No association between<i>CALHM1</i>and risk for Alzheimer dementia in a Belgian population

Sleegers, Kristel; Brouwers, Nathalie; Bettens, Karolien; Engelborghs, Sebastiaan; Miegroet, Helen Van; Deyn, Peter Paul De; Broeckhoven, Christine Van

doi:10.1002/humu.20990

Cited by 23 publications

(17 citation statements)

References 22 publications

(12 reference statements)

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“…Bertram et al (2008) investigated several independent data sets of Caucasian patients and controls and found no association between rs2986017 polymorphism and Alzheimer's disease. The CALHM1 genotype distribution reported by Minster et al (2009) seems very similar to that found by Beecham et al (2009) and Sleegers et al (2009) without any statistically significant difference between the case and control groups.…”

Section: Discussionsupporting

confidence: 78%

“…This is relevant, as recent association studies failed to support the hypothesis that the CALHM1 rs2986017 polymorphism may represent a susceptibility factor for Alzheimer's disease Beecham et al, 2009;Minster et al, 2009;Sleegers et al, 2009). The CALHM1 T and the APOE e4 alleles together may intensify the effects of each other, as both of them can influence the generation of Ab 42 ; therefore, we also investigated a possible genetic interaction between them.…”

Section: Introductionmentioning

confidence: 95%

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No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population

Fehér

Juhász

Rimanóczy

et al. 2011

Psychiatric Genetics

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Calcium homeostasis modulator 1 (CALHM1), a promising candidate gene for Alzheimer's disease risk, has been recently identified. We tested the hypothesis that the T-allelic variant of the CALHM1 rs2986017 polymorphism confers susceptibility to Alzheimer's disease in a Hungarian case-control sample that was also genotyped for apolipoprotein E. This study included 238 probable patients with Alzheimer's disease who met the diagnostic criteria for National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and 202 elderly healthy control participants. We failed to detect an association between the CALHM1 polymorphism and the risk for Alzheimer's disease (P=0.153 for genotypes and P=0.090 for alleles), nor did we find an effect on age at onset. However, a potential weak correlation between the presence of the T allele (CT and TT genotypestogether) and Alzheimer's disease was observed (P=0.056).

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 95%

No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population

Fehér

Juhász

Rimanóczy

et al. 2011

Psychiatric Genetics

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“…Electrophysiological data have demonstrated that CALHM1 is the pore subunit of a plasma membrane non-selective channel that regulates cortical neuronal excitability and Ca 2+ homeostasis in response to extracellular Ca 2+ levels and voltage [20]. Genetic epidemiological studies have suggested that a proline-to-leucine polymorphism (rs2986017) at residue 86 (p. P86L) in CALHM1 could modify the age-at-onset of AD [17,21-23], albeit this was not observed in all association studies [24,25]. …”

Section: Introductionmentioning

confidence: 99%

Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer’s Disease Patients Alter Calcium Homeostasis

et al. 2013

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Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.

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“…Increased CALHM1 expression in cell culture systems was found to enhance intracellular calcium concentration (33)(34)(35) and to reduce Aβ accumulation (33). The P86L polymorphism in the CALHM1 gene (rs2986017) has been associated with increased risk for late-onset AD in some (33,(36)(37)(38), but not all studies (39)(40)(41)(42)(43). Three independent studies, in addition to our initial report (33), also have shown association between an earlier age at onset of AD and homozygosity of the rare allele in CALHM1 P86L (36,40) or a marker in the vicinity of the CALHM1 gene (44).…”

Section: Introductionmentioning

confidence: 99%

CALHM1 P86L Polymorphism Modulates CSF Aβ Levels in Cognitively Healthy Individuals at Risk for Alzheimer’s Disease

Koppel

Campagne

Dreses-Werringloer

et al. 2011

Mol Med

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The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling intracellular calcium homeostasis and amyloid-β (Aβ) peptide metabolism, a key event in the etiology of Alzheimer's disease (AD). The P86L polymorphism in CALHM1 (rs2986017) initially was proposed to impair CALHM1 functionally and to lead to an increase in Aβ accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence Aβ metabolism in vivo by increasing Aβ levels in human cerebrospinal fluid (CSF). Although the role of CALHM1 in AD risk remains uncertain, concordant data have now emerged showing that CALHM1 P86L is associated with an earlier age at onset of AD. Here, we have analyzed the association of CALHM1 P86L with CSF Aβ in samples from 203 AD cases and 46 young cognitively healthy individuals with a positive family history of AD. We failed to detect an association between the CALHM1 polymorphism and CSF Aβ levels in AD patients. Our data, however, revealed a significant association of CALHM1 P86L with elevated CSF Aβ42 and Aβ40 in the normal cohort at risk for AD. This work shows that CALHM1 modulates CSF Aβ levels in presymptomatic individuals, strengthening the notion that CALHM1 is involved in AD pathogenesis. These data further demonstrate the utility of endophenotype-based approaches focusing on CSF biomarkers for the identification or validation of risk factors for AD.

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No association betweenCALHM1and risk for Alzheimer dementia in a Belgian population

Cited by 23 publications

References 22 publications

No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population

No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population

Rare Variants in Calcium Homeostasis Modulator 1 (CALHM1) Found in Early Onset Alzheimer’s Disease Patients Alter Calcium Homeostasis

CALHM1 P86L Polymorphism Modulates CSF Aβ Levels in Cognitively Healthy Individuals at Risk for Alzheimer’s Disease

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