Michelle Christina Johansen, MD
Radmanesh F, Falcone GJ, Anderson CD, McWilliams D, Devan WJ, Brown WM, et al. Rare Coding Variation and Risk of Intracerebral Hemorrhage. Stroke. 2015
The world of intracranial hemorrhage (ICH) is too often left at the doorstep of neurosurgery while vascular neurology focuses on ischemic stroke. As residents and fellows, we learn the basic pathophysiology and localization in order to derive likely etiology, but do we really understand what predisposes one person with the same risk factors to ICH versus another?
Radmanesh et al. through a collaborative effort sought to identify rare coding variants that might be associated with the presence of ICH. 757 cases and 795 controls were genotyped and a meta-analyses of single-variant and gene-based association was computed. The group found a signal with three common variants on chromosome 19q13 which encompassed TOMM40, APOE and APOC1. However after adjusting for the APOE epsilon alleles (ε2 and ε4 alleles), it was no longer associated with ICH. The group concludes that the small sample size severely limits the data analysis and that studies in the future must pull together resources from international consortia.
Where does this leave the vascular neurologist? There have been critics of the genome-wide association study (GWAS) movement stating that GWAS has yet to deliver meaningful biologically relevant knowledge, results are spurious and the substantial grant money invested has been wasteful. There has been literature that offers evidence to the contrary. There have been recent discoveries in ALS, MS and RA from such targeted genetic research. As pointed out in this study, the price of performing a genome-wide association study has continued to decrease making it more plausible.
What about ICH? It is interesting that the investigators found an association with APOE, something more familiar perhaps to those in the cognitive realm. The presence of one or more copies of the ε4 allele is a potent risk factor for the occurrence of Alzheimer dementia. Is there perhaps some underlying pathophysiology that leads to an association between this and the presence of cerebral amyloid angiopathy? In one study in Neurology 2014, the presence of APOE variants was found to increase the risk of lobar ICH independent of the presence of Warfarin, although notably this study was also limited by power. TOMM40 lies close to APOE. How does it play a role? A total of 14 SNPs within TOMM40 were associated with AD but not CAA-related ICH according to Valant et al. in 2012.
There is clearly more work to be done in the field of ICH genetics. As academic centers focus on building secure genetic databases and increase collaboration, we will learn more about rare variants and then perhaps begin to understand the pathogenic pathway leading to ICH.