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Allen D. Roses - One of the best experts on this subject based on the ideXlab platform.
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The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Kahli Zeitlow, Lefko Charlambous, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L. Rock, Ann M. Saunders, Allen D. Roses, W. Kirby GottschalkAbstract:A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE e3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression. MitoTracker Green fluorescence and autophagic vesicle staining was the same in control and over-expressing cells, but TOM40 over-expression was associated with increased expression of TOM20, a preprotein receptor of the TOM complex, the mitochondrial chaperone HSPA9, and PDHE1a, and increased activities of the oxidative phosphorylation complexes I and IV and of the TCA member α-ketoglutaric acid dehydrogenase. Consistent with the complex I findings, respiration was more sensitive to inhibition by rotenone in control cells than in the TOM40 over-expressing cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over-expressing cells. Spare respiratory capacity was greater in the TOM40 over-expressing cells than in the controls. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data suggest elevated expression of TOM40 may be protective of mitochondrial function.
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apoe e4 TOMM40 523 haplotypes and the risk of alzheimer s disease in older caucasian and african americans
PLOS ONE, 2017Co-Authors: Michael W. Lutz, Ann M. Saunders, Allen D. Roses, Daniel K. Burns, Robert S. Wilson, Jingyun Yang, Chris Gaiteri, Philip L. De JagerAbstract:Patterns of linkage between the e4 allele of Apolipoprotein E (APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE e4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-e4 carriers and almost all (94.2%) of the e4 carriers had ‘523-L. The classification was highly concordant. Each e4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-e4 carriers had ‘523-L, but only 47.8% of the e4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between e4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the e4-‘523-L haplotype had stronger effect on risk of AD dementia than other e4-‘523 haplotypes.
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APOE ε4-TOMM40 ‘523 haplotypes and the risk of Alzheimer’s disease in older Caucasian and African Americans
PloS one, 2017Co-Authors: Michael W. Lutz, Ann M. Saunders, Allen D. Roses, Daniel K. Burns, Robert S. Wilson, Jingyun Yang, Chris Gaiteri, Philip L. De Jager, Lisa L. BarnesAbstract:Patterns of linkage between the e4 allele of Apolipoprotein E (APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE e4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-e4 carriers and almost all (94.2%) of the e4 carriers had ‘523-L. The classification was highly concordant. Each e4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-e4 carriers had ‘523-L, but only 47.8% of the e4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between e4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the e4-‘523-L haplotype had stronger effect on risk of AD dementia than other e4-‘523 haplotypes.
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Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2017Co-Authors: Auriel A. Willette, Allen D. Roses, Michael W. Lutz, Rebecca L. Koscik, Bruce P. Hermann, Barbara B. Bendlin, Joseph L. Webb, Alexandra M.v. Wennberg, N. Maritza DowlingAbstract:Abstract Introduction Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa ( TOMM40 ) rs10524523 (‘523) poly-T length on memory decline. Methods For 912 nonapolipoprotein e4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 ‘523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed. Results For FH negative participants, gene-dose preservation of memory and global cognition was seen for "very long" versus "short" carriers. For FH positive, an opposite gene-dose decline was seen for very long versus short carriers. Maternal FH was a stronger predictor in aged, but not middle-aged, participants. Similar gene-dose effects were seen for the mitochondrial biomarker aspartate aminotransferase. Discussion These results may clarify conflicting findings on TOMM40 poly-T length and AD-related decline.
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The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Shobana Subramanian, Allen D. Roses, William K. Gottschalk, So Young Kim, Ornit Chiba-falekAbstract:Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer's disease, and longevity. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear transcription factor that plays a role in human complex traits that are also genetically associated with the chromosome 19q13.32 region. Here, we study the effects of PPARγ on the regional expression regulation of the genes clustered within chromosome 19q13.32, specifically TOMM40, APOE, and APOC1, applying two complementary approaches. Using the short hairpin RNA (shRNA) method in the HepG2 cell-line we knocked down PPARγ expression and measured the effect on mRNA expression. We discovered PPARγ knock down increased the levels of TOMM40-, APOE-, and APOC1-mRNAs, with the highest increase in expression observed for APOE-mRNA. To complement the PPARγ knockdown findings we also examined the effects of low doses of PPARγ agonists (nM range) on mRNA expression of these genes. Low (nM) concentrations of pioglitazone (Pio) decreased transcription of TOMM40, APOE, and APOC1 genes, with the lowest mRNA levels for each gene observed at 1.5nM. Similar to the effect of PPARγ knockdown, the strongest response to pioglitazone was also observed for APOE-mRNA, and rosiglitazone (Rosi), another PPARγ agonist, produced results that were consistent with these. In conclusion, our results further established a role for PPARγ in regional transcriptional regulation of chr19q13.32, underpinning the association between PPARγ, the chr19q13.32 genes cluster, and human complex traits and disease.
Michael W. Lutz - One of the best experts on this subject based on the ideXlab platform.
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The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018Co-Authors: Ornit Chiba-falek, William K. Gottschalk, Michael W. LutzAbstract:Abstract The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 poly-T with the risk and age of onset of late-onset Alzheimer's disease (LOAD). Following the original discovery, additional studies found associations between the TOMM40 poly-T and LOAD-related phenotypes independent of APOE genotypes, while others did not replicate these associations. Furthermore, the identity of the TOMM40 poly-T risk allele has been controversial between different LOAD-related phenotypes. Here, we propose a framework to address the conflicting findings with respect to the TOMM40 poly-T allele associations with LOAD phenotypes and their functional effects. The framework is used to interpret previous studies as means to gain insights regarding the nature of the risk allele, very long versus short. We suggest that the identity of the TOMM40 poly-T risk allele depends on the phenotype being evaluated, the ages of the study subjects at the time of assessment, and the context of the APOE genotypes. In concluding remarks, we outline future studies that will inform the mechanistic interpretation of the genetic data.
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Characterization of APOE and TOMM40 allele frequencies in the Japanese population.
Alzheimer's & dementia (New York N. Y.), 2017Co-Authors: Akira Nishimura, Ann M. Saunders, Michael W. Lutz, Hidenori Nonomura, Shingo Tanaka, Michihiro Yoshida, Yuka Maruyama, Yutaka Aritomi, Daniel K. Burns, Grant RunyanAbstract:Abstract Introduction Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E ( APOE ) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 ( TOMM40 ) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known. Methods Whole blood samples were collected from 300 Japanese subjects, and genomic DNA was extracted to determine APOE alleles and TOMM40 rs10524523 genotypes. Results Our results indicated that the APOE e3– TOMM40 ′523 short haplotype is less frequent in Japanese subjects than in Caucasians, whereas the APOE e3– TOMM40 ′523 long and APOE e3– TOMM40 ′523 very long haplotypes are more frequent in Japanese subjects than in Caucasians. We also showed that the APOE e4– TOMM40 ′523 short haplotype, which was noted to be frequently observed in African Americans, was also found in the Japanese population, although it is extremely rare in the Caucasian population. Discussion A biomarker risk assignment algorithm, using a combination of APOE, TOMM40 ′523 genotype, and age, has been developed to assign near-term risk for developing the onset of mild cognitive impairment due to AD and is being used as an enrichment tool in an ongoing delay-of-onset clinical trial. Understanding the characterization of APOE and TOMM40 allele frequencies in the Japanese population is the first step in developing a risk algorithm for AD research and clinical applications for AD prevention in Japan.
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apoe e4 TOMM40 523 haplotypes and the risk of alzheimer s disease in older caucasian and african americans
PLOS ONE, 2017Co-Authors: Michael W. Lutz, Ann M. Saunders, Allen D. Roses, Daniel K. Burns, Robert S. Wilson, Jingyun Yang, Chris Gaiteri, Philip L. De JagerAbstract:Patterns of linkage between the e4 allele of Apolipoprotein E (APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE e4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-e4 carriers and almost all (94.2%) of the e4 carriers had ‘523-L. The classification was highly concordant. Each e4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-e4 carriers had ‘523-L, but only 47.8% of the e4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between e4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the e4-‘523-L haplotype had stronger effect on risk of AD dementia than other e4-‘523 haplotypes.
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APOE ε4-TOMM40 ‘523 haplotypes and the risk of Alzheimer’s disease in older Caucasian and African Americans
PloS one, 2017Co-Authors: Michael W. Lutz, Ann M. Saunders, Allen D. Roses, Daniel K. Burns, Robert S. Wilson, Jingyun Yang, Chris Gaiteri, Philip L. De Jager, Lisa L. BarnesAbstract:Patterns of linkage between the e4 allele of Apolipoprotein E (APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE e4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-e4 carriers and almost all (94.2%) of the e4 carriers had ‘523-L. The classification was highly concordant. Each e4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-e4 carriers had ‘523-L, but only 47.8% of the e4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between e4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the e4-‘523-L haplotype had stronger effect on risk of AD dementia than other e4-‘523 haplotypes.
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Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2017Co-Authors: Auriel A. Willette, Allen D. Roses, Michael W. Lutz, Rebecca L. Koscik, Bruce P. Hermann, Barbara B. Bendlin, Joseph L. Webb, Alexandra M.v. Wennberg, N. Maritza DowlingAbstract:Abstract Introduction Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa ( TOMM40 ) rs10524523 (‘523) poly-T length on memory decline. Methods For 912 nonapolipoprotein e4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 ‘523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed. Results For FH negative participants, gene-dose preservation of memory and global cognition was seen for "very long" versus "short" carriers. For FH positive, an opposite gene-dose decline was seen for very long versus short carriers. Maternal FH was a stronger predictor in aged, but not middle-aged, participants. Similar gene-dose effects were seen for the mitochondrial biomarker aspartate aminotransferase. Discussion These results may clarify conflicting findings on TOMM40 poly-T length and AD-related decline.
Ann M. Saunders - One of the best experts on this subject based on the ideXlab platform.
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Characterization of APOE and TOMM40 allele frequencies in the Japanese population.
Alzheimer's & dementia (New York N. Y.), 2017Co-Authors: Akira Nishimura, Ann M. Saunders, Michael W. Lutz, Hidenori Nonomura, Shingo Tanaka, Michihiro Yoshida, Yuka Maruyama, Yutaka Aritomi, Daniel K. Burns, Grant RunyanAbstract:Abstract Introduction Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E ( APOE ) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 ( TOMM40 ) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known. Methods Whole blood samples were collected from 300 Japanese subjects, and genomic DNA was extracted to determine APOE alleles and TOMM40 rs10524523 genotypes. Results Our results indicated that the APOE e3– TOMM40 ′523 short haplotype is less frequent in Japanese subjects than in Caucasians, whereas the APOE e3– TOMM40 ′523 long and APOE e3– TOMM40 ′523 very long haplotypes are more frequent in Japanese subjects than in Caucasians. We also showed that the APOE e4– TOMM40 ′523 short haplotype, which was noted to be frequently observed in African Americans, was also found in the Japanese population, although it is extremely rare in the Caucasian population. Discussion A biomarker risk assignment algorithm, using a combination of APOE, TOMM40 ′523 genotype, and age, has been developed to assign near-term risk for developing the onset of mild cognitive impairment due to AD and is being used as an enrichment tool in an ongoing delay-of-onset clinical trial. Understanding the characterization of APOE and TOMM40 allele frequencies in the Japanese population is the first step in developing a risk algorithm for AD research and clinical applications for AD prevention in Japan.
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The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Kahli Zeitlow, Lefko Charlambous, Sonal Gagrani, Mirta Mihovilovic, Shuhong Luo, Daniel L. Rock, Ann M. Saunders, Allen D. Roses, W. Kirby GottschalkAbstract:A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE e3/3 background, the S/VL and VL/VL genotypes are more protective than S/S. The '523 poly-T has regulatory properties, in that the VL poly-T results in higher expression than the S poly-T in luciferase expression systems. The aim of the current work was to identify effects on cellular bioenergetics of increased TOM40 protein expression. MitoTracker Green fluorescence and autophagic vesicle staining was the same in control and over-expressing cells, but TOM40 over-expression was associated with increased expression of TOM20, a preprotein receptor of the TOM complex, the mitochondrial chaperone HSPA9, and PDHE1a, and increased activities of the oxidative phosphorylation complexes I and IV and of the TCA member α-ketoglutaric acid dehydrogenase. Consistent with the complex I findings, respiration was more sensitive to inhibition by rotenone in control cells than in the TOM40 over-expressing cells. In the absence of inhibitors, total cellular ATP, the mitochondrial membrane potential, and respiration were elevated in the over-expressing cells. Spare respiratory capacity was greater in the TOM40 over-expressing cells than in the controls. TOM40 over-expression blocked Ab-elicited decreases in the mitochondrial membrane potential, cellular ATP levels, and cellular viability in the control cells. These data suggest elevated expression of TOM40 may be protective of mitochondrial function.
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apoe e4 TOMM40 523 haplotypes and the risk of alzheimer s disease in older caucasian and african americans
PLOS ONE, 2017Co-Authors: Michael W. Lutz, Ann M. Saunders, Allen D. Roses, Daniel K. Burns, Robert S. Wilson, Jingyun Yang, Chris Gaiteri, Philip L. De JagerAbstract:Patterns of linkage between the e4 allele of Apolipoprotein E (APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE e4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-e4 carriers and almost all (94.2%) of the e4 carriers had ‘523-L. The classification was highly concordant. Each e4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-e4 carriers had ‘523-L, but only 47.8% of the e4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between e4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the e4-‘523-L haplotype had stronger effect on risk of AD dementia than other e4-‘523 haplotypes.
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APOE ε4-TOMM40 ‘523 haplotypes and the risk of Alzheimer’s disease in older Caucasian and African Americans
PloS one, 2017Co-Authors: Michael W. Lutz, Ann M. Saunders, Allen D. Roses, Daniel K. Burns, Robert S. Wilson, Jingyun Yang, Chris Gaiteri, Philip L. De Jager, Lisa L. BarnesAbstract:Patterns of linkage between the e4 allele of Apolipoprotein E (APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE e4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-e4 carriers and almost all (94.2%) of the e4 carriers had ‘523-L. The classification was highly concordant. Each e4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-e4 carriers had ‘523-L, but only 47.8% of the e4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between e4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the e4-‘523-L haplotype had stronger effect on risk of AD dementia than other e4-‘523 haplotypes.
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understanding the genetics of apoe and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of alzheimer s disease
Alzheimers & Dementia, 2016Co-Authors: Allen D. Roses, Ann M. Saunders, William K. Gottschalk, Daniel K. Burns, Scott S Sundseth, Michael W. LutzAbstract:Abstract The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E ( APOE ) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the " APOE " region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics.
Sarah E. Harris - One of the best experts on this subject based on the ideXlab platform.
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apoe TOMM40 genetic loci white matter hyperintensities and cerebral microbleeds
International Journal of Stroke, 2015Co-Authors: Donald M. Lyall, Ann M. Saunders, Allen D. Roses, Michael W. Lutz, Sarah E. Harris, Mark E. Bastin, Susana Muñoz Maniega, Catherine MurrayAbstract:Background Two markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease. Aim and/or hypothesis To test for independent associations between two Alzheimer's disease-susceptibility gene loci – APOE e and the TOMM40 ‘523’ poly-T repeat – and white matter hyperintensities/cerebral microbleed burden in community-dwelling older adults. Methods Participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE e and TOMM40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71–74). Results No significant effects of APOE e or TOMM40 523 genotypes on white matter hyperintensities or cerebral microbleed burden were found amongst 624 participants. Conclusions Lack of association between two Alzheimer's disease susceptibility gene loci and markers of cerebral small vessel disease may reflect the relative health of this population compared with those in other studies in the literature.
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APOE/TOMM40 genetic loci, white matter hyperintensities, and cerebral microbleeds
International journal of stroke : official journal of the International Stroke Society, 2015Co-Authors: Donald M. Lyall, Ann M. Saunders, Allen D. Roses, Michael W. Lutz, Sarah E. Harris, Mark E. Bastin, Susana Muñoz Maniega, Catherine Murray, Maria C. Del Valdés Hernández, Natalie A. RoyleAbstract:Background Two markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease. Aim and/or hypothesis To test for independent associations between two Alzheimer's disease-susceptibility gene loci – APOE e and the TOMM40 ‘523’ poly-T repeat – and white matter hyperintensities/cerebral microbleed burden in community-dwelling older adults. Methods Participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE e and TOMM40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71–74). Results No significant effects of APOE e or TOMM40 523 genotypes on white matter hyperintensities or cerebral microbleed burden were found amongst 624 participants. Conclusions Lack of association between two Alzheimer's disease susceptibility gene loci and markers of cerebral small vessel disease may reflect the relative health of this population compared with those in other studies in the literature.
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are apoe ɛ genotype and TOMM40 poly t repeat length associations with cognitive ageing mediated by brain white matter tract integrity
Translational Psychiatry, 2014Co-Authors: Donald M. Lyall, Ann M. Saunders, Michael W. Lutz, Sarah E. Harris, Mark E. Bastin, Catherine Murray, A. D. Roses, Munoz S ManiegaAbstract:Genetic polymorphisms in the APOE e and TOMM40 ‘523’ poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer’s disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE e2/e3/e4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.
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Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.
Neurobiology of aging, 2014Co-Authors: Donald M. Lyall, Ann M. Saunders, Allen D. Roses, Michael W. Lutz, Sarah E. Harris, Mark E. Bastin, Susana Muñoz Maniega, Catherine Murray, Maria C. Del Valdés Hernández, Natalie A. RoyleAbstract:Apolipoprotein E (APOE) e genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer’s disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 (“523”) variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether thereareindependenteffectsof apolipoproteinE (APOE) andTOMM40genotypesonhumanbrain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (meanage ¼72.70years,standarddeviation ¼0.74,Napproximately ¼640e650; formostanalyses).Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of e4 “risk” allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE e3/e4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40523“short”alleleshowedlowerwhitematterintegritywhencomparedwithcarriersofthe“long” and “very-long” alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.
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Alzheimer’s Disease Susceptibility Genes APOE and TOMM40, and Hippocampal Volumes in the Lothian Birth Cohort 1936
PloS one, 2013Co-Authors: Donald M. Lyall, Ann M. Saunders, Allen D. Roses, Michael W. Lutz, Sarah E. Harris, Natalie A. Royle, Mark E. Bastin, Susana Muñoz Maniega, Catherine Murray, Maria C. Del Valdés HernándezAbstract:The APOE e and TOMM40 rs10524523 (‘523’) variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer’s disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE e and TOMM40 ‘523’ genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE e2/e3/e4 status and TOMM40 ‘523’ poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636). No significant effects of APOE e or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE e or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1) their specific techniques in adjusting for brain size; 2) assessing more detailed sub-divisions of the hippocampal formation; and 3) testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.
A. D. Roses - One of the best experts on this subject based on the ideXlab platform.
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are apoe ɛ genotype and TOMM40 poly t repeat length associations with cognitive ageing mediated by brain white matter tract integrity
Translational Psychiatry, 2014Co-Authors: Donald M. Lyall, Ann M. Saunders, Michael W. Lutz, Sarah E. Harris, Mark E. Bastin, Catherine Murray, A. D. Roses, Munoz S ManiegaAbstract:Genetic polymorphisms in the APOE e and TOMM40 ‘523’ poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer’s disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE e2/e3/e4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.
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Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms
Neuromuscular disorders : NMD, 2013Co-Authors: Francis Mastaglia, Ann M. Saunders, Michael W. Lutz, Arada Rojana-udomsart, Ian James, Merrilee Needham, Timothy Day, L. Kiers, J.a. Corbett, A. D. RosesAbstract:A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer’s disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer’s disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE e3/e3 or e3/e4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.
