Advances in Genetics 2010
2011; Lippincott Williams & Wilkins; Volume: 42; Issue: 2 Linguagem: Inglês
10.1161/strokeaha.110.605089
ISSN1524-4628
Autores Tópico(s)Connective tissue disorders research
ResumoHomeStrokeVol. 42, No. 2Advances in Genetics 2010 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBAdvances in Genetics 2010 James F. Meschia, MD James F. MeschiaJames F. Meschia From the Mayo Clinic, Jacksonville, FL. Originally published13 Jan 2011https://doi.org/10.1161/STROKEAHA.110.605089Stroke. 2011;42:285–287Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 The last year has seen several advances in genetics relevant to understanding the pathophysiology of stroke and to advancing diagnosis, prognosis, and care.Chromosome 9p21.3 LocusOne of the most intriguing associations is that of a risk locus on chromosome 9p21.3 with ischemic stroke. This locus was first discovered by genomewide association to be a risk factor for coronary artery disease1–3 before studies showed a relationship with ischemic stroke.4,5 The locus also associates with intracranial and aortic aneurysms.6 The causative variant remains unknown. Recently, chromosome 9p21.3 has also been associated with platelet reactivity.7 This increased platelet reactivity may explain the association with myocardial infarction and stroke; it is less clear how increased platelet reactivity might relate to aneurysm formation. The 9p21.3 locus includes a noncoding RNA known as ANRIL, which in turn alters expression of several genes related to cellular proliferation.8 A richer explanation for the pleiotropic effects of the 9p21.3 locus on multiple vascular beds should emerge in the near future.Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy and Conventional Risk FactorsCerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) remains incurable. However, recent clinical observations suggest that the risk of stroke in patients with this disease may be modifiable. A review of 200 consecutive subjects enrolled in the UK CADASIL National Referral Service showed that the risk of stroke increased with conventional risk factors.9 The odds of stroke were 2.5 times greater for patients with hypertension. The number of pack-years of smoking was associated with risk of stroke, and current smoking was associated with earlier age at onset of stroke. These findings support an aggressive, less fatalistic approach to vascular risk factor modification in this patient population.Parental History as a Risk FactorA recent Framingham study greatly added to understanding the relationship between parental history of stroke and risk of stroke in offspring. Parental occurrence of stroke by age 65 years increased the risk of stroke in offspring by 3-fold.10 This elevated risk persisted after adjusting for conventional risk factors. People with a parental history of stroke had higher risk than people without a parental history of stroke across all 5 quintiles of baseline risk estimated using the Framingham Stroke Risk Profile. The greatest effect of parental history of stroke occurred at the highest quintile of risk. Arguments can be made for and against targeted versus mass screening for preventing illness (the so-called Rose dilemma).11 In some settings, targeted screening appears to be more cost-effective for cardiovascular primary prevention.12 Screening for a parental history of stroke may be one way to screen for high-risk populations for targeted stroke prevention. As a screening tool, emerging genomic techniques may not prove superior.Mitochondrial Genetic Risk of Ischemic StrokeInterest in mitochondrial genetics resurged after the report of an association between a common haplogroup and stroke.13 A multicenter mitochondrial genomewide association study found an association with ischemic stroke and a genetic risk score that included summation of the contributions of individual variants.14 No individual variant was significantly associated with ischemic stroke. This can be explained by the low power resulting from low minor allele frequencies and low effect sizes. It may not be possible to use association methods to detect effects for individual mitochondrial variants. Post hoc statistical power calculations suggest that to do this would require >80 000 cases.Hereditary Angiopathy With Nephropathy, Aneurysms, and Muscle Cramps and Carotid AneurysmsA clearer picture is emerging about the cerebrovascular manifestations of hereditary angiopathy with nephropathy, aneurysms and muscle cramps.15 This condition, which is caused by mutations in COL4A1 involving glycine residues in the α-1 chain of Type IV collagen, can cause hematuria, renal cysts, elevations in creatine phosphokinase, and retinal arterial tortuosity. Patients can also have lacunar infarcts, microbleeds, white matter changes, and dilated perivascular spaces. Aneurysms confined to the carotid siphons should heighten suspicion for this condition. These aneurysms may be multiple. Risk of rupture from these carotid aneurysms appears to be low. It is not known whether the risk is lower than the natural history of unruptured aneurysms in unselected patients.16Genetics of Intracerebral HemorrhageConvincing evidence for associations between apolipoprotein alleles ϵ2 and ϵ4 and lobar intracerebral hemorrhage was recently generated by the International Stroke Genetics Consortium.17 The collaboration involved 2189 cases of intracerebral hemorrhage and 4041 control subjects from 7 cohorts. This study included the first genetic association with lobar intracerebral hemorrhage to reach genomewide significance.Pharmacogenomics of Stroke PreventionThe promise of preventing cardioembolism and the perils of causing intracerebral hemorrhage are well known to physicians who treat patients with warfarin.18 There is considerable interindividual variation in response to warfarin dosing, posing challenges to initiation of therapy. A portion of the variable response is due to variations in genotypes in the cytochrome p450 isoform CYP2C9 and the vitamin K epoxide reductase complex subunit 1 VKORC1. Genotype-guided initiation of warfarin has yet to prove better than 5 mg or 10 mg fixed doses in terms of achieving target international normalized ratios.19 So far, no study has been powered to show differences in major bleeding.As attempts are made to individualize treatment with warfarin using pharmacogenomics, novel medications are emerging for indications similar to warfarin. An example would be dabigatran, a direct thrombin inhibitor, which when given at a fixed dose showed comparable safety and efficacy to warfarin with regard to stroke prevention in the setting of atrial fibrillation.20 The warfarin paradigm of drug approval followed by pharmacogenomic discovery is one that should be replaced with drug development that happens concurrently with pharmacogenomics preapproval.DisclosuresDr Meschia is Principal Investigator of the Siblings with Ischemic Stroke Study (SWISS; National Institute of Neurological Disorders and Stroke [NINDS]R01NS39987) and receives additional support from the NINDS U01 (U01 NS069208-01) for his activities chairing the Phenotype Committee for the Stroke Genetics Network.FootnotesCorrespondence to James F. Meschia, MD, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail meschia.[email protected]edu.References1. 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February 2011Vol 42, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.110.605089PMID: 21233470 Manuscript receivedDecember 1, 2010Manuscript acceptedDecember 6, 2010Originally publishedJanuary 13, 2011Manuscript revisedDecember 3, 2010 Keywordsgenomewide associationpharmacogenomicsgeneticsischemic strokefamily history studiesPDF download Advertisement SubjectsGeneticsOmics
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