expression of ZMIZ1 is tightly correlated with that of hundreds of other genes. Further we show expression is partially heritable (heritability 0.26), relatively stable over time, predominantly in plasmacytoid dendritic cells and non-classical monocytes, and that levels of ZMIZ1 protein expression are reduced in MS. ZMIZ1 gene expression is increased in response to calcipotriol (1,25 Vitamin D3) (p < 0.0003) and associated with Epstein Barr Virus (EBV) EBNA-1 antibody titre (p < 0.004). MS therapies fingolimod and dimethyl fumarate altered blood ZMIZ1 gene expression compared to untreated MS. The phenotype indicates susceptibility to MS, and may correspond with clinical response and represent a novel clinical target.
Assuntos
Autoimunidade/genética , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Fenótipo , Fatores de Transcrição/genética , Vitamina D/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genótipo , Herpesvirus Humano 4/imunologia , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Esclerose Múltipla/patologia , Polimorfismo de Nucleotídeo Único , Estações do Ano , Fatores de Transcrição/metabolismo , Vitamina D/farmacologia , Adulto JovemRESUMO
Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD45RO-; CD8CD45RO+ to CD8CD45RO-, NK CD56 dim to bright and monocyte numbers and percentages. Whole blood expression levels of IFNL3, IFNLR1 (interferon lambda receptor 1), IFNLR1-mem (a membrane-associated receptor), IFNLR1-sol (a truncated soluble receptor), MxA and T- and NK (natural killer) cell transcription factors TBX21, GATA3, RORC, FOXP3 and EOMES in two subjects were also determined. CHC patients demonstrated endogenous IFN activation with higher levels of MxA, IFNLR1, IFNLR1-mem and IFNLR1-sol, and IFNL3 genotype-associated differences in transcription factors. Taken together, these data provide evidence of an IFNL3 genotype association with differences in monocyte, T- and NK cell levels in the peripheral blood of patients with CHC. This could underpin genotype associations with spontaneous and treatment-induced HCV clearance and hepatic necroinflammation.
Assuntos
Hepatite C Crônica/imunologia , Interleucinas/genética , Antígenos de Diferenciação/metabolismo , Estudos de Coortes , Citometria de Fluxo , Genótipo , Hepacivirus , Humanos , Interferons , Células Matadoras Naturais/citologia , Monócitos/citologia , Linfócitos T/citologia , Fatores de Transcrição/metabolismo , Carga ViralRESUMO
The vitamin D receptor (VDR) is a ligand-activated transcription factor that regulates gene expression in many cell types, including immune cells. It requires binding of 1,25 dihydroxy vitamin D3 (1,25D3) for activation. Many autoimmune diseases show latitude-dependent prevalence and/or association with vitamin D deficiency, and vitamin D supplementation is commonly used in their clinical management. 1,25D3 is regulated by genes associated with the risk of autoimmune diseases and predominantly expressed in myeloid cells. We determined the VDR cistrome in monocytes and monocyte-derived inflammatory (DC1) and tolerogenic dendritic cells (DC2). VDR motifs were highly overrepresented in ChIP-Seq peaks in stimulated monocyte (40%), DC1 (21%) and DC2 (47%), PAssuntos
Artrite Reumatoide/genética
, Esclerose Múltipla/genética
, Receptores de Calcitriol/genética
, Artrite Reumatoide/imunologia
, Fatores de Transcrição de Zíper de Leucina Básica/genética
, Fatores de Transcrição de Zíper de Leucina Básica/metabolismo
, Estudos de Casos e Controles
, Células Dendríticas/metabolismo
, Humanos
, Monócitos/metabolismo
, Esclerose Múltipla/imunologia
, Polimorfismo Genético
, Receptores de Calcitriol/metabolismo
, Elementos de Resposta
, Vitamina D/metabolismo
RESUMO
OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥ 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥ 20 g/day for ≥ 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.
Assuntos
Hepacivirus/genética , Hepatite C Crônica/complicações , Cirrose Hepática/etiologia , Polimorfismo de Nucleotídeo Único , RNA Viral/análise , Medição de Risco/métodos , Biópsia , Progressão da Doença , Feminino , Estudo de Associação Genômica Ampla , Hepatite C Crônica/virologia , Humanos , Incidência , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Masculino , Estudos Retrospectivos , Fatores de Risco , Suíça/epidemiologia , Fatores de TempoRESUMO
The IFNL3 genotype predicts the clearance of hepatitis C virus (HCV), spontaneously and with interferon (IFN)-based therapy. The responder genotype is associated with lower expression of interferon stimulated genes (ISGs) in liver biopsies from chronic hepatitis C patients. However, ISGs represent many interacting molecular pathways, and we hypothesised that the IFNL3 genotype may produce a characteristic pattern of ISG expression explaining the effect of genotype on viral clearance. For the first time, we identified an association between a cluster of ISGs, the metallothioneins (MTs) and IFNL3 genotype. Importantly, MTs were significantly upregulated (in contrast to most other ISGs) in HCV-infected liver biopsies of rs8099917 responders. An association between lower fibrosis scores and higher MT levels was demonstrated underlying clinical relevance of this association. As expected, overall ISGs were significantly downregulated in biopsies from subjects with the IFNL3 rs8099917 responder genotype (P=2.38 × 10(-7)). Peripheral blood analysis revealed paradoxical and not previously described findings with upregulation of ISGs seen in the responder genotype (P=1.00 × 10(-4)). The higher MT expression in responders may contribute to their improved viral clearance and MT-inducing agents may be useful adjuncts to therapy for HCV. Upregulation of immune cell ISGs in responders may also contribute to the IFNL3 genotype effect.
Assuntos
Hepatite C Crônica/tratamento farmacológico , Interleucinas/genética , Metalotioneína/biossíntese , Carga Viral/genética , Genótipo , Hepacivirus , Humanos , Fatores Reguladores de Interferon/genética , Interferon-alfa/uso terapêutico , Interferons , Fígado/patologia , Fígado/virologia , Cirrose Hepática/genética , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Resultado do Tratamento , Regulação para CimaRESUMO
IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Receptores CCR5/genética , Deleção de Sequência , Adulto , Austrália , Sequência de Bases , Estudos de Coortes , Estudos Transversais , Quimioterapia Combinada , Epistasia Genética , Europa (Continente) , Feminino , Genótipo , Hepatite C Crônica/etnologia , Hepatite C Crônica/genética , Humanos , Interferon-alfa/uso terapêutico , Interferons , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Ribavirina/uso terapêutico , Resultado do Tratamento , População Branca/genéticaAssuntos
Neuropatias Amiloides Familiares/diagnóstico , Amiloide/química , Mutação de Sentido Incorreto , Mutação Puntual , Pré-Albumina/análise , Transtornos da Visão/diagnóstico , Corpo Vítreo/química , Substituição de Aminoácidos , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Pré-Albumina/genética , Análise de Sequência de DNA , Transtornos da Visão/etiologia , Transtornos da Visão/cirurgia , Acuidade Visual , Vitrectomia , Corpo Vítreo/cirurgiaRESUMO
We previously found an association between faster CD4+ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-α (IL-7Rα) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n=352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Rα single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n=57). Soluble (s)IL-7Rα levels were measured by ELISA. In UARTO, IL-7Rα haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P=0.020) and no association was found with LMM (P=0.958). The tagging-SNP for IL-7Rα haplotype-2 (rs6897932) was associated with decreased sIL-7Rα (P<0.001). The haplotypes for the IL-7Rα were significantly different in Africans and Caucasians. Using IL-7Rα genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P=0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P=0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Rα haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Rα SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/genética , Infecções por HIV/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-7/genética , Adulto , Terapia Antirretroviral de Alta Atividade , População Negra/genética , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Infecções por HIV/tratamento farmacológico , Haplótipos , Humanos , Masculino , Prognóstico , Receptores de Interleucina-7/sangue , Análise de Sobrevida , População Branca/genéticaAssuntos
Hidrocarboneto de Aril Hidroxilases/genética , Alucinações/induzido quimicamente , Alucinações/genética , Polimorfismo Genético/genética , Pirimidinas/efeitos adversos , Triazóis/efeitos adversos , Adulto , Citocromo P-450 CYP2C19 , Feminino , Alucinações/enzimologia , Humanos , VoriconazolRESUMO
IL7 regulates T cell survival, differentiation and proliferation. The alpha chain of its receptor, CD127, is polymorphic, and its haplotypes are associated with recovery from transplantation and with the autoimmune disease multiple sclerosis (MS), especially primary progressive MS (PPMS). We demonstrate that two CD127 haplotypes are highly associated with the proportion of the mRNA encoding the soluble isoform of CD127 (PAssuntos
Haplótipos
, Esclerose Múltipla/genética
, Neutrófilos/metabolismo
, Receptores de Interleucina-7/genética
, Células Th1/metabolismo
, Alelos
, Estudos de Casos e Controles
, Estudos de Coortes
, Feminino
, Expressão Gênica
, Heterozigoto
, Humanos
, Masculino
, RNA Mensageiro/metabolismo
, Estatística como Assunto
RESUMO
OBJECTIVE: To prospectively monitor inflammatory activity over a prolonged period in a cohort of Turkish patients with FMF, their healthy relatives and healthy controls and to relate this to their MEFV genotypes. METHODS: 43 patients with FMF and 75 of their asymptomatic relatives underwent fortnightly assessments and venesection for measurement of CRP and SAA over 5 months. 50 unrelated healthy population matched controls were also studied. MEFV genotyping was performed on all participants and comparisons were made between the different groups. RESULTS: Paired MEFV mutations were detected in 84% of FMF patients and single mutations in 12%. Substantial acute phase reactivity was seen among the patients with FMF during attacks (median SAA 693 mg/l, CRP 115 mg/l). Between attacks there was also some inflammatory activity (median SAA 6 mg/l, CRP 4 mg/l). Among healthy controls 16% were heterozygotes for MEFV mutations and 4% had two mutations. As expected there was a substantial carrier rate among healthy relatives with mutations detected in almost 92%. Asymptomatic MEFV heterozygotes had elevated acute phase proteins compared to wild type subjects. CONCLUSION: Substantial sub-clinical inflammation occurs widely and over prolonged periods in patients with FMF, indicating that the relatively infrequent clinically overt attacks represent the 'tip of the iceberg' in this disorder. Both basal and peak acute phase protein concentrations were greater in MEFV heterozygotes than in wild-type controls, regardless of mutation demonstrating a 'pro-inflammatory' phenotype among FMF carriers. Upregulation of the acute phase response among carriers of FMF may augment their innate host response and contribute to better resistance to infection.
Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Heterozigoto , Mutação , Reação de Fase Aguda/sangue , Reação de Fase Aguda/etiologia , Reação de Fase Aguda/genética , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/complicações , Genótipo , Humanos , Estudos Prospectivos , Pirina , Proteína Amiloide A Sérica/metabolismoRESUMO
The MSSE gene predisposes to multiple invasive but self-healing skin tumours (multiple self-healing epitheliomata). MSSE was previously mapped to chromosome 9q22-q31 and a shared haplotype in affected families suggested a founder mutation. We have refined the MSSE critical region (<1 cM, <1 Mb) between the zinc-finger gene ZNF169 and the Fanconi anaemia gene FANCC. By genetic mapping we have excluded ZNF169 and FANCC as well as PTCH (PATCHED) and TGFBR1 (transforming growth factor beta receptor type-1) genes. The CDC14B cell cycle phosphatase gene also lies in the region but screening of the complete coding region revealed no mutation in MSSE patients. Somatic cell hybrids created by haploid conversion of an MSSE patient's cells enabled screening of the MSSE chromosome 9 and showed no CDC14B deletion or mutation that abrogates CDC14B mRNA expression. Thus, CDC14B is unlikely to be the MSSE gene. We also report the first molecular analysis of MSSE tumours showing loss of heterozygosity of the MSSE region, with loss of the normal allele, providing the first evidence that MSSE is a tumour suppressor gene.
Assuntos
Carcinoma/genética , Cromossomos Humanos Par 9 , Perda de Heterozigosidade , Sequência de Bases , Primers do DNA , Haplótipos , Humanos , Células Híbridas , Polimorfismo GenéticoRESUMO
Susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Vital to the migration of cells to sites of inflammation, including the central nervous system, are chemokines, many of which are implicated in MS pathogenesis. Most of the CXC chemokine genes are encoded in a cluster on chromosome 4q13.3-21.1, which has been identified in several genome-wide screens as being potentially associated with MS. We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. Initially, we sequenced the chemokine genes in several DNA pools to identify common polymorphisms, and then genotyped selected SNPs in 373 Australian MS trio families. We found no evidence that the CXC chemokine gene cluster is genetically associated with MS. However, the existence of common variants conferring small risk factors or rare variants with significant risk cannot be excluded.
Assuntos
Quimiocinas CXC/genética , Cromossomos Humanos Par 4 , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Polimorfismo de Nucleotídeo Único , Austrália/epidemiologia , Saúde da Família , Feminino , Marcadores Genéticos , Predisposição Genética para Doença/epidemiologia , Genética Populacional , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Família Multigênica , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Fatores de RiscoRESUMO
Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing-remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P < 10(-4), chi(2)). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), -504 C, was undertransmitted in PPMS trios (P = 0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P = 0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Esclerose Múltipla/genética , Receptores de Interleucina-7/genética , Regulação para Baixo , Feminino , Expressão Gênica , Genótipo , Haplótipos , Humanos , MasculinoRESUMO
Familial Mediterranean fever (FMF) is caused by more than 25 mutations in the gene MEFV, which encodes pyrin (marenostrin), a protein implicated in the regulation of neutrophil activity. Pyrin Q148, is one of the five most common variants in populations in which FMF typically occurs. Our identification of the pyrin Q148 allele in several patients from ethnic groups in which FMF is not classically recognized who had longstanding fevers or AA amyloidosis prompted us to study the prevalence of pyrin Q148 in healthy British, Indian and Chinese subjects. The gene frequency was also sought in 50 British Caucasian patients with inflammatory arthritis, 25 of whom had AA amyloidosis, five Punjabi Indians with AA amyloidosis complicating inflammatory arthritis, and seven British Caucasian patients with uncharacterized longstanding fever syndromes. The allele frequency for pyrin Q148 was 21%, 15% and 0%, respectively, among Punjabi Indian, Chinese and Caucasian British controls, and was significantly increased among the patients with AA amyloidosis and the patients with obscure fever syndromes (p<0.01). Pyrin Q148 is a polymorphism and occurs widely in global terms, and, although it may cause FMF when associated with certain other MEFV mutations, homozygosity for Q148 alone must usually be insufficient to produce FMF in the populations studied. The association of pyrin Q148 with AA amyloidosis and with obscure chronic inflammatory diseases suggests the variant may augment inflammation non-specifically, which might have been beneficial during evolution, but could potentially exacerbate many chronic inflammatory disorders.
Assuntos
Febre Familiar do Mediterrâneo/genética , Mutação/genética , Proteínas/genética , Adulto , Idade de Início , Criança , Proteínas do Citoesqueleto , Febre Familiar do Mediterrâneo/epidemiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Londres/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , PirinaRESUMO
BACKGROUND: Treatment of systemic amyloidosis comprises measures to support failing organ function coupled with attempts to reduce the supply of the respective amyloid fibril precursor protein. Orthotopic hepatic transplantation is effective in familial amyloid polyneuropathy associated with variant transthyretin, because this protein is produced almost exclusively in the liver. Hepatic transplantation has not been performed in hereditary apolipoprotein AI (apoAI) amyloidosis, and the liver's contribution to plasma apoAI levels has not been determined in vivo. METHODS: A 57-year-old Irish man with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which had led to end-stage renal failure and progressive liver dysfunction, underwent hepatorenal transplantation. His outcome was followed clinically and his amyloid deposits were monitored with serum amyloid P component scintigraphy. The proportion of variant apoAI in the plasma was estimated by quantitative isoelectric focusing before and after liver transplantation. RESULTS: Plasma levels of variant apoAI decreased by 50% after liver transplantation, and the patient was asymptomatic 2 years after surgery. Subclinical amyloid deposits that were present in his spleen and heart preoperatively have regressed and stabilized respectively. CONCLUSIONS: Orthotopic liver transplantation substantially reduces the supply of the amyloid fibril precursor protein in hereditary apoAI amyloidosis, and the excellent outcome in this patient probably reflects the balance between deposition and turnover of amyloid having been altered in favor of the latter. These findings support the use of liver transplantation in patients with hereditary apoAI amyloidosis who develop hepatic dysfunction.
Assuntos
Amiloidose/genética , Amiloidose/cirurgia , Apolipoproteína A-I/genética , Transplante de Rim , Transplante de Fígado , Substituição de Aminoácidos , Amiloidose/diagnóstico por imagem , Amiloidose/fisiopatologia , Apolipoproteína A-I/sangue , Sequência de Bases/genética , Eletrocardiografia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Cintilografia , Proteína Amiloide A Sérica/análise , Componente Amiloide P Sérico/análise , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate genetic susceptibility in the first Indian family identified as having an autosomal dominantly inherited periodic fever syndrome. The inflammatory disease was characterized chiefly by arthralgia, skin rashes, and AA amyloidosis. METHODS: Markers from known periodic fever susceptibility loci were investigated in 7 affected and 11 healthy members of a north Indian family. These included the TNFRSF1A locus (formerly known as TNFRI), which is involved in autosomal dominant tumor necrosis factor receptor-associated periodic syndrome on chromosome 12p13, the familial Mediterranean fever locus (MEFV) on chromosome 16p13, the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) locus on chromosome 12q24, and the Muckle-Wells syndrome/familial cold urticaria (MWS/FCU) locus on distal chromosome 1q44. RESULTS: Linkage to both TNFRSF1A and MEFV was definitively excluded, and DNA sequencing of these genes revealed no mutations. Furthermore, there was no evidence of linkage to the HIDS locus. In contrast, significant logarithm of odds scores for 5 markers from the MWS/FCU region were obtained in this family, and the disease segregated with the same haplotype in all affected members. CONCLUSION: We have identified an inherited inflammatory disease in a north Indian family with clinical features overlapping some of those of MWS and FCU. The susceptibility gene maps to distal chromosome 1q44, a region already implicated in both MWS and FCU. Different mutations in the same (or a closely related) gene may be responsible for an inflammatory disease with a broad phenotype among diverse ethnic populations.