MD Conference Express ISC 2012 - (Page 19)
variants of moderate to large effect size, while GWAS finds common variants that are typically of smaller effect size. The authors reviewed families with a dense history of IA and available DNA. Seven families that met their criteria (two or more affected pairs of siblings, three or more family members with IA, or individuals with a confirmed IA but without a family history) were identified. DNA from affected individuals was sent to the Center for Inherited Disease Research (CIDR) (ie, 32 exomes from 32 individuals who were sequenced). Quality filtering produced 93,635 single-nucleotide variants (SNVs). Biologic filters, which retain only the variants that meet the biological hypothesis (ie, rare exonic and amino acid-altering alleles that segregate in Mendelian fashion may contribute to IA pathology), reduced that figure to 871 SNVs. Variants were kept if they were observed in at least three affected individuals in a single family if the SNVs were autosomal dominant or recessive. Of the 871 SNVs, 31 were in the gene otology pathways of interest, such as collagen. Variants in two collagen genes were identified in at least three family members in one of these IA families (Figure 1). These variants are predicted to potentially cause abnormal function in these proteins. Collaborators from Poland have demonstrated that both of these genes are expressed differently in aneurysmal tissue as compared with vascular tissue of the middle meningeal arteries. Figure 2 shows the presence of these variants in affected family members, all of whom were also smokers—the most important environmental risk factor for IA. Further work will need to be done to see whether these gene variants are truly causal in the development of IA. Ultimately, the interplay of three factors—environment (smoking, hypertension), common variants of individual small effects (GWAS), and rare variants with medium to large effects (WES)—likely contributes to disease susceptibility. Figure 1. Collagen Variants.
Col5A2 Exon 23
Compound heterozygote - have one copy of each of these variants in a gene
Figure 2. One Family and Collagen.
Aff Female Unaff Male COL17A1 Compound Het Possible IA Sequenced COL5A2 Compound Het
AAA All sequenced individuals were smokers.
Reproduced with permission from J. Broderick, MD.
Unaff
The identification of susceptibility genes, along with a better understanding of environmental interactions, such as cigarette smoking, may prevent the development of IAs and IA ruptures in people who are at risk for this condition.
SPS3 Study Does Not Support the Use of Combination Therapy for Stroke Prevention
Written by Rita Buckley
Exon 37
T1535C V512A
Homozygote - have 2 copies of one of these variants in a gene
C2498T P833L
Small subcortical strokes, also known as lacunar strokes, constitute more than 25% of brain infarcts and are the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in patients with small subcortical stroke is unclear [Benevente OR et al. Int J Stroke 2011]. Oscar R. Benavente, MD, FRCP(C), University of British Columbia, Vancouver, British Columbia, Canada, presented results from The Secondary Prevention of Small Subcortical Strokes Study: The Antiplatelet Trial Results [SPS3; NCT00059306]. SPS3 was a randomized, double-blind, multicenter, investigator-initiated, international trial that was conducted at 81 clinical sites in eight countries. From March 2003 to April 2011, 3020 patients with symptomatic lacunar strokes in the prior 6 months verified by magnetic resonance imaging were randomized in a
Col17A1 Exon 40 Exon 46
G2755A D919N
C3205T R1069W
Reproduced with permission from J. Broderick, MD.
Highlights from the International Stroke Conference 2012
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Table of Contents for the Digital Edition of MD Conference Express ISC 2012
MD Conference Express ISC 2012
From Neurovascular Laboratory to Clinic: A Journey Through Time
No Compelling Evidence to Use Warfarin or Aspirin in Heart Failure Patients
AXIS 2 Clinical Outcomes No Different Than Placebo
SAMMPRIS: 30-Day Outcomes After Angioplasty and Stenting
Aggressive Medical Therapy Benefits Those Who Fail Antithrombotic Therapy
Initial Clinical Results with TREVO® Mechanical Thrombectomy Device are Promising
Linking sICH Definitions to Outcomes
Solitaire™ Flow Restoration Device Achieves Successful Recanalization Free of Symptomatic Hemorrhage Transformation
FIA II Seeks Genetic Underpinnings of Familial Intracranial Aneurysm
SPS3 Study Does Not Support the Use of Combination Therapy for Stroke Prevention
Novel Agent NA-1 Proves that Ischemic Neuroprotection is Possible in Older Patients
Acute Endovascular Treatment
Neuroimaging
Stroke Guidelines: Current Recommendations in Principle and Practice
The Rising Trend of Ischemic Stroke in the Young
Advanced Neuroimaging Adds Time, Reduces Endovascular Treatment in Clinical Practice
MD Conference Express ISC 2012
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