Alpha-1-antitrypsin deficiency alleles are not associated with cervical artery dissections

Grond‐Ginsbach, Caspar; Engelter, Stefan T.; Werner, Inge; Haußer, Ingrid; Müller, U; Brandt, Tobias; Lyrer, P

doi:10.1212/01.wnl.0000118304.08215.4c

Cited by 20 publications

(13 citation statements)

References 10 publications

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“…38 Additionally, Konrad et al 38 found that the ␣ 1 -AT genotypes did not differ among cases and controls, as did Grond-Ginsbach et al 35 Connective Tissue Disease Three studies were identified from the same research group, with the same subjects being included in subsequent larger studies. 3,4,36 Connective tissue abnormalities were present in 55% (nϭ36/65) 4 and 68% (nϭ17/25) 3 in 2 studies, whereas none of the non-CAD ischemic controls in either study demonstrated such abnormalities.…”

Section: Genetic or Inborn Predisposition/disorders With A Familial Amentioning

confidence: 99%

A Systematic Review of the Risk Factors for Cervical Artery Dissection

Rubinstein

Peerdeman

Tulder

et al. 2005

Stroke

325

202

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Background and Purpose-Cervical artery dissection (CAD) is a recognized cause of ischemic stroke among young and middle-aged individuals. The pathogenesis of dissections is unknown, although numerous constitutional and environmental risk factors have been postulated. To better understand the quality and nature of the research on the pathogenesis of CAD, we performed a systematic review of its risk factors. Methods-PubMed [MEDLINE (1966 to February 22, 2005] and Embase (1980 to February 22, 2005 were searched to identify studies fulfilling the inclusion criteria. Two reviewers independently assessed methodological quality of the primary studies. Relevant data were extracted, including the risk factor(s) investigated, characteristics of the study population, and strength of the association(s). Results-Thirty-one case-control studies were included for analysis. Selection bias, lack of control for confounding, and inadequate method of data analysis were the most common identified methodological shortcomings. Strong associations were reported from individual studies for the following risk factors: aortic root diameter Ͼ34 mm (odds ratio [ORϭ14.2; 95% confidence interval [CI], 3.2 to 63.6), migraine (OR adj , 3.6; 95% CI, 1.5 to 8.6), relative diameter change (Ͼ11.8%) during the cardiac cycle of the common carotid artery (OR adj , 10.0; 95% CI, 1.8 to 54.2), and trivial trauma (in the form of manipulative therapy of the neck) (OR adj , 3.8; 95% CI, 1.3 to 11). A weak association was found for homocysteine (2 studies: OR crude , unknown; 95% CI, 1.05 to 1.52; OR crude , 1.3; 95% CI, 1.0 to 1.7), and recent infection (OR adj , 1.60; 95% CI, 0.67 to 3.80). Two studies had conflicting findings for low levels of ␣ 1 -antitrypsin, with the methodologically stronger study suggesting no association with CAD. Conclusions-CAD is a multi-factorial disease. Many of the reviewed studies contained 2 or more major sources of bias commonly found in case-control studies. Only one study (of homocysteine) used healthy controls, a robust sample size, and had a low risk of biased results. The relationship between atherosclerosis and CAD has been insufficiently examined. (Stroke. 2005;36:1575-1580.)

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Section: Genetic or Inborn Predisposition/disorders With A Familial Amentioning

confidence: 99%

A Systematic Review of the Risk Factors for Cervical Artery Dissection

Rubinstein

Peerdeman

Tulder

et al. 2005

Stroke

325

202

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“…14 Family III was included in a sequence analysis of COL5A1 in 19 patients with CAD. 15 The segregation of ␣-antitrypsin deficiency mutation PiZ was studied before in family V. 16 Family VI are whites from Argentina, family V is German-Swiss, and the other 5 families are from Germany. None of the families was related with each other.…”

Section: Patients and Clinical Diagnosismentioning

confidence: 99%

Familial Cervical Artery Dissections

Martin

Haußer

Lyrer

et al. 2006

Stroke

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Background and Purpose-Genetic risk factors are thought to play a role in the etiology of spontaneous cervical artery dissections (CAD). However, familial CAD is extremely rare. In this study we analyzed patients with familial CAD and asked the question whether familial CAD has particular features. Methods-Seven families with 15 CAD patients were recruited. All patients were carefully investigated by a neurologist, a neuroradiologist, and a dermatologist for clinical characteristics. From 11 patients a skin biopsy was performed to study the morphology of the connective tissue and to analyze the coding sequences of COL3A1, COL5A1, COL5A2, and part of COL1A1. Results-The mean age of the patients (nϭ15, 9 women) at their first dissection was 36.2 years (median age 32 years, range 18 to 59). Two patients had bilateral CAD. One patient had a right and a left internal carotid artery dissection in successive weeks, another patient had 5 dissections over a period of 8 years. A high intrafamilial correlation was found between the affected vessels (ie, the carotid and the vertebral arteries) and between ages at the first dissection. In 1 patient we found clear and reproducible ultrastructural abnormalities in the skin biopsy, but the second patient from the family was not studied, because he died as a result of CAD before this study. The dermal connective tissue aberrations in the examined patient were similar to mild findings in patients with vascular Ehlers-Danlos syndrome (EDS type IV), but might be iatrogenic and related to long-term corticosteroid inhalation therapy. All other analyzed patients showed normal connective tissue morphology. In patients from 6 families we analyzed the whole coding sequence of COL3A1, COL5A1, and COL5A2, and from part of COL1A1. A missense mutation in the COL3A1 gene (leading to a G157S substitution in type III procollagen) was detected in both patients from 1e family. Two patients from another family carried a rare nonsynonymous coding polymorphism in COL5A1 (D192N); 1 of them carried also a rare variant in COL5A2 (T12337). Conclusions-Familial CAD patients are young and probably are at high risk for recurrent or multiple CAD.Ultrastructural alterations of the dermal connective tissue might not be an important risk factor for familial CAD. However, the finding of a COL3A1 mutation revealed the presence of an inherited connective tissue disorder in 1 family.

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“…Despite a biological plausible a priori hypothesis, our results do not support a role for MTHFR/C677T in the aetiology of carotid dissection. Two other candidates, MMP-9 [28] and α 1 -antitrypsin deficiency [29], have been studied in carotid dissection but have not been replicated. Lack of studies therefore prevented these for inclusion into our meta-analysis.…”

Section: Discussionmentioning

confidence: 99%

The Genetics of Carotid Dissection: Meta-Analysis of a MTHFR/C677T Common Molecular Variant

McColgan¹,

Sharma²

2008

Cerebrovasc Dis

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Background and Purpose: Carotid dissection is a recognized cause of stroke. An association has been reported between carotid dissection and elevated homocysteine levels. Homocysteine levels are partly determined by a thermolibile form of methyltetrahydrofolate reductase (MTHFR) which has a common C677T single nucleotide polymorphism (SNP). We sought to undertake a comprehensive genetic meta-analysis of this SNP and its association with carotid dissection. Methods: All case-control studies evaluating MTHFR/C677T in carotid dissection were identified. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) using both fixed and random effects were determined for both dominant and recessive genetic models. Analyses were also undertaken to compare the effects of the homogenous forms of MTHFR/C677T. Results: Four manuscripts analyzing a total of 420 individuals (183 cases and 237 controls) were identified. The pooled OR for the dominant MTHFR/T677 model was 1.36 (95% CI 0.89–2.08; p = 0.16) while the pooled OR for the recessive TT model was 1.07 (95% CI 0.61–1.89; p = 0.81). To ensure a subtle recessive effect was not being masked by the inclusion of the heterozygous genotype, comparison of the CC and TT genotypes in cases against controls was undertaken but no significant association was observed (OR 0.73; 95% CI 0.38–1.40; p = 0.34). Conclusions: Our data does not support an association between the MTHFR/C677T molecular variant and carotid dissection. As this SNP accounts for the majority of the genetic variance of homocysteine levels, our data suggests that homocysteine is unlikely to play a major role in this condition.

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Alpha-1-antitrypsin deficiency alleles are not associated with cervical artery dissections

Cited by 20 publications

References 10 publications

A Systematic Review of the Risk Factors for Cervical Artery Dissection

A Systematic Review of the Risk Factors for Cervical Artery Dissection

Familial Cervical Artery Dissections

The Genetics of Carotid Dissection: Meta-Analysis of a MTHFR/C677T Common Molecular Variant

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