Genetic Profile In Patients With Ruptured and Unruptured Intracranial Aneurysms

Official title

Genetic Profile in Patients With Ruptured and Unruptured Intracranial Aneurysms: Observational Study Aimed at Identifying Genetic Variants Associated With the Risk of Intracranial Aneurysm Rupture

Overview

The project will involve multiple units within our Institute (Neurosurgery, Cerebrovascular Diseases, Neurology IV), as well as additional neurosurgical centers across Italy, for the enrollment of patients with saccular intracranial aneurysms (sIA), both ruptured and unruptured. Based on predefined inclusion and exclusion criteria, the recruitment target over a two-year period is 400 patients with sIA (200 ruptured, 200 unruptured) and 200 healthy controls. The study will not alter clinical practice: treatment decisions for unruptured sIA will be made independently by vascular teams according to routine standards. For each enrolled subject, anonymized clinical data will be collected (age, sex, BMI, lifestyle habits, family history, comorbidities, aneurysmal parameters) to build an integrated database within the Biorepository. Peripheral blood samples will be obtained for genomic analyses, and when available (e.g., during clipping procedures or lumbar puncture), aneurysm wall tissue and/or cerebrospinal fluid (CSF) samples will be collected for expression studies. All materials and data (clinical/genetic) will be coded and stored at the Cryobank of the Fondazione IRCCS Istituto Neurologico Besta. Genomic analyses: a pathway-based Genome-Wide Association Study (GWAS) is planned. Phase I: Genotyping of 200 patients (100 with ruptured sIA, 100 with unruptured sIA) and 100 healthy controls, with combined analysis of genetic data and environmental factors related to rupture risk. Phase II: Validation in an additional cohort of 200 patients (100 ruptured, 100 unruptured) and 100 controls to confirm the associations of identified SNPs.

Detailed description

This observational study aims to identify potential genetic determinants associated with the risk of rupture in saccular intracranial aneurysms (sIA). The study is conducted in collaboration with three Units of the Fondazione IRCCS Istituto Neurologico Carlo Besta in Milan (Neurosurgery Unit II, Cerebrovascular Diseases Unit, Neurology Unit IV), as well as additional neurosurgical centers across Italy, particularly for the enrollment of patients with ruptured sIA who do not present to Besta due to the absence of an Emergency Department.

As an observational study, it does not involve any modification to the routine clinical management of patients with sIA at participating centers. Specifically, the decision to propose surgical or endovascular treatment for patients with ruptured or unruptured aneurysms will be made independently of the study, based on shared criteria discussed during regular multidisciplinary vascular meetings. Furthermore, no additional follow-up is planned beyond what is routinely scheduled for patients undergoing surgical or endovascular treatment for intracranial aneurysms.

Each patient will be asked to provide informed consent through a dedicated form. Once consent is obtained, each participant will be assigned a unique alphanumeric central code, used exclusively for study purposes. Throughout the duration of the project and thereafter, only the responsible physician will be able to link the code to the patient's identity.

Patients will undergo clinical evaluation at the time of enrollment, as part of standard clinical practice. Anonymized clinical data will be recorded in a centralized database and will include: sex, age, height, weight, regular use of illicit substances, alcohol consumption, smoking habits, family history of sIA, arterial hypertension, medical history with particular attention to autoimmune diseases and recent infections, general and neurological assessment, and aneurysmal characteristics (location, maximum diameter, morphology-regular or irregular).

Each patient will also undergo peripheral venous blood sampling for genomic studies. When available (e.g., during clipping procedures or lumbar puncture performed for decompression or other clinical indications), samples of aneurysm wall tissue, subcutaneous arterial wall, and/or cerebrospinal fluid (CSF) will be collected. Biological samples, along with coded clinical and genetic data, will be stored at the Fondazione IRCCS Istituto Neurologico Carlo Besta in separate containers, housed in controlled and locked environments, to establish the first Integrated Italian Biobank for Intracranial Aneurysms.

Regarding genomic analyses, a pathway-based genome-wide association study (GWAS) will be conducted.

* Phase I: DNA extracted and genotyped from 200 patients (100 with ruptured sIA and 100 with unruptured sIA) and 100 healthy controls will be analyzed. Statistical analysis will assess the combined effect of genetic and environmental factors on rupture risk. In this phase, healthy subjects and patients with unruptured sIA will serve as control groups for patients with ruptured sIA. * Phase II: An additional cohort of 200 patients (100 ruptured, 100 unruptured) and 100 healthy controls will be analyzed to validate the single nucleotide polymorphism (SNP) combinations identified in the preliminary phase.

Finally, the genetic and clinical data obtained from the biostatistical analysis of the entire cohort (400 patients and 200 healthy controls) will be used to develop a user-friendly computational tool aimed at estimating the individual risk of rupture in patients with sIA.

Primary outcome measures

• Identification of genetic variants [Time frame: Within 2 years from patient enrollment and genotyping (Phase I and Phase II).]

Secondary outcome measures (2)

• Development of a tool to estimate Rupture Risk [Time frame: Within 3 years, following completion of biostatistical analysis.]
• Creation of a Biobank [Time frame: Ongoing during the 2-year enrollment period and maintained beyond study completion.]

Eligibility criteria

Inclusion criteria

• Adults aged 18 to 80 years, of both sexes
• Patients diagnosed with ruptured or unruptured saccular intracranial aneurysms (sIA)

Exclusion criteria

• Patients with non-saccular intracranial aneurysms
• Patients unable to provide informed consent due to language impairment or altered consciousness, in the absence of a legally appointed guardian

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Italy · 1 center

• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan

Publications

• Yasuno K, Bakircioglu M, Low SK, Bilguvar K, Gaal E, Ruigrok YM, Niemela M, Hata A, Bijlenga P, Kasuya H, Jaaskelainen JE, Krex D, Auburger G, Simon M, Krischek B, Ozturk AK, Mane S, Rinkel GJ, Steinmetz H, Hernesniemi J, Schaller K, Zembutsu H, Inoue I, Palotie A, Cambien F, Nakamura Y, Lifton RP, Gunel M. Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracra PMID 22106312
• Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, Simon M, Krex D, Arlier Z, Nayak N, Ruigrok YM, Niemela M, Tajima A, von und zu Fraunberg M, Doczi T, Wirjatijasa F, Hata A, Blasco J, Oszvald A, Kasuya H, Zilani G, Schoch B, Singh P, Stuer C, Risselada R, Beck J, Sola T, Ricciardi F, Aromaa A, Illig T, Schreiber S, van Duijn CM, van den Berg LH, Perret C, Proust C, Roder C, Ozturk PMID 20364137
• Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 2011 Jul;10(7):626-36. doi: 10.1016/S1474-4422(11)70109-0. PMID 21641282
• Ruigrok YM, Rinkel GJ. Genetics of intracranial aneurysms. Stroke. 2008 Mar;39(3):1049-55. doi: 10.1161/STROKEAHA.107.497305. Epub 2008 Feb 7. PMID 18258833
• Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011 Jun 15;27(12):1739-40. doi: 10.1093/bioinformatics/btr260. Epub 2011 May 5. PMID 21546393
• Kurki MI, Hakkinen SK, Frosen J, Tulamo R, von und zu Fraunberg M, Wong G, Tromp G, Niemela M, Hernesniemi J, Jaaskelainen JE, Yla-Herttuala S. Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of Toll-like receptor signaling and nuclear factor-kappaB, hypoxia-inducible factor-1A, and ETS transcription factors. Neurosurgery. 2011 Jun; PMID 21336216
• Juvela S. Prehemorrhage risk factors for fatal intracranial aneurysm rupture. Stroke. 2003 Aug;34(8):1852-7. doi: 10.1161/01.STR.0000080380.56799.DD. Epub 2003 Jun 26. PMID 12829865
• Juvela S. Natural history of unruptured intracranial aneurysms: risks for aneurysm formation, growth, and rupture. Acta Neurochir Suppl. 2002;82:27-30. doi: 10.1007/978-3-7091-6736-6_5. PMID 12378985

Identifiers

NCT: NCT07233915 · ANEUBIO

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗