The Siblings With Ischemic Stroke Study (SWISS) protocol.

James F Meschia,John Hardy,Robert D Brown,Thomas G Brott,Stephen S Rich,Felix E Chukwudelunzu

doi:10.1186/1471-2350-3-1

Abstract

BackgroundFamily history and twins studies suggest an inherited component to ischemic stroke risk. Candidate gene association studies have been performed but have limited capacity to identify novel risk factor genes. The Siblings With Ischemic Stroke Study (SWISS) aims to conduct a genome-wide scan in sibling pairs concordant or discordant for ischemic stroke to identify novel genetic risk factors through linkage analysis.MethodsScreening at multiple clinical centers identifies patients (probands) with radiographically confirmed ischemic stroke and a family history of at least 1 living full sibling with stroke. After giving informed consent, without violating privacy among other family members, the proband invites siblings concordant and discordant for stroke to participate. Siblings then contact the study coordinating center. The diagnosis of ischemic stroke in potentially concordant siblings is confirmed by systematic centralized review of medical records. The stroke-free status of potentially discordant siblings is confirmed by validated structured telephone interview. Blood samples for DNA analysis are taken from concordant sibling pairs and, if applicable, from 1 discordant sibling. Epstein-Barr virus-transformed lymphoblastoid cell lines are created, and a scan of the human genome is planned.DiscussionConducting adequately powered genomics studies of stroke in humans is challenging because of the heterogeneity of the stroke phenotype and the difficulty of obtaining DNA samples from clinically well-characterized members of a cohort of stroke pedigrees. The multicentered design of this study is intended to efficiently assemble a cohort of ischemic stroke pedigrees without invoking community consent or using cold-calling of pedigree members.

Highlights

History and twins studies suggest an inherited component to ischemic stroke risk
Most known Mendelian stroke disorders present in infancy, childhood, or young adulthood and collectively represent only a small proportion of all stroke cases. Several of these Mendelian disorders were recognized as unique genetic diseases because of striking phenotypic features, such as corneal opacities and angiokeratomas of the skin in Fabry disease
We propose to use model-independent analysis, a method that is designed to detect linkage without the specification of an underlying genetic model and that is robust to contributions by environmental variation

Summary

Introduction

History and twins studies suggest an inherited component to ischemic stroke risk. The Siblings With Ischemic Stroke Study (SWISS) aims to conduct a genome-wide scan in sibling pairs concordant or discordant for ischemic stroke to identify novel genetic risk factors through linkage analysis. The most common type, a profound disturbance of focal cerebral blood flow leads to irreversible parenchymal injury. Most known Mendelian stroke disorders present in infancy, childhood, or young adulthood and collectively represent only a small proportion of all stroke cases. Several of these Mendelian disorders were recognized as unique genetic diseases because of striking phenotypic features, such as corneal opacities and angiokeratomas of the skin in Fabry disease

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