17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischemic Stroke, But Not With Lacunar Stroke Status

Adib-Samii, Poneh; Rost, Natalia S.; Traylor, Matthew; Devan, William J.; Biffi, Alessandro; Lanfranconi, Silvia; Fitzpatrick, Kaitlin; Bevan, Steve; Kanakis, Allison; Valant, Valerie; Gschwendtner, Andreas; Malik, Rainer; Richie, Alexa; Gamble, Dale M; Segal, Helen; Parati, Eugenio; Ciusani, Emilio; Holliday, Elizabeth G.; Maguire, Jane; Wardlaw, Joanna M.; Worrall, Bradford B.; Bis, Joshua C.; Wiggins, Kerri L.; Longstreth, W. T.; Kittner, Steve J.; Cheng, Yu Ching; Mosley, Thomas H.; Falcone, Guido J; Furie, Karen L.; Leiva‐Salinas, Carlos; Lau, Benison C.; Khan, M. S.; Sharma, Pankaj; Fornage, Myriam; Mitchell, Braxton D.; Psaty, Bruce M.; Sudlow, Cathie; Levi, Christopher; Boncoraglio, Giorgio B.; Rothwell, Peter M.; Meschia, James F.; Dichgans, Martin; Rosand, Jonathan; Markus, Hugh S.

doi:10.1161/strokeaha.113.679936

Cited by 43 publications

(30 citation statements)

References 18 publications

(31 reference statements)

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“…The findings of the discovery meta-analyses had been confirmed in an independent sample of 1607 AGES-Reykjavik participants and in 1417 and 1677 elderly white participants from the Three-City-Dijon Study 9 and the Rotterdam Study III 10 as well as in a study of WML burden in persons with a clinical ischemic stroke. 11 The association was also confirmed in an Asian population including 1190 Japanese persons with a mean age of 66 years. 12 The region on chromosome 17 is approximately 100 kb long and harbors several genes with diverse functions such as the 2 tripartite motif-containing genes ( TRIM65 and TRIM47 ) the WW domain binding protein 2 gene ( WBP2 ), the mitochondrial ribosomal protein L38 gene ( MRPL38 ), the Fas-binding factor 1 gene ( FBF1 ), the acyl-coenzyme A oxidase 1 gene (ACOX1) and the C-Elegans homolog ( UNC13D ) gene.…”

Section: Introductionmentioning

confidence: 75%

White Matter Lesion Progression

Hofer

Cavalieri

Bis

et al. 2015

Stroke

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Background and Purpose White matter lesion (WML) progression on magnetic resonance imaging (MRI) is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in seven cohorts risk models including demographics, vascular risk factors plus single nucleotide polymorphisms (SNPs) that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no SNPs achieved genome-wide significance (p-value < 5×10−8). Four loci were suggestive (p-value < 1×10−5) of an association with WML progression: 10q24.32 (rs10883817, p=1.46×10−6); 12q13.13 (rs4761974, p=8.71×10−7); 20p12.1 (rs6135309, p=3.69×10−6); and 4p15.31 (rs7664442, p=2.26×10−6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors and baseline WML burden. Conclusions Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, life-style or host-related biological factors.

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Section: Introductionmentioning

confidence: 75%

White Matter Lesion Progression

Hofer

Cavalieri

Bis

et al. 2015

Stroke

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“…84 The association between these genotypes and WMH volume was confirmed in patients with ischaemic stroke, and in individuals of non-European origin. 85,86 A number of conditions can be considered in the differential diagnosis of WMHs on MRI. 30 Besides ischaemic WMHs, several other white matter changes have a hypoxic-ischaemic origin.…”

Section: Pathophysiology Of Wmhsmentioning

confidence: 99%

White matter hyperintensities, cognitive impairment and dementia: an update

2015

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White matter hyperintensities (WMHs) in the brain are the consequence of cerebral small vessel disease, and can easily be detected on MRI. Over the past three decades, research has shown that the presence and extent of white matter hyperintense signals on MRI are important for clinical outcome, in terms of cognitive and functional impairment. Large, longitudinal population-based and hospital-based studies have confirmed a dose-dependent relationship between WMHs and clinical outcome, and have demonstrated a causal link between large confluent WMHs and dementia and disability. Adequate differential diagnostic assessment and management is of the utmost importance in any patient, but most notably those with incipient cognitive impairment. Novel imaging techniques such as diffusion tensor imaging might reveal subtle damage before it is visible on standard MRI. Even in Alzheimer disease, which is thought to be primarily caused by amyloid, vascular pathology, such as small vessel disease, may be of greater importance than amyloid itself in terms of influencing the disease course, especially in older individuals. Modification of risk factors for small vessel disease could be an important therapeutic goal, although evidence for effective interventions is still lacking. Here, we provide a timely Review on WMHs, including their relationship with cognitive decline and dementia.

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“…5–8 The etiology of WMH remains poorly understood; 9,10 however, heterogeneity of WMH is currently supported by epidemiologic and genetic data. 11,12 …”

Section: Introductionmentioning

confidence: 99%

Determinants of White Matter Hyperintensity Burden Differ at the Extremes of Ages of Ischemic Stroke Onset

Zhang

Cloonan

Fitzpatrick

et al. 2015

Journal of Stroke and Cerebrovascular Diseases

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Background and Purpose Age is a well-known risk factor for both stroke and increased burden of white matter hyperintensity (WMH), as detected on MRI scans. However, in patients diagnosed with ischemic stroke (IS), WMH volume (WMHv) varies significantly across age groups. We sought to examine the determinants of WMH burden across the ages of stroke onset with the goal to uncover potential age-specific stroke prevention targets. Methods Adult subjects from an ongoing hospital-based cohort study of IS patients with admission brain MRI were categorized as having early (<55 years), late (>75 years), or average (55–75 years) age of stroke onset. WMHv was measured using a previously validated, MRI-based semi-automated method and normalized for linear regression analyses. Results Of 1,008 IS subjects, 249 had early-onset stroke (24.7%) and 311 had late-onset stroke (30.9%). In multivariable analysis of WMHv using backward stepwise selection, only age (β=0.02, p=0.018), hypertension (β=0.24, p=0.049), and history of tobacco use (β=0.38, p=0.001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (β=−0.30,p=0.007), hyperlipidemia (β= −0.27, p=0.015), and current alcohol use (β=0.23, p=0.034) were independently associated with WMHv in patients with late-onset stroke. Conclusions History of tobacco use is a strong independent predictor of WMH burden in patients with early-onset stroke, while age is no longer associated with WMHv in IS patients older than 75 years. These findings suggest that the major risk factors to target for stroke prevention differ across age groups and may be modifiable.

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17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischemic Stroke, But Not With Lacunar Stroke Status

Cited by 43 publications

References 18 publications

White Matter Lesion Progression

White Matter Lesion Progression

White matter hyperintensities, cognitive impairment and dementia: an update

Determinants of White Matter Hyperintensity Burden Differ at the Extremes of Ages of Ischemic Stroke Onset

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