RESUMO
BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.
Assuntos
Imunidade Adaptativa/genética , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Antibacterianos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Genes MHC da Classe II , Genes MHC Classe I , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/etnologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Distribuição de Qui-Quadrado , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-A/genética , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Sistema de Registros , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
We present a case of upper gastrointestinal bleeding in an otherwise healthy 18-year-old man who presented with melena. Endoscopy revealed an ulcerated mass in the stomach and pathology confirmed this to be a malignant, poorly differentiated choriocarcinoma. Further imaging showed a left testicular mass with evidence of pulmonary, gastric, and brain metastases, and blood tests revealed an hCG level of 32,219 U/L. He was diagnosed with advanced metastatic testicular choriocarcinoma and underwent intensive induction chemotherapy and an orchidectomy. Metastatic testicular choriocarcinoma is a rare cause of gastrointestinal bleeding.