RESUMO
The human leukocyte antigen (HLA) genotype has been shown to associate with tubulointerstitial nephritis (TIN) and tubulointerstitial nephritis with uveitis syndrome (TINU). The association of HLA genes with TIN was examined in this nation-wide study. HLA genotyping was performed in 31 pediatric patients with biopsy-proven TIN. All patients were examined by an ophthalmologist to diagnose possible uveitis. Class II HLA genotypes of TIN patients were compared with the Finnish reference population. We found a significant association between the HLA alleles DQA1*04:01 [risk ratio (RR) 5.0, 95% confidence interval (CI) 2.0-11.2], DQB1*04:02 (RR 2.7, 95% CI 1.4-5.3), and DRB1*08 (RR 3.8, 95% CI 1.5-8.4) and TIN. Uveitis was found in 20/31 (64.5%) patients. HLA genotyping of the TINU patients showed additional risk HLA alleles: DQA1*01:04 (RR 6.1, 95% CI 1.5-17.8), and DRB1*14 (RR 8.2, 95% CI 2.2-22.1). The alleles DQA1*01:04 (RR 8.8, 95% CI 2.2-26.5), DQA1*04:01 (RR 3.2, 95% CI 1.2-7.3), and DRB1*14 (RR 12.0, 95% CI 3.2-33.0) were more frequent in patients with TIN and chronic uveitis than in reference population. The HLA class II haplotype DQA1*04:01/DQB1:04:02/DRB1*08 was the most common combination in our study population (58.1%). None of the patients had haplotype DQA1*04:01/DQB1*06:02/DRB1*15, which is common in Finland. HLA genotype did not predict the renal outcome. We found a strong association between certain HLA genotypes both in TIN and TINU patients. The TIN/TINU-associated HLA alleles appear to vary depending on study population.
Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/genética , Uveíte/diagnóstico , Uveíte/genética , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Feminino , Finlândia , Estudos de Associação Genética , Genótipo , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Nefrite Intersticial/complicações , Polimorfismo Genético , Valor Preditivo dos Testes , Prognóstico , Risco , Uveíte/complicaçõesRESUMO
Germline mutations in two major susceptibility genes, BRCA1 and BRCA2, account for nearly 20% of familial breast cancers. A majority of the remaining genetic factors involved in heritable breast cancer susceptibility are, however, unknown. Recently, a new BRCA1-interacting protein, receptor associated protein 80 (RAP80), was identified. RAP80 plays an important role in BRCA1-mediated DNA damage responses (DDRs) by recruiting BRCA1 to DNA double-strand breaks (DSBs). A comprehensive screening of DNA from affected index cases of 112 BRCA1/BRCA2 mutation-negative Finnish breast cancer families revealed altogether 10 alterations in RAP80, one of which, c.241-243delGAA, resulted in a single glutamic acid deletion at residue 81 in a highly conserved region of ubiquitin interaction motif 1. The resultant delE81 protein product displayed significantly reduced ubiquitin binding and DSB localization. Expression of the RAP80 delE81 allele impaired both BRCA1 and ABRA1 DSB recruitment, thus compromising BRCA1-mediated DDR signaling. Compared with wild-type RAP80, expression of the delE81 allele was associated with a significant increase in cytogenetically detectable chromosomal aberrations, particularly chromatid breaks. Although evidently quite rare, these results suggest that critical constitutional mutations in RAP80 abrogate DDR function and may be involved in genetic predisposition to cancer.
