Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti-seizure medications.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA-B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value. METHODS: We performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM-induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity. RESULTS: In the primary analysis, nine variants reached genome-wide significance (p < 5e-08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA-B*15:02-negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA-B*15:02 status or zygosity. HLA-B*15:02-positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001; homozygotes: relative risk = .23, p < .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (p < 5e-6) identified through the primary and subanalyses (stratified by HLA-B*15:02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology-related genes. The genes implicated were specific either to the primary analysis (CD9), HLA-B*15:02 carriers (DOCK10), noncarriers (ABCA1), carbamazepine exposure (HLA-E), or phenytoin exposure (CD24). SIGNIFICANCE: We identified variants that could explain why some carriers of HLA-B*15:02 tolerate treatment, and why some noncarriers develop ASM-induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA-B*15:02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM-induced SJS/TEN is complex, likely involving multiple risk variants.

Possible sertraline-induced extrapyramidal adverse effects in an adolescent.

Sertraline has been considered to be a relatively safe selective serotonin reuptake inhibitor for adolescents for a long time. We report herein a case of a 16-year-old Chinese boy with depression who experienced extrapyramidal-like effects, for example, facial spasm, upper limb dystonia, akathisia, and other disturbed behaviors, while being treated with sertraline 200 mg per day. His movement symptoms were significantly alleviated after the discontinuation of sertraline and the administration of scopolamine. This finding indicates that albeit infrequent, sertraline may cause severe extrapyramidal symptoms in adolescent patients, suggesting that clinicians should be alert to the neurological side effects of sertraline in young patients.

Separate and combined effects of Cu and Cd on seedling growth and active oxygen metabolism system of Trifolium repens L.

Pot-culture experiments were used to examine the individual and combined effects of Cu and Cd pollutants on Trifolium repens L. seedlings, both on their growth and their active oxygen metabolism system, mainly superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activities. The results showed that the negative action took place at low concentrations of Cu (less than 500 ppm) and Cd (less than 0.5 ppm), which had no obvious effects on the seedlings' growth. However, as the concentrations of Cu and Cd increased (500-3000 ppm and 0.5-50 ppm respectively), synergistic activities was observed, showing obvious negative effects (P less than 0.05). Compared with the control samples, the seedlings affected by Cu and Cd pollutants were shorter and smaller, their fresh/dry weight and content of soluble protein decreased drastically, their leaf electric conductivity increased, and the contents of their leaf pigments decreased. Chlorophyll a was more sensitive than chlorophyll b to Cu and Cd pollutants, and chlorophyll b was more sensitive than carotenoid. It was also shown that the active oxygen metabolism of T. repens seedlings was destroyed by high amounts of Cu and Cd, the balance of the anti-oxidase system was broken, and the CAT and SOD activities noticeably decreased while POD activity evidently increased. Cd had a more noticeable effect on seedling growth than Cu.