Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE

Bekris, Lynn M.; Lutz, Franziska; Yu, Chang

doi:10.1038/jhg.2011.123

Cited by 88 publications

(90 citation statements)

References 33 publications

(59 reference statements)

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“…The present results showed that rs2075650 was associated with the prevalence of dyslipidemia but not to the serum lipid profiles, suggesting that the effect of this SNP on the development of dyslipidemia may not be significant. The rs2075650 located in the intron 2 of TOMM40 (NCBI Gene) is a proxy of the SNPs that define alleles of the apolipoprotein E gene (APOE) (32). Given that the rs2075650 of TOMM40 is in strong linkage disequilibrium with rs429358 (C→T, Arg130Cys) of APOE, certain clinical implications may originate from APOE (27,32).…”

Section: Discussionmentioning

confidence: 99%

“…The rs2075650 located in the intron 2 of TOMM40 (NCBI Gene) is a proxy of the SNPs that define alleles of the apolipoprotein E gene (APOE) (32). Given that the rs2075650 of TOMM40 is in strong linkage disequilibrium with rs429358 (C→T, Arg130Cys) of APOE, certain clinical implications may originate from APOE (27,32). Although the minor C allele of rs429358 of APOE was shown to be associated with the increased serum LDL-cholesterol level, as well as the increased risk of coronary artery disease and Alzheimer's disease (27,33,34), the association of this SNP with ischemic stroke has not been determined (35).…”

Section: Discussionmentioning

confidence: 99%

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Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke

et al. 2015

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Abstract. Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ 2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P<0.05) associated with the prevalence of ischemic stroke. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, smoking status and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that rs2075650 of TOMM40 (P=0.0443; recessive model; odds ratio=0.50) and rs273909 of SLC22A4 (P= 0.0123; dominant model; odds ratio= 0.45) were significantly associated with ischemic stroke with the minor G and C allele, respectively, being protective against this condition. TOMM40 and SLC22A4 may thus be susceptibility loci for ischemic stroke in Japanese individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke

et al. 2015

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“…However, evidence of an extended TOMM40-APOE haplotype that influences the regional effects and onset age of AD (Bekris et al, 2010;Roses, 2010) suggests that TOMM40 may have APOE-independent effects (Carrasquillo and Morgan, 2012). Even in relation to AD the risk associated with TOMM40 cannot be fully explained by LD, and it has been suggested that other SNPs must contribute (Bekris et al, 2012). Despite TOMM40 rs2075650 being a good candidate for major depressive disorder (MDD), its possible effect on depression-related phenotypes has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

TOMM40 rs2075650 May Represent a New Candidate Gene for Vulnerability to Major Depressive Disorder

McFarquhar

Elliott

McKie

et al. 2014

Neuropsychopharmacol

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Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-toface clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p ¼ 0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p ¼ 0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p ¼ 0.004) and decreased positive memory bias (p ¼ 0.021) together with reduced activity in the posterior (p (FWE) ¼ 0.045) and anterior (p (FWE) ¼ 0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.

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“…The first presentation was given by Lynn M. Bekris (Cleveland, USA) about genetic variations within the apolipoprotein E (APOE) locus and their associations with late-onset AD risk [15,16]. To explore whether APOE locus cis-regulatory elements might contribute to regional gene regulation, Bekris et al produced regulatory region reporter constructs containing haplotypes of APOE locus promoters for APOE, APOC1 and TOMM40 as well as for other potential enhancers.…”

Section: Genomics and Proteomics Of Alzheimer's Diseasementioning

confidence: 99%