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Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.

ABSTRACT: BACKGROUND:Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene. OBJECTIVE:To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset. DESIGN:We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue. SETTING:Alzheimer's Disease Research Center. PARTICIPANTS:Research volunteers who were cognitively normal or had Alzheimer disease. MAIN OUTCOME MEASURES:Disease status and age at onset. RESULTS:We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or ?-amyloid 42 levels or TOMM40 or APOE gene expression. CONCLUSIONS:Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.

SUBMITTER: Cruchaga C

PROVIDER: S-EPMC3204798 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.

Cruchaga Carlos C Nowotny Petra P Kauwe John S K JS Ridge Perry G PG Mayo Kevin K Bertelsen Sarah S Hinrichs Anthony A Fagan Anne M AM Holtzman David M DM Morris John C JC Goate Alison M AM

Archives of neurology 20110801 8

<h4>Background</h4>Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene.<h4>Objective</h4>To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.<h4>Design</h4>We use ...[more]

PMID: 21825236

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Project description:INTRODUCTION: Migraine is a chronic, neurovascular polygenic disease where genetic and environmental factors are involved in its etiology. Dysfunction of neuronal ion transportation can provide a model for predisposition for common forms of migraine. Mutations in genes encoding ion channels disturb the rhythmic function of exposed tissue that may also explain the episodic nature of migraine. Our aim was to study the single nucleotide polymorphisms of CACNA1A gene in migraine patients. MATERIALS AND METHODS: The subjects were the patients of migraine, in the age range of 18-80 years, diagnosed by a Neurologist, as per the diagnostic criteria of International Headache Society (IHS) Classification 2004 after excluding other causes of headache by clinical examination and relevant investigations. The controls were the age and sex matched healthy persons from the same population excluding the relatives of patients. Only those patients and the controls, who voluntarily participated in the study, were taken and their blood samples were taken for the study. Deoxyribonucleic acid (DNA) extraction was performed according to the manufacturer's protocol for Qiagen DNA extraction kits (Qiagen, Hilden, NRW, Germany). DNA content was quantified by spectrophotometric absorption (Nanodrop Spectrophotometer, BioLab, Scoresby, VIC, Australia). Polymerase chain reaction was performed using an iCycler Thermal Cycler (Bio.Rad, Hercules, CA, USA). The polymorphic analysis of CACNA1A gene was carried out by two methods: Restriction fragment length polymorphism and sequencing. RESULTS: The study included a total of 25 patients of migraine, diagnosed on out-patient department basis as per IHS Classification 2004 and compared with age and sex matched 25 healthy controls. Most of the patients 23 (92%) were below the age of 50 years. 20 of the patients (80%) were females and 5 (20%) were males. The polymorphic analysis of CACNA1A gene revealed the presence of only the wild form of the gene for the codon E993V in both case and control groups. CONCLUSION: In our study, we could not find any polymorphism of CACNA1A gene in the selected patients. Instead the wild type of genotype was found in both patients and controls. This negative result presented here, implies that if the CACNA1A gene is involved in typical migraine (with and without aura), its contribution is very modest and therefore difficult to discern. Nevertheless, there are other genes that could be considered potential candidates for typical migraine susceptibility for which further research is needed.

Dataset Information

Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.

Publications

Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.

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