Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan

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Abstract

Background

The association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample.

Methods

We examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke.

Results

There was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively.

Conclusions

This is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke.

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Most cited references 12

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Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

Kirk Lohmueller, Celeste Pearce, Malcolm C. Pike … (2003)

Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.

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Population stratification and spurious allelic association.

Lon Cardon, Lyle J Palmer (2003)

Great efforts and expense have been expended in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, technology for detection and scoring of single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a means for investigation of the genetic causes of complex human diseases. For many diseases, population-based studies of unrelated individuals--in which case-control and cohort studies serve as standard designs for genetic association analysis--can be the most practical and powerful approach. However, extensive debate has arisen about optimum study design, and considerable concern has been expressed that these approaches are prone to population stratification, which can lead to biased or spurious results. Over the past decade, a great shift has been noted, away from case-control and cohort studies, towards family-based association designs. These designs have fewer problems with population stratification but have greater genotyping and sampling requirements, and data can be difficult or impossible to gather. We discuss past evidence for population stratification on genotype-phenotype association studies, review methods to detect and account for it, and present suggestions for future study design and analysis.

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Genomewide association studies of stroke.

Albert Hofman, André G. Uitterlinden, Lenore Launer … (2009)

The genes underlying the risk of stroke in the general population remain undetermined. We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. A genetic locus on chromosome 12p13 is associated with an increased risk of stroke. 2009 Massachusetts Medical Society

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Author and article information

Journal

Journal ID (nlm-ta): J Biomed Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date Collection: 2012

Publication date (Electronic): 3 January 2012

Volume: 19

Issue: 1

Page: 1

Affiliations

[1 ]School of Public Health, Taipei Medical University, Taipei, Taiwan

[2 ]Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA, USA

[3 ]National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA

[4 ]Department of Neurology, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan

[5 ]Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

[6 ]Dr. Chi-Hsing Huang Stroke Research Center, Taipei Medical University, Taipei, Taiwan

[7 ]Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School, Boston, MA 02131, USA

[8 ]Molecular and Integrative Physiological Science Program, Harvard School of Public Health

[9 ]Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan

[10 ]Department of Neurology, Lotung Poh-Ai Hospital, I-Lan, Taiwan

[11 ]Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

[12 ]Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

[13 ]Department of Neurology, Taipei Medical University Hospital and Shuang Ho Hospital, Taipei, Taiwan

[14 ]Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

Article

Publisher ID: 1423-0127-19-1

DOI: 10.1186/1423-0127-19-1

PMC ID: 3269363

PubMed ID: 22212150

SO-VID: a0532a88-2462-447f-a455-9d6b18fe9729

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan

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Abstract

Background

Methods

Results

Conclusions

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Stroke MRI

Most cited references 12

Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

Population stratification and spurious allelic association.

Genomewide association studies of stroke.

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