Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2004;35:2731-2734
Published online before print September 23, 2004, doi: 10.1161/01.STR.0000143328.98154.33
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
35/11_suppl_1/2731    most recent
01.STR.0000143328.98154.33v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gwinn-Hardy, K.
Right arrow Articles by Dawson, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gwinn-Hardy, K.
Right arrow Articles by Dawson, V.
Related Collections
Right arrow Gene expression
Right arrow Gene regulation
Right arrow Genetically altered mice
Right arrow Genomics
Right arrow Genetics of Stroke
Right arrow Genetics of cardiovascular disease

(Stroke. 2004;35:2731.)
© 2004 American Heart Association, Inc.

Articles

Genomics-Proteomics and Stroke

Introduction

Katrina Gwinn-Hardy, MD Valina Dawson, PhD

From the National Institute of Neurological Disorders and Stroke (K.G.-H.), National Institutes of Health, Bethesda, and Institute for Cell Engineering, Department of Neurology (V.D.), Johns Hopkins School of Medicine, Baltimore, Md.

Correspondence to Dr Katrina Gwinn-Hardy, 6001 Executive Blvd 2142, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. E-mail gwinnk{at}ninds.nih.gov


*    Introduction
up arrowTop
 *Introduction
down arrowGenetics and Medical Risk...
 down arrowClosing Remarks
 down arrowReferences
 
Genetic causes of disease, including stroke, range from classic mendelian (a single gene leads to disease) to complex (multiple genes contribute to risk for disease in combination with other genetic and/or environmental factors). One method of identifying genetic risk factors is the candidate gene association study, in which a given polymorphism in a gene of interest is compared between cases or controls; if the polymorphism is more common in affected subjects, a contribution to risk for disease is implied. A candidate gene is usually selected because the gene product is intuitively related to the disease process. Further studies in other populations will reveal whether findings from both association and candidate gene studies can be generalized. Because stroke includes multiple clinically relevant subgroups, the appropriate phenotyping approach is not yet known. It also is unclear whether the biological factors contributing to risk for one type of stroke are the same as those for the other types or whether these are biologically differing entities. Medical risk factors for stroke, such as hypertension, and shared risk factors between stroke and cardiovascular disease, for example, suggest that biological processes overlap across related disorders. Despite the complex biological questions that remain to be answered regarding stroke etiology and risk, genetic studies are of value to elucidate risk factors for stroke, give us clues regarding targets for interventional therapies, and give us insight into the process leading to clinical stroke of all types.

Single gene disorders that cause stroke include hemoglobinopathies, dyslipoproteinemias, and cardioembolic disorders.1,2 Family history of ischemic stroke is a major risk factor for the disease.1,3 Ethnicity is also a risk factor; age-standardized mortality rates for stroke are higher among blacks than whites.4 Family history is an independent risk factor for subarachnoid hemorrhage.5 Most clinicians separate stroke into ischemic and hemorrhagic types as 2 broad categories (and those into subcategories), and one might surmise that such stratification would be important for gene discovery; however, how stroke should be phenotyped and subphenotyped remains to be seen.6 Age of onset may be an important clinical feature that could be useful in stratifying stroke risk, and the age of stroke onset appears to have a familial pattern.7 However, grouping all types of stroke together has been successful in a gene discovery project in Iceland, where a genome scan of 476 patients (from 179 extended Icelandic pedigrees) considered all types of stroke together and revealed linkage to chromosome 5q12.8 Subsequent linkage analysis and fine mapping found a strong association between a subset of lumped phenotypes, carotid disease and cardiogenic stroke, and the gene encoding phosphodiesterase 4D (PDE4D); expression studies supported a biological basis for this linkage.9 In addition, a second putative gene for stroke has been described by the same group. A haplotype at 13q12-13 spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a 2-fold greater risk of myocardial infarction and stroke.10 These 2 genes described by the Icelandic group are termed STRK1 and STRK2 in common parlance.

Genes related to the coagulation system are logical candidates for genetic susceptibility studies. Factor V Leiden and prothrombin (factor II) mutations are putative risk factors for stroke, especially in women on oral contraceptives.11,12 Elevated homocysteine was associated with a risk for stroke in one study,13 but another found no increase in stroke risk associated with a common polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, which leads to increased serum homocysteine concentrations.14 Platelet receptor genes have also been explored as candidates in association studies, although their influence remains debatable.15,16 Other logical candidates are genes coding for enzymes that metabolize medications used to treat stroke. Rates of metabolism by several of the CYP450 enzymes vary because of genetically determined polymorphisms. Recent data reveal that approximately 20% of the white population carries 1 of at least 2 different CYP450 point mutations that cause sensitivity to warfarin.17 This suggests that CYP2C9 genotypes may someday be helpful in planning initial warfarin dosing.

Genotype may add to our understanding of factors that not only contribute to but also reduce risk of types of stroke. Many investigators have taken the candidate gene approach, using genetic engineering technologies to generate transgenic or gene-deficient mice to study the role of specific genes in experimental stroke models.18 For example, deletion of the nitric oxide synthase genes revealed a deleterious function for neuronal and inducible nitric oxide synthase in stroke but a critical role for endothelial nitric oxide synthase in protecting the brain against stroke injury.19 These studies demonstrate that increased expression of endothelial nitric oxide synthase may underlie, at least in part, the protective actions of statins against ischemic injury.20,21 Intriguingly, polymorphisms in endothelial nitric oxide synthase have been linked to risk of cerebral small-vessel disease and cerebral vascular disease,22,23 which highlights the information the candidate gene and experimental stroke models can provide in terms of investigating risk factors and genetic contributions to human stroke. Gene screening strategies and technologies are also beginning to provide valuable clues. In arteriovenous malformations, which in some cases lead to hemorrhagic stroke, the availability of tissue allows microarray gene expression studies. In 1 such study, increased gene expression levels for angiogenesis-related molecules were accompanied by increased levels of their protein product expression.24 It is possible that genes and pathways discovered in this way may be relevant to other types of cerebrovascular abnormalities.


*    Genetics and Medical Risk Factors for Stroke
up arrowTop
 up arrowIntroduction
 *Genetics and Medical Risk...
down arrowClosing Remarks
 down arrowReferences
 
Risk factors for stroke include both medical and family history of cardiac ischemic disease, hypertension, diabetes, and possibly lipid and cholesterol disorders.

Cardiac diseases have a large number of causes, including genetic causes. Mutations in ion channels, contractile proteins, structural proteins, and signaling molecules have been identified as causal for cardiovascular diseases.25 While these and other cardiac disorders might not relate directly to a risk of stroke, they underscore the utility of such studies and give clues regarding possible additional targets for study in stroke.

The risk of stroke is higher in hypertensive than in nonhypertensive relatives of stroke patients, suggesting that underlying etiological factors are shared.26 Ethnic differences may be important for this and other risk factors. Significant evidence for linkage heterogeneity among hypertensive sib pairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke, which may differ between whites and blacks.27 Ischemic damage to the subcortical white matter of the brain, leukoaraiosis, is a frequent complication of hypertension-related microvascular disease and contributes to the risk of stroke and vascular dementia. A large genetic contribution for leukoariosis was suggested in a sib pair study.28 Animal models may illuminate these issues further. For example, in the spontaneously hypertensive stroke-prone rat, protein profiling of kinase substrates identified adenylyl cyclase–associated protein 2, TOAD-64, propionyl CoA carboxylase, APG-1, and valosin-containing protein as possible candidates for further study.29 The angiotensin-converting enzyme gene, known to code for a protein important in hypertension, may carry polymorphisms that are a risk factor for ischemic stroke.30

Although serum cholesterol traditionally has been considered a poor predictor of total stroke risk, elevated serum cholesterol is positively associated with ischemic stroke risk and negatively associated with hemorrhagic stroke risk.31–33 Apolipoproteins are important in neurological illness; the apolipoprotein (apo) {epsilon}4allele (E4) is clearly a risk factor for Alzheimer disease.34 ApoE4 may also be a predisposing genetic marker for ischemic cerebrovascular disease.35 The E2 and/or the E4 alleles may be risk factors for cerebral amyloid angiopathy independent of their influence on the risk for Alzheimer disease, but this remains controversial.36,37 Subjects with an apoE2 or apoE4 allele were found to be at greater risk for intracranial hemorrhage independent of environmental risk factors in 1 study.38

Diabetes, along with hypertension, is considered a modifiable risk factors for stroke.39 Mutations in genes for insulin and insulin-related genes have been shown to be causal for mendelian type I diabetes, and studies of siblings and their HLA types have revealed a genetic component to type I diabetes generally.40–42 It remains to be seen where these genetic features of diabetes overlap the genetic risk for stroke, if at all.


*    Closing Remarks
up arrowTop
 up arrowIntroduction
 up arrowGenetics and Medical Risk...
 *Closing Remarks
down arrowReferences
 
Genetics has revolutionized neurological research. Characterizing the protein products of genes associated with stroke, including those yet to be discovered, their interactions, and the biochemical mechanisms affected, will direct future epidemiological studies, therapeutic targets, and the exploration of gene-environment interactions. Additionally, it is hoped that in the future, genetic factors are likely to allow development of tools for the early detection of stroke and neuroprotective treatments for stroke of all types. It is likely that in order to find common genes of influence on the risk for stroke or protective for stroke, a large sample size is needed of both cases and controls, with associated clinical data. Toward this goal, resources such as at the National Institute of Neurological Disorders and Stroke Repository (http://locus.umdnj.edu/ninds) will be key to allow large and well-characterized sample collections to be pooled to gain statistical power strong enough to find such genes.

Determining the genetic risks for cerebrovascular diseases facilitates our thinking about such diseases in biological terms. We can consider stroke the final outcome of a sequence of cellular events. At each stage, the process is likely modified at the cellular level because of genetic or environmental factors. While stroke subtypes are distinctive clinical entities, biologically it may be that they share common processes resulting in cell dysfunction and demise.

Stratification of stroke subtype and treatment, conversely, may depend on molecular features for accurate diagnosis in the future. Genetic discoveries are likely targets for treatments that will counteract the process leading to cell loss. Clinical features alone are not likely to accomplish biologically meaningful categorization. We must identify additional genetic factors, learn how the biological products interact, and then identify modifying environmental factors. This systematic approach will be the key to our developing preventative strategies for stroke.


*    Acknowledgments
 
Dr Gwinn-Hardy is funded by NINDS and is the Project officer of the NINDS Genetics Repository. Dr Dawson is supported by PHS NS39148, the American Heart Association, and the Mary Lou McIlhaney Scholar Award.

Received June 14, 2004; accepted August 5, 2004.


*    References
up arrowTop
 up arrowIntroduction
 up arrowGenetics and Medical Risk...
 up arrowClosing Remarks
 *References
 

  1. Natowicz M, Kelley RI. Mendelian etiologies of stroke. Ann Neurol. 1987; 22: 175–192.[CrossRef][Medline] [Order article via Infotrieve]
  2. Ruchoux MM, Brulin P, Brillault J, Dehouck MP, Cecchelli R, Bataillard M. Lessons from CADASIL. Ann N Y Acad Sci. 2002; 977: 224–231.[Abstract/Free Full Text]
  3. Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH. Familial aggregation of stroke: the Framingham Study. Stroke. 1993; 24: 1366–1371.[Abstract/Free Full Text]
  4. Ayala C, Greenlund KJ, Croft JB, Keenan NL, Donehoo RS, Giles WH, Kittner SJ, Marks JS. Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995–1998. Am J Epidemiol. 2001; 154: 1057–1063.[Abstract/Free Full Text]
  5. Kissela BM, Sauerbeck L, Woo D, Khoury J, Carrozzella J, Pancioli A, Jauch E, Moomaw CJ, Shukla R, Gebel J, Fontaine R, Broderick J. Subarachnoid hemorrhage: a preventable disease with a heritable component. Stroke. 2002; 33: 1321–1326.[Abstract/Free Full Text]
  6. Meschia JF. Ischaemic stroke: one or several complex genetic disorders? Lancet Neurol. 2003; 2: 459.[CrossRef][Medline] [Order article via Infotrieve]
  7. Meschia JF, Atkinson EJ, O’Brien PC, Brott TG, Brown RD Jr, Hardy J. Familial clustering of stroke according to proband age at onset of presenting ischemic stroke. Stroke. 2003; 34: e89–e91.[Abstract/Free Full Text]
  8. Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, Shkolny D, Einarsson G, Gudjonsdottir HM, Valdimarsson EM, Einarsson OB, Thorgeirsson G, Hadzic R, Jonsdottir S, Reynisdottir ST, Bjarnadottir SM, Gudmundsdottir T, Gudlaugsdottir GJ, Gill R, Lindpaintner K, Sainz J, Hannesson HH, Sigurdsson GT, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet. 2002; 70: 593–603.[CrossRef][Medline] [Order article via Infotrieve]
  9. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003; 35: 131–138.[CrossRef][Medline] [Order article via Infotrieve]
  10. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SF, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR, Stefansson K. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004; 36: 233–239.[CrossRef][Medline] [Order article via Infotrieve]
  11. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995; 332: 912–917.[Abstract/Free Full Text]
  12. Longstreth WT Jr, Rosendaal FR, Siscovick DS, Vos HL, Schwartz SM, Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke. 1998; 29: 577–580.[Abstract/Free Full Text]
  13. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentrations and risk of stroke in middle-aged British men. Lancet. 1995; 346: 1395–1398.[CrossRef][Medline] [Order article via Infotrieve]
  14. Markus HS, Ali N, Swaminathan R, Sankaralingam A, Molloy J, Powell J. A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease. Stroke. 1997; 28: 1739–1743.[Abstract/Free Full Text]
  15. Carlsson LE, Greinacher A, Spitzer C, Walther R, Kessler C. Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX) and collagen (GPIa/Iia) are not correlated with an increased risk for stroke. Stroke. 1997; 28: 1392–1395.[Abstract/Free Full Text]
  16. Wagner KR, Giles WH, Johnson CJ, Ou CY, Bray PF, Goldschmidt-Clermont PJ, Croft JB, Brown VK, Stern BJ, Feeser BR, Buchholz DW, Earley CJ, Macko RF, McCarter RJ, Sloan MA, Stolley PD, Wityk RJ, Wozniak MA, Price TR, Kittner SJ. Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: the Stroke Prevention in Young Women Study. Stroke. 1998; 29: 581–585.[Abstract/Free Full Text]
  17. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of the polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999; 353: 717–719.[CrossRef][Medline] [Order article via Infotrieve]
  18. Liang D, Dawson TM, Dawson VL. What have genetically engineered mice taught us about ischemic injury? Curr Mol Med. 2004; 4: 207–225.[CrossRef][Medline] [Order article via Infotrieve]
  19. Dalkara T, Endres M, Moskowitz MA. Mechanisms of NO neurotoxicity. Prog Brain Res. 1998; 118: 231–239.[Medline] [Order article via Infotrieve]
  20. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998; 95: 8880–8885.[Abstract/Free Full Text]
  21. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003; 326: 1423.[Abstract/Free Full Text]
  22. Hassan A, Gormley K, O’Sullivan M, Knight J, Sham P, Vallance P, Bamford J, Markus H. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke. 2004; 35: 654–659.[Abstract/Free Full Text]
  23. Markus HS, Ruigrok Y, Ali N, Powell JF, Endothelial nitric oxide synthase exon 7 polymorphism, ischemic cerebrovascular disease, and carotid atheroma. Stroke. 1998; 29: 1908–1911.[Abstract/Free Full Text]
  24. Hashimoto T, Lawton MT, Wen G, Yang GY, Chaly T Jr, Stewart CL, Dressman HK, Barbaro NM, Marchuk DA, Young WL. Gene microarray analysis of human brain arteriovenous malformations. Neurosurgery. 2004; 54: 410–423;discussion 423–425.
  25. Keating MT, Sanguinetti MC. Molecular genetic insights into cardiovascular disease. Science. 1996; 272: 681–685.[Abstract]
  26. Nicolaou M, DeStefano AL, Gavras I, Cupples LA, Manolis AJ, Baldwin CT, Gavras H, Farrer LA. Genetic predisposition to stroke in relatives of hypertensives. Stroke. 2000; 31: 487–492.[Abstract/Free Full Text]
  27. Morrison AC, Brown A, Kardia SL, Turner ST, Boerwinkle E, for the Genetic Epidemiology Network of Arteriopathy (GENOA) Study. Genetic Epidemiology Network of Arteriopathy (GENOA) Study: evaluating the context-dependent effect of family history of stroke in a genome scan for hypertension. Stroke. 2003; 34: 1170–1175.[Abstract/Free Full Text]
  28. Turner ST, Jack CR, Fornage M, Mosley TH, Boerwinkle E, de Andrade M. Heritability of leukoaraiosis in hypertensive sibships. Hypertension. 2004; 43: 483–487.[Abstract/Free Full Text]
  29. Fornage M, Swank MW, Boerwinkle E, Doris PA. Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility. Physiol Genomics. 2003; 15: 75–83.[Abstract/Free Full Text]
  30. Agerholm-Larsen B, Tybjaerg-Hansen A, Frikke-Schmidt R, Gronholdt ML, Jensen G, Nordestgaard BG. ACE gene polymorphism as a risk factor for ischemic cerebrovascular disease. Ann Intern Med. 1997; 127: 346–355.[Abstract/Free Full Text]
  31. Postiglione A, Napoli C. Hyperlipidaemia and atherosclerotic cerebrovascular disease. Curr Opin Lipidol. 1995; 6: 236–242.[Medline] [Order article via Infotrieve]
  32. Ansell BJ. Cholesterol, stroke risk, and stroke prevention. Curr Atheroscler Rep. 2000; 2: 92–96.[Medline] [Order article via Infotrieve]
  33. Gorelick PB, Schneck M, Berglund LF, Feinberg W, Goldstone J. Status of lipids as a risk factor for stroke. Neuroepidemiology. 1997; 16: 107–115.[Medline] [Order article via Infotrieve]
  34. Roses AD. Apolipoprotein E in neurology. Curr Opin Neurol. 1996; 9: 265–270.[Medline] [Order article via Infotrieve]
  35. Pedro-Botet J, Senti M, Nogues X, Rubies-Prat J, Roquer J, D’Olhaberriague L, Olive J. Lipoprotein and apolipoprotein profile in men with ischemic stroke: role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992; 23: 1556–1562.[Abstract/Free Full Text]
  36. Pedro-Botet J, Senti M, Nogues X, Rubies-Prat J, Roquer J, D’Olhaberriague L, Olive J. High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1997; 41: 716–721.[CrossRef][Medline] [Order article via Infotrieve]
  37. Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995; 38: 254–259.[CrossRef][Medline] [Order article via Infotrieve]
  38. Woo D, Sauerbeck LR, Kissela BM, Khoury JC, Szaflarski JP, Gebel J, Shukla R, Pancioli AM, Jauch EC, Menon AG, Deka R, Carrozzella JA, Moomaw CJ, Fontaine RN, Broderick JP. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a populations-based study. Stroke. 2002; 33: 1190–1196.[Abstract/Free Full Text]
  39. Sacco RL. Reducing the risk of stroke in diabetes: what have we learned that is new? Diabetes Obes Metab. 2002; 4 (suppl 1): S27–S34.
  40. Awata T, Kurihara S, Kikuchi C, Takei S, Inoue I, Ishii C, Takahashi K, Negishi K, Yoshida Y, Hagura R, Kanazawa Y, Katayama S. Evidence for association between the class 1 subset of the insulin gene minisatellite (IDDM 2 locus) and IDDM in the NIDDM. Diabetes. 1997; 46: 1725–1732.[Abstract]
  41. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996; 384: 458–460.[CrossRef][Medline] [Order article via Infotrieve]
  42. Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994; 371: 130–136.[CrossRef][Medline] [Order article via Infotrieve]




This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
35/11_suppl_1/2731    most recent
01.STR.0000143328.98154.33v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gwinn-Hardy, K.
Right arrow Articles by Dawson, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gwinn-Hardy, K.
Right arrow Articles by Dawson, V.
Related Collections
Right arrow Gene expression
Right arrow Gene regulation
Right arrow Genetically altered mice
Right arrow Genomics
Right arrow Genetics of Stroke
Right arrow Genetics of cardiovascular disease

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2004 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.