Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection

Object Approximately 20% of patients with an intracranial saccular aneurysm report a family history of intracranial aneurysm (IA) or subarachnoid hemorrhage. A better understanding of predictors of aneurysm detection in familial IA may allow more targeted aneurysm screening strategies. Methods The Familial Intracranial Aneurysm (FIA) study is a multicenter study, in which the primary objective is to define the susceptibility genes related to the formation of IA. First-degree relatives (FDRs) of those affected with IA are offered screening with magnetic resonance (MR) angiography if they were previously unaffected, are ≥ 30 years of age, and have a history of smoking and/or hypertension. Independent predictors of aneurysm detection on MR angiography were determined using the generalized estimating equation version of logistic regression. Results Among the first 303 patients screened with MR angiography, 58 (19.1%) had at least 1 IA, including 24% of women and 11.7% of men. Ten (17.2%) of 58 affected patients had multiple aneurysms. Independent predictors of aneurysm detection included female sex (odds ratio [OR] 2.46, p = 0.001), pack-years of cigarette smoking (OR 3.24 for 20 pack-years of cigarette smoking compared with never having smoked, p < 0.001), and duration of hypertension (OR 1.26 comparing those with 10 years of hypertension to those with no hypertension, p = 0.006). Conclusions In the FIA study, among the affected patients’ FDRs who are > 30 years of age, those who are women or who have a history of smoking or hypertension are at increased risk of suffering an IA and should be strongly considered for screening

Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein E (<it>APOE</it>) and elastin (<it>ELN</it>) are plausible candidate genes involved in the pathogenesis of stroke. We tested for association of variants in <it>APOE </it>and <it>ELN </it>with subarachnoid hemorrhage (SAH) in a population-based study. We genotyped 12 single nucleotide polymorphisms (SNPs) on <it>APOE </it>and 10 SNPs on <it>ELN </it>in a sample of 309 Caucasian individuals, of whom 107 are SAH cases and 202 are age-, race-, and gender-matched controls from the Greater Cincinnati/Northern Kentucky region. Associations were tested at genotype, allele, and haplotype levels. A genomic control analysis was performed to check for spurious associations resulting from population substructure.</p> <p>Results</p> <p>At the <it>APOE </it>locus, no individual SNP was associated with SAH after correction for multiple comparisons. Haplotype analysis revealed significant association of the major haplotype (Hap1) in <it>APOE </it>with SAH (<it>p </it>= 0.001). The association stemmed from both the 5' promoter and the 3' region of the <it>APOE </it>gene. <it>APOE </it>ε2 and ε 4 were not significantly associated with SAH. No association was observed for <it>ELN </it>at genotype, allele, or haplotype level and our study failed to confirm previous reports of <it>ELN </it>association with aneurysmal SAH.</p> <p>Conclusion</p> <p>This study suggests a role of the <it>APOE </it>gene in the etiology of aneurysmal SAH.</p

PRIORITIZATION OF RESULTS FROM WHOLE EXOME SEQUENCING IN FAMILIAL INTRACRANIAL ANEURYSM

poster abstractWhole exome sequencing (WES) is an innovative approach to identifying rare variants associated with disease; however, reducing the large number of variants to a useful set of candidate genes is challenging. We developed a ranking system utilizing data from a previous genome-wide linkage analysis and various bioinformatics databases to prioritize the results of WES from families having multiple members with intracranial aneurysms. WES was performed in 35 affected individuals and 10 unaffected individ-uals across 7 families. All samples were genotyped (Illumina® OmniExpress) and sequenced (Agilent© SureSelect™ 50Mb Human All Exon Kit). Linkage analysis (Illumina 6K) was previously performed using autosomal domi-nant/recessive modes of inheritance. Application of quality filters resulted in 91,659 single nucleotide variants (SNVs). Nonsynonymous SNVs within an exon having an allele frequency of <3% were retained. Further filtering was performed based on Mendelian in-heritance (autosomal dominant or recessive). A ranking system prioritized retained variants based on the inheritance pattern specific to each family, occurrence in multiple families, relation to pathways and genes of interest, degree of penetrance, presence within a linkage peak, and whether the re-sultant proteins were predicted to be deleterious. Out of a 9-point score, 292 variants in 190 genes received scores of at least 5. Of these, 14 variants in 10 genes met the majority of prioritization criteria by achieving scores of over 7. While several WES studies have been successful at identifying genes im-portant to rare diseases, few have examined how to produce a list of candi-date genes contributing to a complex disease from WES data. We show that a ranking system that combines WES with bioinformatics resources and link-age data is a powerful approach to prioritize candidate genes for a complex disease like familial intracranial aneurysms. Subsequent studies are required to validate the utility of this approach

ENFERMEDADES RELACIONADAS AL ESTILO DE VIDA EN LIMA, PERÚ

Introducción: Las enfermedades relacionadas al estilo de vida son uno de los mayores retos de salud del siglo 21. Objetivos: El propósito de esta investigación fue obtener una base de datos para estudiar la prevalencia de enfermedades de las personas que viven en pobreza en Lima, Perú. Metodología: La investigación estuvo localizada en los distritos de Comas y Carabayllo en Lima, Perú. Contamos con un total de 829 adultos y 770 niños (0-17 años de edad) participantes. La data fue recolectada a través de clínicas comunitarias gratuitas, estas incluyeron muestras de sangre para evaluar la hemoglobina, glucosa, hemoglobina glicosilada, lípidos, vitamina D, y anticuerpos en contra de Chagas y Helicobacter pylori. Para la población pediátrica sólo se utilizó los records médicos; no se utilizaron muestras de sangre con propósitos de investigación. Resultados: Los resultados más significativos fueron: 50,9% con presión arterial sanguínea elevada siendo sistólica o diastólica, 47% Con hemoglobina glicosilada elevada, 24% glucosa en ayuno elevada, 57,2% con un al menos un parámetro elevado del panel lípido, 32,6% hemoglobina baja, 97,2% Vitamina D baja, 59% positivo para anticuerpos de Helicobacter, y 5,6% positivo con anticuerpos de Chagas. La prevalencia de sobrepeso y obesidad fue 65,1% para adultos y 42,3% para la población pediátrica. Conclusión: Los resultados demuestran anomalías relacionadas al estilo de vida. Esta información puede utilizarse para desarrollar estrategias de prevención y tratamiento de las enfermedades relacionadas al estilo de vida, con enfoque en la educación y cambios en el estilo de vida. &nbsp; DOI: https://doi.org/10.25176/RFMH.v17.n2.83

Genome screen in familial intracranial aneurysm

Research articl

The Familial Intracranial Aneurysm (FIA) study protocol

BACKGROUND: Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S. annually and nearly half of the affected persons are dead within the first 30 days. Survivors of ruptured IAs are often left with substantial disability. Thus, primary prevention of aneurysm formation and rupture is of paramount importance. Prior studies indicate that genetic factors are important in the formation and rupture of IAs. The long-term goal of the Familial Intracranial Aneurysm (FIA) Study is to identify genes that underlie the development and rupture of intracranial aneurysms (IA). METHODS/DESIGN: The FIA Study includes 26 clinical centers which have extensive experience in the clinical management and imaging of intracerebral aneurysms. 475 families with affected sib pairs or with multiple affected relatives will be enrolled through retrospective and prospective screening of potential subjects with an IA. After giving informed consent, the proband or their spokesperson invites other family members to participate. Each participant is interviewed using a standardized questionnaire which covers medical history, social history and demographic information. In addition blood is drawn from each participant for DNA isolation and immortalization of lymphocytes. High- risk family members without a previously diagnosed IA undergo magnetic resonance angiography (MRA) to identify asymptomatic unruptured aneurysms. A 10 cM genome screen will be performed to identify FIA susceptibility loci. Due to the significant mortality of affected individuals, novel approaches are employed to reconstruct the genotype of critical deceased individuals. These include the intensive recruitment of the spouse and children of deceased, affected individuals. DISCUSSION: A successful, adequately-powered genetic linkage study of IA is challenging given the very high, early mortality of ruptured IA. Design features in the FIA Study that address this challenge include recruitment at a large number of highly active clinical centers, comprehensive screening and recruitment techniques, non-invasive vascular imaging of high-risk subjects, genome reconstruction of dead affected individuals using marker data from closely related family members, and inclusion of environmental covariates in the statistical analysis