Contents lists available at ScienceDirect Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres Immunogenetic protective factors in Genetic Generalized Epilepsy João Chaves a,b,1 , Ricardo Martins-Ferreira a,c,1 , Ana Marta Ferreira a,c , Sandra Brás c , Cláudia Carvalho a,c , Andreia Bettencourt a,c , Raquel Samões b , Fábio Monteiro c , Joel Freitas d , Rui Chorão b , João Lopes d , João Ramalheira d , Berta Martins da Silva a,c , Paulo Pinho Costa a,c,e , António Martins da Silva a,d , Bárbara Leal a,c, * a UMIB, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal b Serviço de Neurologia, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-003 Porto, Portugal c Lab. Imunogenética, DPIM, ICBAS-UPorto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal d Serviço de Neurofisiologia, Hospital de Santo António - Centro Hospitalar Universitário do Porto, Largo Prof. Abel Salazar, 4099-003 Porto, Portugal e Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Porto. Rua Pedro Nunes, n. º 88, 4099-032 Porto, Portugal ARTICLE INFO Keywords: Epilepsy Genetic Generalized Epilepsies Inflammation Genetic susceptibility ABSTRACT Background: Genetic Generalized Epilepsies (GGEs) are a heterogeneous group of syndromes characterized by generalized seizure activity that affects both hemispheres, with mainly genetic causes. Neuroinflammation has been established as an important mechanism in epileptogenesis. The ability to develop an appropriated immune response is strongly determined by immunogenetic factors. In this setting, our aim was to evaluate potential associations between GGEs and immunogenetic factors. Methods: The rs16944 (IL-1β -511 T > C) polymorphism and the HLA-DRB1 locus were genotyped in a Portuguese GGE population. Association with two clinicopathological features, photosensitivity and refractori- ness, was investigated. This case-control study included 323 GGE patients (187 F, 136 M, 34.0 ± 13.9 years of age), 145 of which with JME diagnosis (88 F, 57 M, 34.1 ± 14.0 years), and 282 healthy controls (174 F, 108 M, 37.7 ± 11.6 years). Results: Decreased frequencies of the HLA-DRB1*09 and DRB1*13 alleles were observed in the GGE population. HLA-DRB1*07 frequency was increased in JME. Rs16944 allelic frequencies were similar between patients and controls. Conclusions: These results, not entirely consistent with previous reports, suggest that HLA molecules may have a complex role in epileptogenesis. 1. Introduction Genetic Generalized Epilepsies (GGEs) are a heterogeneous group of epilepsy syndromes with primarily genetic causes (Mullen and Berkovic, 2018; Mulley et al., 2005; Scheffer et al., 2017), and account for nearly 20 % of all epilepsies (Jallon and Latour, 2005). GGEs are characterized by an electroclinical phenotype with generalized spike and wave discharges that engage both hemispheric structures (Gallentine and Mikati, 2012; Helbig, 2015; Mullen and Berkovic, 2018). The characterization of GGEs’ aetiology is quite complex and the level of understanding on GGEs genetic susceptibility is very low, with different studies failing to report a predominant genetic susceptibility pattern (Mullen and Berkovic, 2018; Poduri and Lowenstein, 2011). Genetic does not necessarily imply inheritance, as just 8 % of GGE patients’ siblings present epilepsy. Plus, only 2–8 % of GGEs are monogenic. Most GGEs present a complex inheritance model, in which meiotic reshuffling originates a particular combination of susceptibility alleles. Individually, each allele is unable to cause epilepsy. It has been proposed that the additive and epistatic contribution of all predisposi- tion alleles is ultimately responsible for triggering neuronal excitability over a seizure threshold, and, consequently, the development epilepsy (Mulley et al., 2005; Prasad et al., 2013; Scheffer et al., 2017). Neuroinflammation is now a well-established epileptogenic process. A persistent inflammatory state alongside epileptogenesis has been extensively described. It involves both innate and adaptive immunity https://doi.org/10.1016/j.eplepsyres.2020.106396 Received 15 April 2020; Received in revised form 2 June 2020; Accepted 10 June 2020 ⁎ Corresponding author at: UMIB, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto Lab. Imunogenética, DPIM, ICBAS-UPorto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. E-mail address: baguerraleal@gmail.com (B. Leal). 1 Both authors contributed equally to this work. Epilepsy Research 166 (2020) 106396 Available online 16 June 2020 0920-1211/ © 2020 Elsevier B.V. All rights reserved. T