SUDEP genetics is an important area and we must acknowledge

SUDEP purchase Asiaticoside is an important area, and we must acknowledge limitations to our study. The number of individuals who succumbed to SUDEP is small. Whilst there are new efforts to address this problem, to date case recognition and ascertainment (Smithson et al., 2014), collection of suitable samples and difficulties in obtaining WES data from certain types of material, have hampered progress and limited numbers. Dravet Syndrome is over-represented in both SUDEP and epilepsy control groups compared to the general population of people with epilepsy, though we note that SUDEP is also more common in people with Dravet Syndrome than in the overall population of people with epilepsy. Whilst we cannot exclude the possibility that any individual in our epilepsy control might succumb to SUDEP in the future, none has yet despite an expectation that a proportion might have been expected to do so, such that our epilepsy control group is enriched with those at lower risk of SUDEP. Although a significantly higher prevalence of male gender and convulsive seizures in the 12-month period before last follow-up or death was observed in the SUDEP cases compared to the epilepsy controls, these differences do not survive correction for multiple comparisons. Nevertheless, the differences merit some discussion. Male gender has been associated with a 1.4-fold increased risk for SUDEP in a combined analysis of case–control studies (Hesdorffer et al., 2011). Other previous studies did not confirm this association (Walczak et al., 2001; P-Codrea Tigaran et al., 2005; Vlooswijk et al., 2007) and more recently a mouse model of SUDEP did not show significantly different susceptibility to seizure-induced respiratory arrest between males and females (Faingold and Randall, 2013). Overall, the difference in the proportion of males in the SUDEP and epilepsy control groups may therefore not be biologically relevant, and is not in any case statistically significant after correction for multiple comparisons. The difference in convulsive seizure frequency between the SUDEP and epilepsy control groups is also not significant after correction for multiple comparisons, but it is interesting to speculate whether genome-wide burden of deleterious variants is an explanation that might underlie this epidemiologically-derived risk factor, tying epilepsy severity into genomic burden.
Author Contributions
Conflicts of Interest
Acknowledgements
This study makes use of data generated by the UCL-exomes Consortium. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.
Introduction 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, referred as statins, are widely used to improve serum lipid profiles. In addition to the established value for coronary protection, statins are thought to be beneficial for stroke prevention. Indeed, statin use was associated with 19 to 46% reduction of stroke risk (Pearson, 1998; Plehn et al., 1999; White et al., 2000; Sever et al., 2003; Kushiro et al., 2009; Nomura et al., 2015). However, these findings were derived from patients without prior stroke, and such preventive effect is less robust for patients with occurred stroke. For instance, in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, the use of atorvastatin was associated with 16% reduction in the risk for recurrent stroke (Amarenco et al., 2006). Also, a meta-analysis of 8 studies demonstrated that statin therapy has only a marginal effect to reduce occurrence of subsequent stroke in patients with prior stroke or transient ischemic stroke (TIA) (Manktelow and Potter, 2009). Indeed, stroke is a heterogeneous disease with different etiologies, with or without underlying arterial pathologies. Thus, the benefits of statins may be different depending on the subtypes of stroke. For instance, given the structural difference between major cerebral arteries and the perforating branches, the effects of statins can differ between atherothrombotic and lacunar infarctions. Moreover, the use of statins might increase the risk of hemorrhagic stroke (Amarenco et al., 2006; Collins et al., 2004; Boekholdt et al., 2014). Nevertheless, the majority of prior studies defined stroke as a whole, with no distinction between subtypes. Also, although the current international guidelines uniformly recommend the use of statins for secondary stroke prevention (European Stroke Organisation Executive Committee and ESO Writing Committee, 2008; Usherwood, 2013; Kernan et al., 2014), prevalence of lacunar infarction and cerebral hemorrhage is substantially higher in Asian than in Caucasian, requiring further studies to determine whether such guidelines are readily applicable to Asian.