Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Kilarski, Laura L.; Achterberg, Sefanja; Devan, William J.; Traylor, Matthew; Malik, Rainer; Lindgren, Arne; Paré, Guillaume; Sharma, Pankaj; A, Słowik; Thijs, Vincent; Walters, Matthew; Worrall, Bradford B.; Sale, Michèle M.; Algra, Ale; Kappelle, L. Jaap; Wijmenga, Cisca; Norrving, Bo; Sandling, Johanna K.; Rönnblom, Lars; Goris, An; Franke, André; Sudlow, Cathie; Rothwell, Peter M.; Levi, Christopher; Holliday, Elizabeth G.; Fornage, Myriam; Psaty, Bruce M.; Grétarsdóttir, Sólveig; Thorsteinsdottir, U; Seshadri, Sudha; Mitchell, Braxton D.; Kittner, Steven J.; Clarke, Robert; Hopewell, Jemma C.; Bis, Joshua C.; Boncoraglio, Giorgio B.; Meschia, James F.; Ikram, M. Arfan; Hansen, Björn M.; Montaner, Joan; Þorleifsson, Guðmar; Stefanson, Kari; Rosand, Jonathan; Bakker, Paul I. W. de; Farrall, Martin; Dichgans, Martin; Markus, Hugh S.; Bevan, Steve

doi:10.1212/wnl.0000000000000707

Cited by 87 publications

(67 citation statements)

References 23 publications

(33 reference statements)

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“…10 Another, the 12q24.12 locus, was first identified as a novel association with all ischemic stroke subtypes and was not mediated by conventional cardiovascular risk factors. 9 However, a recent study demonstrated that the 12q24 locus was specifically associated with the small artery occlusion stroke subtype, rather than for all stroke subtypes. 11 These data highlight the potential involvement of the ALDH2 gene in the risk of ischemic stroke.…”

Section: Discussionmentioning

confidence: 97%

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Sung

Lee

et al. 2016

Stroke

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Background and Purpose— The * 2 allele of the aldehyde dehydrogenase 2 gene (ALDH2 ) is the most common variant in Asian populations. The variant resulting in enzyme dysfunction was highly related to coronary artery disease. Recently, genome-wide association studies also discovered that the 12q24 locus near ALDH2 gene was associated with hypertension and ischemic stroke. This study intended to further investigate whether the above variant of ALDH2 increases the risk for ischemic stroke in Taiwanese. Methods— A case–control study was conducted on 914 patients with acute ischemic stroke and 746 nonstroke controls. Polymerase chain reaction and sequencing were used to identify the ALDH2 genotype. Vascular risk factors, stroke subtypes, vascular stenosis, and stroke outcomes were analyzed. Results— ALDH2 genotypes differed significantly between male controls (* 1/*1 versus * 1/*2 versus * 2/*2 =53.8% versus 39.9% versus 6.4%) and male patients with ischemic stroke (* 1/*1 versus * 1/*2 versus * 2/*2 =51.5% versus 37.3% versus 11.2%; P =0.048). No significant difference was found between groups for female patients ( P =0.228). Multivariate logistic regression analysis revealed that the ALDH2*2/*2 genotype was an independent risk factor for ischemic stroke in male patients (odds ratio, 1.93 [95% confidence interval, 1.07–3.46]; P =0.028). Further analysis of men with ischemic stroke demonstrated that the polymorphism of ALDH2 was not related to vascular risk factors, severity of vascular atherosclerosis, stroke subtypes, and stroke functional outcomes. Conclusions— The study demonstrated that ALDH2*2/*2 may be an independent risk factor for ischemic stroke in Taiwanese men, but not in Taiwanese women.

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Section: Discussionmentioning

confidence: 97%

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Sung

Lee

et al. 2016

Stroke

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“…In selecting IS associated SNPs, we considered the five loci (9p21, HDAC9, PITX2, ZFHX3 , and 12q24.12 ) associated with stroke in METASTROKE and in a recent publication 38, 39. We set a p ‐value threshold of p = 0.01 to determine significance, using the Bonferroni method to correct for five independent tests.…”

Section: Participants and Methodsmentioning

confidence: 99%

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Traylor¹,

Adib-Samii²,

Harold³

et al. 2016

Annals of Neurology

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ObjectiveIncreasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.MethodsUsing genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred.ResultsWe found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response.InterpretationOur findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747

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“…Detection of a significant association does not mean that the identified SNP is causal; it is usually merely a marker for a causal functional SNP that is located on a nearby region of the genome. ); monomorphic in white populations, and no association between this gene region and stroke was found in the METASTROKE study 20 All ischaemic stroke 27,29 12p13 12q24…”

Section: Implications For the Clinicianmentioning

confidence: 97%

“…20,28 The first association of a genetic variant with all types of ischaemic stroke to be replicated convincingly was reported with a locus at 12q24 (OR 1.1). 29 The same gene region has been associated with cardiovascular risk factors, including hypertension and type 1 diabetes mellitus, 29 although the SNP associated with these diseases was not the same as that found to be associated with stroke. The mechanism of action, and whether or not the association occurs independently of or via conventional risk factors, is not clear.…”

Section: Small-vessel Disease (Lacunar Stroke)mentioning

confidence: 99%

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

Markus

Bevan

2014

Nat Rev Neurol

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| The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings.

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Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Cited by 87 publications

References 23 publications

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

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Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Cited by 87 publications

References 23 publications

Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

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Product

Resources

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Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men