RESUMO
Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder, and only a few cases have been reported to be complicated with autoimmune hemolytic anemia (AIHA). A 43-year-old man who presented with multiple swollen lymph nodes was diagnosed with iMCD. He was also diagnosed with AIHA based on laboratory findings, including the results of a bone marrow aspiration study. The patient was treated with tocilizumab; however, the effect was limited, probably due to anti-drug antibodies. Tocilizumab was therefore switched to rituximab, and his anemia was improved. Complication with AIHA should be carefully considered when iMCD patients present with severe anemia.
Assuntos
Anemia Hemolítica Autoimune/complicações , Hiperplasia do Linfonodo Gigante/complicações , Adulto , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Masculino , Rituximab/uso terapêuticoRESUMO
OBJECTIVE: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. METHODS: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. RESULTS: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion). CONCLUSIONS: Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.
Assuntos
Gota/genética , Hiperuricemia/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Povo Asiático/genética , Miosinas Cardíacas/genética , Estudos de Casos e Controles , Proteínas do Ovo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/etiologia , Gota/urina , Humanos , Hiperuricemia/complicações , Hiperuricemia/urina , Japão , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Cadeias Leves de Miosina/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Ácido Úrico/urinaRESUMO
Gout is a common disease resulting from hyperuricemia which causes acute arthritis. Recently, genome-wide association studies revealed an association between serum uric acid levels and a common variant of leucine-rich repeat-containing 16A (LRRC16A) gene. However, it remains to be clarified whether LRRC16A contributes to the susceptibility to gout. In this study, we investigated the relationship between rs742132 in LRRC16A and gout. A total of 545 Japanese male gout cases and 1,115 male individuals as a control group were genotyped. rs742132 A/A genotype significantly increased the risk of gout, conferring an odds ratio of 1.30 (95 % CI 1.05-1.60; p = 0.015). LRRC16A encodes a protein called capping protein ARP2/3 and myosin-I linker (CARMIL), which serves as an inhibitor of the actin capping protein (CP). CP is an essential element of the actin cytoskeleton, which binds to the barbed end of the actin filament and regulates its polymerization. In the apical membrane of proximal tubular cells in the human kidney, the urate-transporting multimolecular complex (urate transportsome) is proposed to consist of several urate transporters and scaffolding proteins, which interact with the actin cytoskeleton. Thus, if there is a CARMIL dysfunction and regulatory disability in actin polymerization, urate transportsome may be unable to operate appropriately. We have shown for the first time that CARMIL/LRRC16A was associated with gout, which could be due to urate transportsome failure.