Page 88 - Read Online

A GENETIC APPROACH disease. Furthermore, low-frequency predisposing
genetic abnormalities are typically found in isolated
Progress in understanding IA pathogenesis has been populations with small founder populations,
slowed by its multifactorial nature. Heritable genetic subsequent bottleneck affects, and genetic drift. One
variance has long been recognized as an IA risk such population, with a higher rate of IA incidence, is the
factor. Indeed familial genetic predisposition leads to thoroughly characterized genetic isolate of Finland. [35]
increases in IA prevalence. [29,30] The establishment of A recent study revealed four novel low-frequency risk
gene-prevalence and pathway-prevalence correlations loci utilizing an alternative genetic approach. [36] The
may illuminate novel facets of IA pathophysiology study focused on the Finnish population, enriched
worthy of noninvasive therapeutic intervention. This the percentage of familial IA patients in the discovery
section will discuss variety recent genetic methods sample, and increased genome-wide coverage through
and their significance with respect to the inflammatory imputing genotyped variants against the 1000 genomes
pathophysiology of IA. project reference panel (v3, March 2012 release). [36]
The first novel variant rs74972714 at 2q23.3 is located
The aforementioned considerations motivated the use 40 Kb downstream of LYPD6. [36] LYPD6 can inhibit
of genome-wide association study (GWAS) to identify transcriptional activity of the AP-1 transcription factor
common genetic variants in patients who harbor complex, a key activated mediator of inflammation
IAs. Recent GWAS have identified several novel IA in endothelial cells subject to atherogenic blood flow
susceptibility loci, many unsurprisingly associated with conditions. [37,38] The variant rs113816216 at 5q31.3 is
structural genes. [31,32] Comprehensive meta-analysis of located in the intron of FSTL4, a poorly characterized
all genetic association studies (including GWASs) of gene. [36] However, the FSTL4 paralog FSTL1 encodes
sporadic IA found 19 single nucleotide polymorphism a protein that induces innate immunity by acting as
associations across the expansive international a toll-like receptor-4 (TLR-4) agonist. [39] The variant
discovery cohort. [33] The strongest three of these rs150927513 at 7p22.1 is located in the intron of
associations were robust to sensitivity analyses for Radil. [36] Radil has been implicated in the control
statistical heterogeneity and ethnicity. Critically, this of neutrophil adhesion and chemotaxis. [40] Finally,
[33]
meta-analysis confirmed that the previously studied two IA associated common variants, rs12472355 and
proinflammatory cytokine IL-6 G572C single nucleotide rs919433 at 2q33.1 were located 30 Kb upstream
polymorphism was also statistically associated with and intronic of ANKRD44, respectively. [36] ANKRD44
sporadic IA. However, initial sensitivity analysis is a likely subunit of protein phosphotase-6 whose
[6]
revealed statistical heterogeneity among sample studies. functions include inhibition of NF-κB activation. [41,42]
Specifically, when one Chinese study was excluded, the Ultimately, this study suggests varied investigative
association no longer held. [33] These variable results methodologies may yield novel associations in diseases
suggest more work is needed to precisely define this with complex inheritance patterns and illustrates the
genetic association and role of IL-6 in IA biology. use of population isolates as genetic tools. Collectively
the genetic analyses presented in this section further
In the genomic era, many candidate gene association highlight inflammation’s role in IA biology.
studies and GWAS have identified common genetic
variants that predispose individuals to IA. These INFLAMMATORY GENE EXPRESSION PROFILING
methods have recently been bolstered by pathway
and network-based analysis (PANOGA) of GWAS Many studies have attempted to quantify characteristic
data, which ultimately highlights uncommon gene expression patterns in IA. These potentially
genetic variants in common pathologically relevant powerful and informative studies (as reviewed
[5]
biological pathways. These approaches make use of extensively by Chalouhi et al. ) are limited by inherent
protein-protein interaction networks. For example, differences in cohort size, quantification techniques,
such PANOGA analysis of GWAS data recently status of sample aneurysms examined (onset vs.
implicated pathways conserved across aneurysmal rupture), and control tissue used. As such, the results
population cohorts, including (named by KEGG term) have been unsurprisingly heterogeneous. This section
T-cell receptor signaling and chemokine signaling. [34] will discuss recent novel approaches, including a
Such methods reinforce inflammations importance discussion of peripheral blood cell transcriptome
in sporadic IA formation and will play an important analysis in patients with aneurysmal SAH.
role in elucidating the complex genetic etiology of IA
formation and rupture. To tackle the problem of biological heterogeneity among
sample aneurysms, Nakaoka et al. determined the gene
[43]
As noted above, common genetic variance only explains expression levels in 8 ruptured cerebral arteries (within
a fraction of the heritability in cases of complex 24 h post SAH), 5 unruptured cerebral aneurysms,

80 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015