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To investigate the association between drug resistant epilepsy (DRE) and single nucleotide polymorphisms (SNPs) in whole-exome sequencing (WES).
Patients with epilepsy, who visited in our hospital, were enrolled in this study and divided into a drug-resistant group and a monotherapy-effective group based on treatment outcomes. Baseline demographic characteristics, medical history and laboratory test results were collected. Seizure outcomes were observed after more than 12 months under adequate treatment. WES was performed on 12 extreme cases (6 patients with resistant to three antiepileptic drugs vs. 6 patients effectively treated with monotherapy and undergoing dose reduction) to identify candidate SNPs. These candidate SNPs were then validated in the larger cohort to explore the association with DRE.
A tota of 560 patients were enrolled, 153 were DRE group and 407 were monotherapy-effective group. The median age in the monotherapy-effective group and the drug-resistant group was 19 years old and 25 years old, respectively; the median weight were 50 kg and 55 kg, respectively. All these differences between the two groups were statistically significant (all P<0.05); the proportion of structural etiology was 55.56% in the drug-resistant group and 45.46% in the monotherapy-effective group; the proportion of infectious etiology were 3.92% and 2.21%; the proportion of immune etiology were 3.27% and 1.23%; the proportion of metabolic and genetic etiology were 5.88% and 11.30%; the proportion of dual etiologies were 1.96% and 1.23%; the proportion of patients with impaired consciousness were 56.21% and 39.07%; the proportion of second-generation antiseizure medication as initial medication regimen were 50.98% and 65.46%; the proportion of malformation of cortical development were 10.46% and 2.95%; the proportion of hippocampal sclerosis were 15.03% and 9.58%; the proportion of hypoxic-ischemic encephalopathy were 3.92% and 1.47%; the proportion of vascular malformation were 4.58% and 3.93%; the proportion of traumatic brain injury were 1.31% and 3.44%; the proportion with brain tumor were 3.92% and 2.21%; the proportion with dual pathologies were 1.96% and 0.98%; the proportion of abnormal nonepileptogenic were 23.53% and 29.48%. Baseline information showed statistically significant differences in age, weight, etiology, presence of impaired awareness, initial medication regimen and neuroimaging results (P<0.05, P<0.001). 102 candidate SNPs were selected for genotyping and association analysis in larger cohort including 560 patients. 5 SNPs were identified to be significantly associated with DRE. Multivariate logistic regression incorporating both clinical and genetic factors revealed that hippocampal sclerosis, malformation of cortical development, hypoxic-ischemic, presence of impaired awareness, as well as the SCN2A rs17183814 GG and SPATA31 rs1919128 GA genotypes were risk factors for drug resistance (SCN2A rs17183814 GG: P=0.027; SPATA31 rs1919128 GA: P=0.014).
SCN2A rs17183814 and SPATA31 rs1919128 were found to be associated with drug resistance. Carriers of the GG genotypes of SCN2A rs17183814 and GA genotype of SPATA31 rs1919128 are more likely to develop DRE.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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