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- Lambrechts, Diether, et al.
(författare)
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Meta-analysis of VEGF variations in ALS : increased susceptibility in male carriers of the -2578AA genotype
- 2008
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Ingår i: Journal of Medical Genetics. - London : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 46:12, s. 840-846
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Tidskriftsartikel (refereegranskat)abstract
- Background: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. Methods and findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (−2578C/A, −1154G/A and −634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the −2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. Conclusions: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF −2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.
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| 3. |
- Turner, Martin R, et al.
(författare)
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Cortical involvement in four cases of primary lateral sclerosis using [(11)C]-flumazenil PET.
- 2007
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 254:8, s. 1033-6
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Tidskriftsartikel (refereegranskat)abstract
- Four PLS patients underwent cerebral [(11)C]-flumazenil PET. They were compared firstly with a group of controls, then later directly with a group of sporadic ALS patients and a familial ALS group homozygous for the 'D90A' SOD1 gene mutation. There was a similar pattern of decreased binding in PLS patients when compared to controls as that seen in a previous study of sporadic ALS patients, supporting the concept that PLS is part of the same overall spectrum of MND. However, in direct group comparisons, both sporadic and homD90A ALS patients demonstrated relative decreases in anterior and orbito-frontal binding compared to PLS patients, suggesting that there may be differences in cortical vulnerability between phenotypic groups.
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| 4. |
- Turner, Martin R, et al.
(författare)
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Volumetric cortical loss in sporadic and familial amyotrophic lateral sclerosis.
- 2007
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Ingår i: Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. - : Informa UK Limited. - 1471-180X. ; 8:6, s. 343-7
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Tidskriftsartikel (refereegranskat)abstract
- Patients homozygous for the D90A mutation of the SOD1 gene (homD90A) demonstrate markedly slower progression of disease than those patients with sporadic ALS (SALS). PET studies have demonstrated a different cortical vulnerability in the two groups, reflected also in neurophysiological studies showing reduced cortical excitability in homD90A. Voxel-based morphometric analysis of magnetic resonance images (MRIs) enables the detection of regional differences in grey matter volume, and can be used to localize cortical atrophy in vivo. In this study, segmented, spatially normalized, modulated and smoothed grey matter portions of the MRIs from 23 SALS and seven homD90A patients with similar disability, were compared with those from 28 healthy control subjects. The SALS group showed bilateral areas of atrophy mainly confined to motor and pre-motor cortices. Cortical changes in the homD90A group were more pronounced within the frontal lobes when both were compared with healthy controls. This study provides further evidence for a different pattern of cortical neuronal vulnerability in homD90A versus SALS patients that may provide insight as to their slower rate of disease progression.
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| 5. |
- van de Giessen, Elsmarieke, et al.
(författare)
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Association study on glutathione S-transferase omega 1 and 2 and familial ALS
- 2008
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Ingår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders. - : Informa UK Limited. - 1466-0822 .- 1743-4483. ; 9:2, s. 81-84
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Tidskriftsartikel (refereegranskat)abstract
- Glutathione S-transferase omega 1 and 2 (GSTO1 and 2) protect from oxidative stress, a possible pathogenic mechanism underlying the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Significant association of age of onset in Alzheimer's patients with GSTO1 and 2 had recently been identified, suggesting a possibly similar association with ALS. In this study 12 Hapmap tagged SNPs in GSTO1 and 2 were genotyped in 251 Caucasian British, Australian and Swedish familial ALS (FALS) cases. No association was found for age of onset and survival of FALS in the British and Australian patients. In the Swedish patients, association for age of onset was found with several SNPs (p = 0.003-0.048). These results suggest a possible effect of the GSTO1 and 2 locus on age of onset of FALS.
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- van Es, Michael A, et al.
(författare)
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Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 1083-1087
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
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