Intracranial aneurysm genetics
see Intracranial aneurysm in tuberous sclerosis complex
The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit ∼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (CPNE7, ICAM5, STAT2, and RAF1). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; P = 4.6 × 10-8) 1).
In comparison to sporadic aneurysms, familial aneurysms tend to be larger, more often located at the middle cerebral artery, and more likely to be multiple.
Other than familiar occurrence, there are several heritable conditions associated with intracranial aneurysm formation, including autosomal dominant polycystic kidney disease, neurofibromatosis type I, Marfan syndrome, multiple endocrine neoplasia type I, pseudoxanthoma elasticum, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos syndrome type II and IV.
The familial occurrence and the association with heritable conditions indicate that genetic factors may play a role in the development of intracranial aneurysms.
Genome-wide linkage studies in families and sib pairs with intracranial aneurysms have identified several loci on chromosomes showing suggestive evidence of linkage, particularly on chromosomes 1p34.3-p36.13, 7q11, 19q13.3, and Xp22. For the loci on 1p34.3-p36.13 and 7q11, a moderate positive association with positional candidate genes has been demonstrated (perlecan gene, elastin gene, collagen type 1 A2 gene). Moreover, 3 of the polymorphisms analyzed in 2 genes (endothelial nitric oxide synthase T786C, interleukin-6 G572C, and interleukin-6 G174C) were found to be significantly associated with ruptured/unruptured aneurysms: the endothelial nitric oxide synthase gene single-nucleotide polymorphisms increased the risk, while IL-6 G174C seemed protective. More recently, two genomic loci (endothelin receptor A and cyclin-dependent kinase inhibitor 2BAS) have been found to be significantly associated with intracranial aneurysms in the Japanese population; endothelin-1 is a potent vasoconstrictor produced by the endothelial cells.
Until now, there are no diagnostic tests for specific genetic risk factors to identify patients who are at a high risk of developing intracranial aneurysms. Knowledge of the genetic determinants may be useful in order to allow clues on stopping aneurysm formation and obtain diagnostic tools for identifying individuals at increased risk. Further multicenter studies have to be carried out 2).
The purpose of a study of Zholdybayeva et al. was to explore the relationship between single nucleotide polymorphisms (SNPs) and intracranial aneurysm (IA) in Kazakhstan population. The patients were genotyped for 60 single nucleotide polymorphisms. Genotyping was performed on the QuantStudio 12K Flex (Life Technologies). A linear regression analysis found 13 SNPs' significant association with development and rupture of IA: the rs1800956 polymorphism of the ENG gene, rs1756 46 polymorphism of the JDP2 gene, variant rs1800255 of the COL3A1, rs4667622 of the UBR3, rs2374513 of the c12orf75, rs3742321 polymorphism of the StAR, the rs3782356 polymorphism of MLL2 gene, rs3932338 to 214 kilobases downstream of PRDM9, rs7550260 polymorphism of the ARHGEF, rs1504749 polymorphism of the SOX17, the rs173686 polymorphism of CSPG2 gene, rs6460071 located on LIMK1 gene, and the rs4934 polymorphism of SERPINA3. A total of 13 SNPs were identified as potential genetic markers for the development and risk of rupture of intracranial aneurysms in the Kazakh population. Similar results were obtained after adjusting for the confounding factors of arterial hypertension and age 3).
Identification of the genetic factors involved is critical for disease prevention and treatment. No diagnostic test based on genetic knowledge is currently available to identify theses mutations and patients who are at higher risk for developing IAs. In the longer term, a more comprehensive understanding of independent and interdependent molecular pathways germane to IA formation and rupture may guide the physician in developing targeted therapies and optimizing prognostic risk assessment 4).
Exome sequencing was performed in 12 families with histories of multiple cases of IA (number of cases per family ≥3), with a total of 42 cases. Various filtering strategies were used to select the candidate variants. Replicate association studies of several candidate variants were performed in probands of 24 additional IA families and 426 sporadic IA cases. Functional analysis for the mutations was conducted.
After sequencing and filtering, 78 variants were selected for the following reasons: allele frequencies of variants in 42 patients was significantly (P<0.05) larger than expected; variants were completely shared by all patients with IA within ≥1 family; variants predicted damage to the structure or function of the protein by PolyPhen-2 (Polymorphism Phenotyping V2) and SIFT (Sorting Intolerance From Tolerant).
Results suggest that reduced integrity of the endothelial wall, as conferred by ADAMTS variants, together with inflammatory processes and defective vascular remodeling plays an important role in pathogenesis, although the mechanism of action remains unknown. This findings may lead to specific screening of at-risk populations in the future 5).
Yan et al. selected 10 variants from 9 genes (GPR63, ADAMST15, MLL2, IL10RA, PAFAH2, THBD, IL11RA, FILIP1L, and ZNF222) to form 78 candidate variants by considering commonness in families, known disease genes, or ontology association with angiogenesis. Replicate association studies revealed that only p.E133Q in ADAMTS15 was aggregated in the familial IA cases (odds ratio, 5.96; 95% confidence interval, 2.40-14.82; P=0.0001; significant after the Bonferroni correction [P=0.05/78=0.0006]). Silencing ADAMTS15 and overexpression of ADAMTS15 p.E133Q accelerated endothelial cell migration, suggesting that ADAMTS15 may have antiangiogenic activity.
ADAMTS15 is a candidate gene for IAs 6).
The variant rs1722561 of Kallikreins might reduce the risk of sporadic IAs among individuals of Chinese Han ethnicity. This study confirms the association between Kallikreins and IAs 7).
MicroRNA and aneurysm
The molecular mechanisms behind intracranial aneurysm formation and rupture remain poorly understood.
The MicroRNA and mRNA interactions and expression levels in cerebral aneurysm tissue from human subjects were profiled.
A prospective case-control study was performed on human subjects to characterize the differential expression of mRNA and MicroRNA in unruptured cerebral aneurysms in comparison with control tissue (healthy superficial temporal arteries [STA]). Ion Torrent was used for deep RNA sequencing. Affymetrix MicroRNA microarrays were used to analyze MicroRNA expression, whereas NanoString nCounter technology was used for validation of the identified targets.
Overall, 7 unruptured intracranial aneurysm and 10 STA specimens were collected. Several differentially expressed genes were identified in aneurysm tissue, with MMP-13 (fold change 7.21) and various collagen genes (COL1A1, COL5A1, COL5A2) being among the most upregulated. In addition, multiple MicroRNAs were significantly differentially expressed, with miR 21 (fold change 16.97) being the most upregulated, and miR 143-5p (fold change -11.14) being the most downregulated. From these, miR-21, miR-143, and miR 145 had several significantly anticorrelated target genes in the cohort that are associated with smooth muscle cell function, extracellular matrix remodeling, inflammation signaling, and lipid accumulation. All these processes are crucial to the pathophysiology of cerebral aneurysms.
This analysis identified differentially expressed genes and MicroRNAs in unruptured human cerebral aneurysms, suggesting the possibility of a role for MicroRNAs in aneurysm formation. Further investigation for their importance as therapeutic targets is needed 8).