Common variation in
            <i>COL4A1/COL4A2</i>
            is associated with sporadic cerebral small vessel disease

Rannikmäe, Kristiina; Davies, Gail; Thomson, Pippa A.; Bevan, Steve; Devan, William J.; Falcone, Guido J; Traylor, Matthew; Anderson, Chris; Battey, Thomas W.K.; Radmanesh, Farid; Deka, Ranjan; Woo, Jessica G.; Martin, Lisa J.; Jiménez‐Conde, Jordi; Selim, Magdy; Brown, Devin L.; Silliman, Scott; Kidwell, Chelsea S.; Montaner, Joan; Langefeld, Carl D.; Słowik, Agnieszka; Hansen, Björn M.; Lindgren, Arne; Meschia, James F.; Fornage, Myriam; Bis, Joshua C.; Debette, Stéphanie; Ikram, M. Arfan; Longstreth, W. T.; Schmidt, Reinhold; Zhang, Cathy R.; Yang, Qiong; Sharma, Pankaj; Kittner, Steven J.; Mitchell, Braxton D.; Holliday, Elizabeth G.; Levi, Christopher; Attia, John; Rothwell, Peter M.; Poole, D L; Boncoraglio, Giorgio B.; Psaty, Bruce M.; Malik, Rainer; Rost, Natalia S.; Worrall, Bradford B.; Dichgans, Martin; Agtmael, Tom Van; Woo, Daniel; Markus, Hugh S.; Seshadri, Sudha; Rosand, Jonathan; Sudlow, Cathie

doi:10.1212/wnl.0000000000001309

Cited by 117 publications

(89 citation statements)

References 36 publications

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“…An international, multicenter candidate gene study 16 evaluated the role of common mutations in these genes in nonlobar ICH, small vessel ischemic stroke and magnetic resonance imaging-defined white matter hyperintensities. An intronic locus within COL4A2 was strongly associated specifically with risk of nonlobar ICH, with rs9521733, the top associated SNP within this locus, resulting in a 29% increase in risk of this type of brain bleed.…”

Section: Col4a1 and Col4a2: An Example Of Rare And Common Genetic Conmentioning

confidence: 99%

Genetics of Spontaneous Intracerebral Hemorrhage

Falcone

Woo

2017

Stroke

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Section: Col4a1 and Col4a2: An Example Of Rare And Common Genetic Conmentioning

confidence: 99%

Genetics of Spontaneous Intracerebral Hemorrhage

Falcone

Woo

2017

Stroke

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“…For lacunar stroke, several genetic loci have been identified for sporadic lacunar stroke and singlegene disorders causing cerebral small vessel diseases. 113,114 With these results, there have been efforts to generate a genetic risk score for ischemic stroke, but further studies are needed because the improvement in clinical risk prediction with genetic models was found to be small.…”

Section: Research Needs and Gapsmentioning

confidence: 99%

Nontraditional Risk Factors for Ischemic Stroke

Bang

Ovbiagele

Kim

2015

Stroke

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A lthough it is encouraging that during the past decade there has been a notable decline in the incidence of stroke in several countries around the world, 1-6 further reductions in stroke occurrence will require even better treatment of conventional risk factors, as well as the identification and treatment of nontraditional risk factors. 7 Hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, atrial fibrillation, and carotid stenosis are definite causal risk factors because randomized controlled trials showed that treating them reduced the incidence of ischemic stroke/transient ischemic attack (TIA) or because epidemiological studies have shown that they are prospectively and independently associated with incident risk of stroke.8 Several risk models and risk calculators are available for stroke. However, they include only a few traditional risk factors, and not all ischemic strokes are explained by these factors. About 60% to 80% of all ischemic strokes can be attributed to these factors.8 Adding more factors may improve the predictive values of the risk models for stroke, and controlling nontraditional risk factors may further reduce stroke risks. The INTERSTROKE study, which examined 10 factors including less traditional factors such as obesity, psychosocial stress and depression, and ratio of apolipoprotein B to A1, found that these conditions were linked to 90% of the risk of stroke. 9The carotid substudy of Northern Manhattan studies showed that traditional risk factors explain only a minority of the variability in carotid plaque, suggesting a possible role for unaccounted nontraditional risk factors in the development of atherosclerotic plaque. 10,11 The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study confirmed the existence of a stroke belt in the southeastern United States, where the rates of stroke mortality were higher (>40%) than those of other regions.12 However, in this study, only modest differences were found in 9 known risk factors common to stroke screening (the Framingham Stroke Risk Score) between the stroke belt and the stroke buckle compared with the rest of the United States. Similarly, a stroke belt with high stroke incidence was found in north and west China. 13Of note, a high prevalence of obesity was reported in stroke belts of both United States and China (Figure). These findings indirectly suggest a role for nontraditional risk factors to predict and prevent stroke. Search Strategy and Selection CriteriaIn this review, we defined traditional risk factors as those used in the Framingham study (ie, age, sex, hypertension, diabetes mellitus, cigarette smoking, cardiovascular disease [CVD], atrial fibrillation, and left ventricular hypertrophy) 15 and hypercholesterolemia. Others are defined as nontraditional risk factors if the association between the factors and the occurrence of stroke was demonstrated with plausible biological explanation. We identified references for this review by searching PubMed and ClinicalTrials.gov published in En...

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“…Furthermore, it has been suggested that shared molecular mechanisms could underlie both monogenic and sporadic SVD, and some support for this hypothesis is emerging from studies looking at associations between common polymorphism in genes causing monogenic SVD and sporadic SVD. Common variants in COL4A1/A2 were associated with a spectrum of SVD phenotypes including lacunar stroke, WMH and subcortical ICH [56]. Common Notch3 polymorphisms were associated with an increased risk of age-and hypertension-related white matter lesions [57], although this finding could not be replicated in younger onset lacunar stroke [5].…”

Section: What Can We Learn From Monogenic Svd About Disease Mechanisms?mentioning

confidence: 99%

“…Increased blood brain barrier (BBB) permeability is associated with increasing age, and is thought to be a contributing factor to sporadic small vessel disease [62]. The mechanism of stroke in COL4A1 and COL4A2-related arteriopathy, combined with the finding that more common variants in COL4A1 are associated with sporadic SVD [56], thus providing further evidence for the role of BBB compromise, whether due to genetics or ageing, in sporadic SVD.…”

Section: Loss Of Vessel Wall Integritymentioning

confidence: 99%

Monogenic causes of stroke: now and the future

Tan

Markus

2015

J Neurol

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Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single-gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants.

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Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease

Abstract: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

Cited by 117 publications

References 36 publications

Genetics of Spontaneous Intracerebral Hemorrhage

Genetics of Spontaneous Intracerebral Hemorrhage

Nontraditional Risk Factors for Ischemic Stroke

Monogenic causes of stroke: now and the future

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