Systemic inflammatory response has been implicated as a contributor to the onset of febrile seizures (FS). The four novel indices of the inflammatory response such as, neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), platelet count (PLT) ratio and red blood cell distribution width (RDW) have been investigated in FS susceptibility and FS types (simple febrile seizure and complex febrile seizure). However, the potential role of these inflammatory markers and MPV/PLT ratio (MPR) in Chinese children with FS has yet to be fully determined. This study investigated the relevance of NLR, MPV, PLT, MPR and RDW in febrile children with and without seizures. 249 children with FS and 249 age matched controls were included in this study. NLR and MPR were calculated from complete blood cell counts prior to therapy. Differences in age, gender and these inflammatory markers between the FS group and the control group were evaluated using the chi-square test, t-test or logistic regression analysis. Receiver Operating Characteristic (ROC) curve was used to determine the optimal cut-off value of NLR and MPR for FS risk. Interactions between NLR and MPR on the additive scale were calculated by using the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S). It has been shown that the elevated NLR and MPR levels were associated with increased risk of FS. The optimal cut-off values of NLR and MPR for FS risk were 1.13 and 0.0335 with an area under the curve (AUC) of 0.768 and 0.689, respectively. Additionally, a significant synergistic interaction between NLR and MPR was found on an additive scale. The mean levels of MPV were lower and NLR levels were higher in complex febrile seizure (CFS) than simple febrile seizure (SFS), and the differences were statistically significant. ROC analysis showed that the optimal cut-off value for NLR was 2.549 with 65.9% sensitivity and 57.5% specificity. However, no statistically significant differences were found regarding average values of MPR and RDW between CFS and SFS. In conclusion, elevated NLR and MPR add evidence to the implication of white cells subsets in FS risk, and our results confirmed that NLR is an independent, albeit limited, predictor in differentiating between CFS and SFS. Moreover, NLR and MPR may have a synergistic effect that can influence the occurrence of FS.

Infection with Epstein-Barr virus (EBV) and HLA-DRB1*1501-positivity is a risk factor for multiple sclerosis (MS), but whether an interaction between these two factors causes MS is unclear. We therefore conducted a meta-analysis on the effect of the interaction between HLA-DRB1*1501 and EBV infection on MS. Searches of PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and the Wanfan databases through February 2015 yielded 5 studies that met the criteria for inclusion in the meta-analysis. EBV infection and HLA-DRB1*1501-positivity were dichotomized. The additive (S) and multiplicative interaction indexes (OR) between EBV infection and HLA-DRB1*1501 and their 95% confidence intervals (95%CI) were calculated for each study and then combined in a meta-analysis. EBV infection was significantly associated with MS (OR = 2.60; 95%CI, 1.48–4.59). HLA-DRB1*1501 was associated with a significantly increased risk of MS (OR, 3.06; 95%CI, 2.30–4.08). An interaction effect between EBV infection and HLA-DRB1*1501 on MS was observed on the additive scale (S, 1.43; 95%CI, 1.05–1.95, P = 0.023), but no interaction effect was observed on the multiplicative scale (OR, 0.86, 95%CI, 0.59–1.26). This meta-analysis provides strong evidence that EBV alone, HLA-DRB1*1501 alone or their interaction is associated with an elevated risks of MS.

YWHAG, which encodes an adapter protein 14-3-3γ, is highly expressed in the brain and regulates a diverse range of cell signaling pathways. Previously, eight YWHAG mutations have been identified in patients with epileptic encephalopathy (EE). In this study, using trios-based whole exome sequencing, we identified two novel YWHAG mutations in two unrelated families with childhood myoclonic epilepsy and/or febrile seizures (FS). The identified mutations included a heterozygous truncating mutation (c.124C>T/p.Arg42Ter) and a de novo missense mutation (c.373A>G/p.Lys125Glu). The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment. The other affected individuals presented FS. The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic. Analysis on all missense mutations showed that nine mutations were located within 14-3-3γ binding groove and another mutation was located at residues critical for dimerization, indicating a molecular sub-regional effect. Mutation Arg132Cys, which was identified recurrently in five patients with EE, would have the strongest influence on binding affinity. 14-3-3γ dimers supports target proteins activity. Thus, a heterozygous missense mutation would lead to majority dimers being mutants; whereas a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, being one of the explanations for phenotypical variation. This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS. The spectrum of epilepsy caused by YWHAG mutations potentially range from mild myoclonic epilepsy and FS to severe EE.

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ObjectiveThe LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy.MethodsTrios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases.ResultsSix pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes.ConclusionRecessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.

Human papillomavirus (HPV) infection is a definite risk factor for cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The cGAS-STING pathway in innate immunity plays an important role in protecting against HPV infection. Chen et al. described that the rs2516448 SNP in the MHC locus may affect susceptibility to cervical cancer, a finding that we attempted to replicate in a Chinese population. To investigate the effects of cGAS, STING and MHC polymorphisms on susceptibility to cervical precancerous lesions, 9 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions were also evaluated. We found a significantly decreased risk of cervical precancerous lesions for the GG genotype of rs311678 in the cGAS gene (ORadjusted = 0.40, 95% CI: 0.16−0.98). Moreover, MDR analysis identified a significant three-locus interaction model, involving HPV infection, age at menarche and rs311678 in cGAS. Additionally, a significant antagonistic interaction between HPV infection and rs311678 was found on an additive scale. In conclusion, our results indicate that the rs311678 polymorphism in the cGAS gene confers genetic susceptibility to cervical precancerous lesions. Moreover, the three-way gene-environment interactions further demonstrate that the rs311678 polymorphism in cGAS can significantly decrease the risk of HPV infection and the elder at menarche.

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