RESUMEN
Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.
Asunto(s)
ADN/genética , Endodesoxirribonucleasas/genética , Lupus Eritematoso Sistémico/genética , Mutación , Animales , Estudios de Casos y Controles , ADN/sangre , Fragmentación del ADN , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animales de Enfermedad , Endodesoxirribonucleasas/deficiencia , Endodesoxirribonucleasas/metabolismo , Terapia Genética , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Humanos , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Transgénicos , Especificidad por Sustrato , Transducción GenéticaRESUMEN
A previous study conducted in Taiwan found a 100% association between HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals.
