1. No category

Advances in Stroke
Advances in Genetics 2010
James F. Meschia, MD
T
he last year has seen several advances in genetics
relevant to understanding the pathophysiology of stroke
and to advancing diagnosis, prognosis, and care.
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.
Chromosome 9p21.3 Locus
Downloaded from http://stroke.ahajournals.org/ by guest on October 9, 2016
One 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.
Mitochondrial Genetic Risk of
Ischemic Stroke
Interest 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.
Cerebral Autosomal-Dominant Arteriopathy With
Subcortical Infarcts and Leukoencephalopathy and
Conventional Risk Factors
Cerebral 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.
Hereditary Angiopathy With Nephropathy,
Aneurysms, and Muscle Cramps and
Carotid Aneurysms
A 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 ␣-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 multi-
Parental History as a Risk Factor
A 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
Received December 1, 2010; final revision received December 3, 2010; accepted December 6, 2010.
From the Mayo Clinic, Jacksonville, FL.
Correspondence to James F. Meschia, MD, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail [email protected]
(Stroke. 2011;42:285-287.)
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.110.605089
285
286
Stroke
February 2011
ple. 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.16
3.
Genetics of Intracerebral Hemorrhage
Convincing evidence for associations between apolipoprotein alleles ⑀2 and ⑀4 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 Prevention
Downloaded from http://stroke.ahajournals.org/ by guest on October 9, 2016
The 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.
Disclosures
Dr 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.
4.
5.
6.
7.
8.
9.
10.
11.
12.
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H, Meitinger T, Wichmann E, Mitchell BD, Furie K, Slowik A, Rich SS,
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Muller-Myhsok B, Dichgans M. Sequence variants on chromosome
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Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn
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Granger CB, Reilly MP, Austin H, Levey AI, Vaccarino V, Palsdottir
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KEY WORDS: family history studies 䡲 genetics
䡲 ischemic stroke 䡲 pharmacogenomics
䡲
genomewide association
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Advances in Genetics 2010
James F. Meschia
Downloaded from http://stroke.ahajournals.org/ by guest on October 9, 2016
Stroke. published online January 13, 2011;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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Stroke
February 2011
Advances in Stroke
2010 年遗传学研究新进展
Advances in Genetics 2010
James F. Meschia, MD
(Stroke. 2011;42:285-287.　复旦大学附属华山医院神经内科　董漪 译 程忻 董强 校 )
过去的一年中，遗传学研究的一些新进展有助
于进一步认识卒中的病理生理机制，推动卒中诊断、
吸烟与卒中发病年龄提前相关。这些结果提示应采
取积极的措施调控这部分患者的血管危险因素。
治疗和预后的发展。
父母卒中史成为一种危险因素
染色体 9p21.3 位点是与缺血性卒中风险相关的
近来 Framingham 研究明确证实了父母卒中史
与子女发生卒中风险的相关性。父母在 65 岁前发
最有趣的位点之一。该位点首先在全基因组关联研究
生卒中，可使子女的卒中风险增加至 3 倍 [10]，且校
中被发现与冠状动脉疾病风险相关 [1-3]，之后才被证
正传统的危险因素后，增加的风险依然存在。通过
Framingham 卒中风险评估基线的结果经五分法分组
染色体9p21.3位点
实与缺血性卒中相关
[4,5]
，其还与颅内及主动脉动脉
[6]
瘤相关 ，但其中的疾病机制尚不明确。近来，染色
体 9p21.3 位点也被发现与血小板反应性相关 [7]，增加
后，在所有患者范围内均得出有父母卒中史的患者
的血小板反应性可解释与心肌梗塞及卒中的关系，但
险评分最高的五分之一患者中，父母卒中史所体现
其与动脉瘤形成的关系尚不明确。9p21.3 位点包含
一非编码 RNA，即 ANRIL，可以调节与细胞增殖相
的效果最大。为预防疾病，是进行针对性筛查抑或
关的一些基因的表达 [8]。不久的将来，9p21.3 位点
下，针对性筛查在心血管疾病的一级预防中更经济
在多种血管床上的多效性会得到越来越多的阐明。
[12]
其卒中风险高于没有父母卒中史的患者。而且在风
大范围筛查，这点始终存在着争论 [11]。在某些情况
。筛查父母卒中史可能是筛选需要进行针对性卒
中预防的高危人群的一种方式。作为一种筛查手段，
染色体显性遗传脑动脉病合并皮质下梗塞和
白质脑病(CADASIL)与传统的危险因素
新兴基因学技术并不具有优越性。
染色体显性遗传脑动脉病合并皮质下梗塞和白
质脑病 (Cerebral autosomal-dominant arteriopathy with
自报道了一常见的单倍体与卒中的关系 [13] 之
subcortical infarcts and leukoencephalopathy，CADA-
后，线粒体遗传的研究热点重新被点燃。一项多中
SIL) 目前尚不能治愈。然而，最近的临床观察研究
心线粒体全基因组关联研究分析发现缺血性卒中与
发现此类患者的卒中风险可以被调控。一篇综述分
析了英国国家 CADASIL 数据库 (UK CADASIL Na-
遗传风险评分相关，该遗传风险评分包括各个变异
tional Referral Service) 中连续纳入的 200 例患者，发
相关，这可能与低频等位基因造成的作用较轻相关。
[9]
缺血性卒中的线粒体遗传风险
型的累计值 [14]，但任意单个变异型与缺血性卒中不
现其卒中风险的增加与传统的危险因素相关 。高
血压患者的卒中风险是无高血压患者的 2.5 倍。吸
然而，无法通过基因组关联研究的方法探索单个线
粒体变异型的作用。Post hoc 统计学效力检验提示需
烟量 ( 包—年数 ) 也与卒中风险相关，并且当前正在
要筛查 >80 000 例患者。
From the Mayo Clinic, Jacksonville, FL.
Correspondence to James F. Meschia, MD, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail [email protected]
(Stroke. 2011;42:285-287.)
© 2011 American Heart Association, Inc.
56
Meschia
遗传性血管病伴发肾病、动脉瘤、
肌肉痉挛及颈动脉瘤
2.
Stroke Genetics in 2010
Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T,
Jonasdottir A, Jonasdottir A, Sigurdsson A, Baker A, Palsson A, Masson G,
Gudbjartsson DF, Magnusson KP, Andersen K, Levey AI, Backman VM, Mat-
遗传性血管病伴发肾病、动脉瘤和肌肉痉挛的
脑血管病临床表现越来越清楚 [15]。该病是因 IV 型
thiasdottir S, Jonsdottir T, Palsson S, Einarsdottir H, Gunnarsdottir S, Gylfason
胶原 α-1 链上的甘氨酸残基的 COL4A1 突变，产生
A, Stefansson K. A common variant on chromosome 9p21 affects the risk of
血尿、肾囊肿、肌酸磷酸激酶升高和视网膜动脉迂曲。
A, Vaccarino V, Hooper WC, Reilly MP, Granger CB, Austin H, Rader DJ,
Shah SH, Quyyumi AA, Gulcher JR, Thorgeirsson G, Thorsteinsdottir U, Kong
myocardial infarction. Science. 2007;316:1491–1493.
3.
McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR,
患者也可出现腔隙性梗塞、微出血、白质病变和血
Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E,
管旁间隙增宽。颈动脉虹吸部出现动脉瘤时需高度
Hobbs HH, Cohen JC. A common allele on chromosome 9 associated with
怀疑此疾病，且这类动脉瘤可多发，但动脉瘤破裂
coronary heart disease. Science. 2007;316:1488 –1491.
4.
analyses suggest ischemic stroke and heart disease share an association with
的风险较小。但其风险是否低于未经选择的未破裂
动脉瘤患者自然病程中的破裂风险尚不得而知 [16]。
Matarin M, Brown WM, Singleton A, Hardy JA, Meschia JF. Whole genome
polymorphisms on chromosome 9p21. Stroke. 2008;39:1586–1589.
5.
Gschwendtner A, Bevan S, Cole JW, Plourde A, Matarin M, Ross-Adams H,
Meitinger T, Wichmann E, Mitchell BD, Furie K, Slowik A, Rich SS, Syme PD,
MacLeod MJ, Meschia JF, Rosand J, Kittner SJ, Markus HS, Muller-Myhsok B,
颅内出血的遗传学研究
国际卒中遗传合作组 (International Stroke Genetics Consortium) 最近发现脂蛋白等位基因 ε2 和 ε4 与
Dichgans M. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 2009;65:531–539.
6.
Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S, Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A,
脑叶出血相关 [17]。合作组共纳入了 7 个队列的 2189
例脑出血的患者及 4041 例对照组。本研究包括了与
Jaaskelainen JE, Kyo Y, Lenk GM, Sakalihasan N, Kostulas K, Gottsater A,
Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K,
Jorgensen T, Shah SH, Quyyumi AA, Granger CB, Reilly MP, Austin H, Levey
脑叶出血显著相关的首个基因组关联。
AI, Vaccarino V, Palsdottir E, Walters GB, Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell RE, Sveinbjornsdottir S, Hernesniemi J,
Niemela M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven
卒中预防的药物基因组学
EL, Teijink JA, Grobbee DE, Rader DJ, Collier DA, Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson EM, Magnadottir HB, Wijmenga C, Tromp G,
内科医师熟知华法林是预防心源性栓塞的有效
Baas AF, Ruigrok YM, van Rij AM, Kuivaniemi H, Powell JT, Matthiasson SE,
措施，但缺点是其可能致脑出血 [18]。但个体对华法
Gulcher JR, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K. The
same sequence variant on 9p21 associates with myocardial infarction, abdomi-
林剂量反应的差异性较大，因而启动华法林治疗面
临挑战。个体反应的差异性主要是由于细胞色素酶
p450 的同型异构体 CYP2C9 和维生素 K 环氧化物还
nal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40:217–224.
7.
Musunuru K, Post WS, Herzog W, Shen H, O’Connell JR, McArdle PF, Ryan
KA, Gibson Q, Cheng YC, Clearfield E, Johnson AD, Tofler G, Yang Q,
原酶复合物亚基 1 VKORC1。为达到国际标准化比
O’Donnell CJ, Becker DM, Yanek LR, Becker LC, Faraday N, Bielak LF, Pey-
率的目标值，仍需进一步研究以明确基因型指导下启
动华法林治疗是否优于 5 mg 或 10 mg 的固定剂量 [19]，
phisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism
ser PA, Shuldiner AR, Mitchell BD. Association of single nucleotide polymorfor increased vascular disease. Circ Cardiovasc Genet. 2010;3:445–453.
8.
但迄今为止尚无研究提示两者的主要出血风险存在
Jarinova O, Stewart AF, Roberts R, Wells G, Lau P, Naing T, Buerki C, McLean
BW, Cook RC, Parker JS, McPherson R. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol.
差异。
作为根据药物基因组学探索华法林个体化治疗
2009;29:1671–1677.
9.
Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL
的尝试，与华法林有相似适应症的新药开始上市，
and the effect of cardiovascular risk factors on phenotype: study in 200 con-
其中之一是达比加群。其作为凝血酶直接抑制剂，
10. Seshadri S, Beiser A, Pikula A, Himali JJ, Kelly-Hayes M, Debette S, DeSte-
可给予固定剂量，并显示与华法林预防房颤患者发
生卒中相类似的安全性和有效性 [20]。药物开发和药
物基因组学预准的共同发展将取代现行的先有药物
批准，随后进行药物基因组学研究的现状。
secutively recruited individuals. Stroke. 2010;41:630–634.
fano AL, Romero JR, Kase CS, Wolf PA. Parental occurrence of stroke and risk
of stroke in their children: the Framingham study. Circulation. 2010;121:1304–
1312.
11. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14:32–38.
12. Lawson KD, Fenwick EA, Pell AC, Pell JP. Comparison of mass and targeted
screening strategies for cardiovascular risk: simulation of the effectiveness,
cost-effectiveness and coverage using a cross-sectional survey of 3921 people.
参考文献
1.
Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon
RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, Konig IR, Stevens SE,
Szymczak S, Tregouet DA, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F,
Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG,
Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson
JR, Schunkert H. Genomewide association analysis of coronary artery disease.
N Engl J Med. 2007;357:443–453.
Heart. 2010;96:208–212.
13. Chinnery PF, Elliott HR, Syed A, Rothwell PM. Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic
association study. Lancet Neurol. 2010;9:498–503.
14. Anderson CD, Biffi A, Rahman R, Ross OA, Jagiella JM, Kissela B, Cole JW,
Cortellini L, Rost NS, Cheng YC, Greenberg SM, de Bakker PI, Brown RD Jr,
Brott TG, Mitchell BD, Broderick JP, Worrall BB, Furie KL, Kittner SJ, Woo D,
Slowik A, Meschia JF, Saxena R, Rosand J. Common mitochondrial sequence
variants in ischemic stroke. Ann Neurol. 2010 Sept 13 [Epub ahead of print].
57
Stroke
February 2011
15. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro
18. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to pre-
B, Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC
vent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med.
syndrome. Neurology. 2009;73:1873–1882.
1999;131:492–501.
16. Wiebers DO, Whisnant JP, Huston J III, Meissner I, Brown RD Jr, Piepgras DG,
19. Heneghan C, Tyndel S, Bankhead C, Wan Y, Keeling D, Perera R, Ward A.
Forbes GS, Thielen K, Nichols D, O’Fallon WM, Peacock J, Jaeger L, Kassell
Optimal loading dose for the initiation of warfarin: a systematic review. BMC
NF, Kongable-Beckman GL, Torner JC. Unruptured intracranial aneurysms:
natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362:103–110.
Cardiovasc Disord. 2010;10:18.
20. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A,
Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D,
17. Biffi A, Sonni A, Anderson CD, Kissela B, Jagiella JM, Schmidt H, Jimenez-
Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L.
Conde J, Hansen BM, Fernandez-Cadenas I, Cortellini L, Ayres A, Schwab K,
Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med.
Juchniewicz K, Urbanik A, Rost NS, Viswanathan A, Seifert-Held T, Stoegerer
2009;361:1139–1151.
EM, Tomas M, Rabionet R, Estivill X, Brown DL, Silliman SL, Selim M, Worrall BB, Meschia JF, Montaner J, Lindgren A, Roquer J, Schmidt R, Greenberg
SM, Slowik A, Broderick JP, Woo D, Rosand J. Variants at APOE influence risk
of deep and lobar intracerebral hemorrhage. Ann Neurol. 2010 Nov 8 [Epub
ahead of print].
58
关键词 ：家族史研究，遗传学，全基因组关联研究，缺血
性卒中，药物基因组学
Avances en ictus
Avances en genética 2010
James F. Meschia, MD
E
Antecedentes parentales como factor de riesgo
n el pasado año se han producido varios avances en el
campo de la genética que tienen interés para el conocimiento de la fisiopatología del ictus y para el avance en su
diagnóstico, pronóstico y asistencia.
Un reciente estudio de Framinghan ha aportado nuevas informaciones importantes para comprender la relación entre los
antecedentes de ictus en los progenitores y el riesgo de ictus
en los hijos. El hecho de que se haya producido un ictus en
los padres antes de los 65 años de edad aumenta el riesgo de
ictus de los hijos en 3 veces10. Este riesgo elevado persistía tras
introducir un ajuste respecto a los factores de riesgo convencionales. Los individuos con antecedentes de ictus en los progenitores mostraron un riesgo superior al de los que no tenían
estos antecedentes familiares en los 5 quintiles de riesgo basal
estimado con el Framingham Stroke Risk Profile. El efecto
máximo de los antecedentes de ictus en los progenitores fue el
observado en el quintil de riesgo más alto. Hay argumentos a
favor y en contra del empleo de pruebas de detección dirigidas
o masivas para la prevención de la enfermedad (el denominado
dilema de Rose)11. En algunos contextos, las pruebas de detección dirigidas parecen tener una relación coste-efectividad
más favorable para la prevención cardiovascular primaria12. La
detección sistemática de los antecedentes de ictus en los progenitores puede ser una forma de identificar poblaciones de
alto riesgo para una prevención del ictus en individuos seleccionados. Como instrumento de detección, es posible que las
técnicas genómicas emergentes no sean superiores.
Locus cromosómico 9p21.3
Una de las asociaciones más intrigantes es la de un locus de
riesgo situado en el cromosoma 9p21.3 con el ictus isquémico. Este locus fue identificado inicialmente mediante un estudio de asociación de genoma completo como factor de riesgo
para la enfermedad coronaria1–3 antes de que otros estudios
mostraran una relación con el ictus isquémico4,5. El locus se
asocia también a aneurismas intracraneales y aórticos6. La
variante causal continúa siendo desconocida. Recientemente,
el cromosoma 9p21.3 se ha asociado también a la reactividad plaquetaria7. Este aumento de la reactividad plaquetaria
puede explicar la asociación con el infarto de miocardio y el
ictus; es menos claro, en cambio, de qué manera el aumento
de la reactividad plaquetaria podría estar relacionado con la
formación de un aneurisma. El locus 9p21.3 incluye un ARN
no codificador al que se denomina ANRIL, que a su vez modifica la expresión de varios genes relacionados con la proliferación celular8. En un futuro próximo deberá aparecer una
explicación más amplia de los efectos pleiotrópicos del locus
9p21.3 en múltiples lechos vasculares.
Riesgo genético mitocondrial de ictus isquémico
Arteriopatía autosómica dominante cerebral
con infartos subcorticales y leucoencefalopatía y
factores de riesgo convencionales
El interés por la genética mitocondrial resurgió tras la descripción de una asociación entre un haplogrupo frecuente y
el ictus13. En un estudio multicéntrico de asociación de genoma completo mitocondrial se observó una asociación con
el ictus isquémico y una puntuación de riesgo genético que
incluía una suma de las contribuciones de diversas variantes
individuales14. No hubo ninguna variante individual que se
asociara de manera significativa al ictus isquémico. Esto puede explicarse por la baja potencia estadística motivada por la
baja frecuencia de alelos menores y la magnitud limitada de
los efectos. Tal vez no sea posible utilizar métodos de asociación para detectar los efectos de variantes mitocondriales
individuales. Los cálculos de la potencia estadística post hoc
sugieren que para ello serían necesarios más de 80.000 casos.
La arteriopatía autosómica dominante cerebral con infartos subcorticales y leucoencefalopatía (CADASIL) es un
trastorno que continúa siendo incurable. Sin embargo, algunas observaciones recientes sugieren que el riesgo de
ictus en los pacientes con esta enfermedad puede ser modificable. En una revisión de 200 pacientes consecutivos
incluidos en el CADASIL National Referral Service del
Reino Unido, se observó que el riesgo de ictus aumentaba
con los factores de riesgo convencionales 9. La probabilidad de ictus fue 2,5 veces mayor en los pacientes con hipertensión. El número de paquetes-años de tabaquismo se
asoció al riesgo de ictus, y el tabaquismo actual se asoció
a una edad de inicio del ictus más temprana. Estos resultados respaldan un abordaje agresivo y menos fatalista de
la modificación de los factores de riesgo vascular en esta
población de pacientes.
Angiopatía hereditaria con nefropatía, aneurismas
y calambres musculares y aneurismas de carótida
Está apareciendo una imagen más clara de las manifestaciones cerebrovasculares de la angiopatía hereditaria con nefropatía, aneu-
Recibido el 1 de diciembre de 2010; versión final recibida el 3 de diciembre de 2010; aceptado el 6 de diciembre de 2010.
Mayo Clinic, Jacksonville, FL.
Remitir la correspondencia a James F. Meschia, MD, 4500 San Pablo Road, Jacksonville, FL 32224. Correo electrónico [email protected]
(Traducido del inglés: Advances in Genetics 2010. Stroke, 2011;42:285-287.)
© 2011 American Heart Association, Inc.
Stroke está disponible en http://www.stroke.ahajournals.org
86
DOI: 10.1161/STROKEAHA.110.605089
Meschia Avances en genética 2010 87
rismas y calambres musculares15. Este trastorno, que es causado
por mutaciones en el COL4A1 que afectan a los residuos de glicina de la cadena α-1 del colágeno tipo IV, pueden causar hematuria, quistes renales, elevaciones de la creatinfosfocinasa y tortuosidad arterial retiniana. Los pacientes pueden presentar también
infartos lacunares, microhemorragias, alteraciones de la sustancia
blanca y espacios perivasculares dilatados. Los aneurismas limitados a los sifones carotídeos deben hacer sospechar la presencia de
este trastorno. Estos aneurismas pueden ser múltiples. El riesgo de
ruptura de estos aneurismas carotídeos parece ser bajo. No se sabe
si el riesgo es inferior al de la evolución natural de los aneurismas
sin ruptura en pacientes no seleccionados16.
Genética de la hemorragia intracerebral
Recientemente, el International Stroke Genetics Consortium
ha generado una evidencia convincente que indica la presencia de asociaciones entre los alelos de apolipoproteína ε2 y
ε4 y la hemorragia intracerebral lobular17. Este estudio de colaboración incluyó 2.189 casos de hemorragia intracerebral y
4.041 controles de 7 cohortes. El estudio incluyó la primera
asociación genética con la hemorragia intracerebral lobular
que alcanza significación en un análisis de genoma completo.
Farmacogenómica de la prevención del ictus
Los resultados prometedores respecto a la posibilidad de prevenir el cardioembolismo y los peligros de causar una hemorragia intracerebral son bien conocidos por los médicos
que tratan a pacientes con warfarina18. Existe una considerable variación interindividual en cuanto a la respuesta a las
dosis de warfarina, y ello plantea dificultades para iniciar
el tratamiento. Una parte de la respuesta variable se debe a
las diferencias en los genotipos en cuanto a la isoforma del
citocromo P450 CYP2C9 y la subunidad 1 del complejo de
vitamina K epóxido reductasa VKORC1. No se ha demostrado todavía que la instauración del tratamiento con warfarina
basada en el genotipo sea mejor que el empleo de dosis fijas
de 5 ó 10 mg por lo que respecta a la obtención de los objetivos de la ratio internacional normalizada19. Por el momento,
no hay ningún estudio con la potencia suficiente para mostrar
diferencias en cuanto a las hemorragias mayores.
Junto con los nuevos intentos de individualizar el tratamiento con warfarina mediante el empleo de la farmacogenómica, están apareciendo nuevas medicaciones para indicaciones similares a las de la warfarina. Un ejemplo puede ser
dabigatrán, un inhibidor directo de trombina, que cuando se
administra a una dosis fija muestra una seguridad y una eficacia comparables a las de warfarina en cuanto a la prevención
del ictus en el contexto de la fibrilación auricular20. El paradigma de la warfarina como un fármaco tras cuya aprobación
se realiza el descubrimiento farmacogenómico deberá ser
sustituido por el desarrollo de fármacos realizado de forma
simultánea con la preaprobación farmacogenómica.
Declaraciones de conflictos de intereses
El Dr. Meschia es investigador principal del estudio Siblings with Ischemic Stroke Study (SWISS; National Institute of Neurological Disorders and Stroke [NINDS]
R01NS39987) y recibe financiación adicional del NINDS
U01 (U01 NS069208-01) para su actuación como presidente
de la Phenotype Committee for the Stroke Genetics Network
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9. Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of
CADASIL and the effect of cardiovascular risk factors on phenotype:
study in 200 consecutively recruited individuals. Stroke. 2010;41:
630 – 634.
10. Seshadri S, Beiser A, Pikula A, Himali JJ, Kelly-Hayes M, Debette S,
DeStefano AL, Romero JR, Kase CS, Wolf PA. Parental occurrence of
stroke and risk of stroke in their children: the Framingham study. Circulation. 2010;121:1304 –1312.
11. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14:
32–38.
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targeted screening strategies for cardiovascular risk: simulation of the
effectiveness, cost-effectiveness and coverage using a cross-sectional
survey of 3921 people. Heart. 2010;96:208 –212.
13. Chinnery PF, Elliott HR, Syed A, Rothwell PM. Mitochondrial DNA
haplogroups and risk of transient ischaemic attack and ischaemic stroke:
a genetic association study. Lancet Neurol. 2010;9:498 –503.
14. Anderson CD, Biffi A, Rahman R, Ross OA, Jagiella JM, Kissela B, Cole
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88 Stroke Julio 2011
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13. Chinnery PF, Elliott HR, Syed A, Rothwell PM. Mitochondrial DNA
haplogroups and risk of transient ischaemic attack and ischaemic stroke:
a genetic association study. Lancet Neurol. 2010;9:498 –503.
14. Anderson CD, Biffi A, Rahman R, Ross OA, Jagiella JM, Kissela B, Cole
JW, Cortellini L, Rost NS, Cheng YC, Greenberg SM, de Bakker PI,
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KL, Kittner SJ, Woo D, Slowik A, Meschia JF, Saxena R, Rosand
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Marro B, Ronco P. Cerebrovascular disease related to COL4A1 mutations
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on May
17,GS,
2011
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Forbes
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Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC.
Unruptured intracranial aneurysms: natural history, clinical outcome,
and risks of surgical and endovascular treatment. Lancet. 2003;362:
103–110.
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Jimenez-Conde J, Hansen BM, Fernandez-Cadenas I, Cortellini L,
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Viswanathan A, Seifert-Held T, Stoegerer EM, Tomas M, Rabionet
R, Estivill X, Brown DL, Silliman SL, Selim M, Worrall BB, Meschia
JF, Montaner J, Lindgren A, Roquer J, Schmidt R, Greenberg SM,
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and risks of surgical and endovascular treatment. Lancet. 2003;362:
103–110.
Biffi A, Sonni A, Anderson CD, Kissela B, Jagiella JM, Schmidt H,
Jimenez-Conde J, Hansen BM, Fernandez-Cadenas I, Cortellini L,
Ayres A, Schwab K, Juchniewicz K, Urbanik A, Rost NS,
Viswanathan A, Seifert-Held T, Stoegerer EM, Tomas M, Rabionet
R, Estivill X, Brown DL, Silliman SL, Selim M, Worrall BB, Meschia
JF, Montaner J, Lindgren A, Roquer J, Schmidt R, Greenberg SM,
Slowik A, Broderick JP, Woo D, Rosand J. Variants at APOE
influence risk of deep and lobar intracerebral hemorrhage. Ann
Neurol. 2010 Nov 8 [Epub ahead of print].
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy
to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann
Intern Med. 1999;131:492–501.
Heneghan C, Tyndel S, Bankhead C, Wan Y, Keeling D, Perera R, Ward
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Palabras Clave: family history studies n genetics n genomewide
association n ischemic stroke n pharmacogenomics
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