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Gentic polymorphisms associated with stroke, methods of detection and uses thereof

a gene polymorphism and stroke technology, applied in the field of vascular disease, can solve the problems of ischemic stroke, brain injury or death, and greater danger of hemorrhagic stroke, although less prevalent, and achieve the effect of reducing the risk of an individual

Inactive Publication Date: 2009-09-03
CELERA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030]The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer statin treatment to an individual who has previously had a stroke, or who is at risk for having a stroke in the future, methods for selecting a particular statin-based treatment regimen such as dosage and frequency of administration of statin, or a particular form / type of statin such as a particular pharmaceutical formulation or statin compound, methods for administering an alternative, non-statin-based treatment to individuals who are predicted to be unlikely to respond positively to statin treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from statin treatment, etc. The present invention also provides methods for selecting individuals to whom a statin or other therapeutic will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a statin or other therapeutic agent based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the statin treatment and / or excluding individuals from the trial who are unlikely to respond positively from the statin treatment). The present invention further provides methods for reducing an individual's risk of having a stroke by administering statin treatment, including preventing a first or recurrent stroke by administering statin treatment, when said individual carries one or more SNPs identified herein as being associated with stroke risk or stroke statin response.
[0111]Table 13 shows that Val allele homozygotes of ABCG2 Val12Met, compared with the Met allele carriers, are associated with increased risk of incident ischemic stroke in both white and African American Participants of CHS.

Problems solved by technology

Stroke occurs when an artery bringing oxygen and nutrients to the brain either ruptures, causing hemorrhagic stroke, or gets occluded, causing ischemic stroke.
In both ischemic and hemorrhagic stroke, a cascade of cellular changes due to ischemia or increased cranial pressure leads to injuries or death of the brain cells.
The hemorrhagic stroke, although less prevalent, poses a greater danger.
The acute nature of stroke leaves physicians with little time to prevent or lessen the devastation of brain damage.
The resultant increase in LDL catabolism results in decreased circulating LDL, a major risk factor for vascular disease.
Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances.
For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal.
A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein.
Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product.
Such variant products can result in a pathological condition, e.g., genetic disease.
Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous.

Method used

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  • Gentic polymorphisms associated with stroke, methods of detection and uses thereof
  • Gentic polymorphisms associated with stroke, methods of detection and uses thereof
  • Gentic polymorphisms associated with stroke, methods of detection and uses thereof

Examples

Experimental program
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examples

[0467]The following examples are offered to illustrate, but not to limit the claimed invention.

example one

SNPs Associated with Stroke in the Atherosclerosis Risk in Communities (ARIC) Study

[0468]Overview

[0469]51 SNPs associated with coronary heart disease (CHD) in multiple antecedent studies (Bare et al. 2007) were analyzed to determine whether these SNPs are associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. To carry out this analysis, 495 validated ischemic strokes were identified from the multi-ethnic ARIC cohort of 14,215 individuals by following the cohort for an average of 13.5 years for potential cerebrovascular events. Risk alleles for 51 SNPs were specified based on the results from at least two antecedent studies in which these SNPs were associated with CHD. As a result of this analysis, Cox proportional hazards models, adjusted for age and gender, identified three SNPs in whites / Caucasians (these terms are used herein interchangeably) and two SNPs in blacks / African Americans (these terms are used herein interchangeably) that were...

example two

Corresponding to Example Two

[0520]1. Brass L M, Isaacsohn J L, Merikangas K R, Robinette C D. A study of twins and stroke. Stroke. 1992; 23:221-223[0521]2. Bak S, Gaist D, Sindrup S H, Skytthe A, Christensen K. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke. 2002; 33:769-774[0522]3. Welin L, Svardsudd K, Wilhelmsen L, Larsson B, Tibblin G. Analysis of risk factors for stroke in a cohort of men born in 1913. N Engl J Med. 1987; 317:521-526[0523]4. Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E. Parental history of cardiovascular disease and risk of stroke. A prospective follow-up of 14371 middle-aged men and women in Finland. Stroke. 1997; 28:1361-1366[0524]5. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C J, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y. Heart disease and ...

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Abstract

The present invention provides compositions and methods based on genetic polymorphisms that are associated with vascular diseases such as stroke. In particular, the present invention relates to genetic polymorphisms that have utility for such uses as predicting disease risk or predicting an individual's response to a treatment such as statins, including groups of polymorphisms that may be used as a signature marker set for such uses, as well as nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

Description

FIELD OF THE INVENTION[0001]The present invention is in the field of vascular disease, particularly stroke, and drug response, particularly response to statin treatment. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with vascular disease, including but not limited to cerebrovascular diseases such as stroke, and / or variability in responsiveness to statin treatment (including preventive treatment) between different individuals. The SNPs disclosed herein can be used, for example, as targets for diagnostic / prognostic reagents as well as for therapeutic agents. In particular, the SNPs of the present invention are useful for identifying an individual who is at an increased or decreased risk of having a stroke, for early detection of stroke risk, for providing clinically important information for the prevention and / or treatment of stroke, for predicting the seriousness or consequences of stroke in ...

Claims

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Application Information

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IPC IPC(8): A61K31/505C12Q1/68A61K31/22A61K31/40A61K31/35A61K31/435A61K31/404A61P25/00
CPCA61K31/22A61K31/35A61K31/40A61K31/404A61K31/435C12Q2600/156C12Q2600/118C12Q2600/172C12Q1/6883A61P25/00A61P43/00A61P9/00A61P9/10Y02E60/10
Inventor LUKE, MAYDEVLIN, JAMES J.
Owner CELERA CORPORATION
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