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TOMM40 rs2075650, TOMM40 rs157580 and TOMM40 PolyT Polymorphism Effects on Ventricular Enlargement in Individuals with and Without Mild Cognitive Impairment
S178
Poster Presentations P1
Australia, Randwick-Sydney, Australia; 7Neuroscience Research Australia; School of Medical Science, University of New South Wales, Sydney, Australia, Randwick-Sydney, Australia; 8Brain & Ageing Research Program, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, the Prince of Wales Hospital, Sydney, Australia, Randwick-Sydney, Australia. Background: White matter lesions (WMLs), seen as hyperintensities on T2-weighted MRI brain scans of older individuals, are thought to be related to cerebral small vessel disease and are often associated with subtle cognitive and functional impairments. WMLs also show a strong correlation with a wide range of neurodegenerative and neuropsychiatric disorders including Alzheimer’s disease and dementia. In addition to age and vascular risk factors, genetic factors have been implicated for WMLs. As oxidative stress is linked to cerebral ischemia and has been shown to play a role in the aetiology of WMLs, genes involved in oxidative stress pathways are candidates for the genetic basis of WMLs. We examined whether a common polymorphism in paraoxonase 2 (PON2)gene is associated with the presence of WMLs. This polymorphism leads to the substitution of serine (Ser) to cysteine (Cys) at codon 311 (Ser311Cys, rs7493) and results in decreased antioxidant activity of the paraoxonase 2 enzyme. Methods: A sample of 445 Australians aged 60-65 was drawn from a larger longitudinal study, the Personality and Total Health (PATH) Through Life Project. PON2 genotyping was determined using a Taqman assay and participants were classified as either PON2 311Cys carriers or non-carriers. The associations between PON2Ser311Cys polymorphism and WMLs were determined using analysis of covariance, controlling for intracranial volume, sex and age. Sex-specific analyses were carried out using the same ANCOVA model, when the sample was stratified by sex. Results: PON2 Ser311Cys polymorphism was not associated with any of WML measures in whole-sample analyses. When the sample was stratified by sex, the Cys allele was associated with total WMLs (p ¼ 0.019), deep WMLs (p ¼ 0.023) and periventricular lesions (p ¼ 0.022) in females only. None of the WML measures showed association with PON2Ser311Cys polymorphism in males. Conclusions: PON2 Ser311Cyspolymorphism is associated with WMLs, but in females only. Our results are in line with prior findings that women are more susceptible to the carcinogenic effects of free radicals compared to men. Our study suggests that women are more prone to the destructive effects of impairments in antioxidant enzymes activities, which might consequently result in brain lesions in the setting of ischemia. P1-209
TOMM40 RS2075650, TOMM40 RS157580 AND TOMM40 POLYT POLYMORPHISM EFFECTS ON VENTRICULAR ENLARGEMENT IN INDIVIDUALS WITH AND WITHOUT MILD COGNITIVE IMPAIRMENT
Sona Babakchanian1, Kristy Hwang1, Giovanni Coppola1, Erick Klein1, Jessica Lane1, Sterling Johnson2, Paul Thompson1, Jason Lee1, Jeffrey Cummings3, Liana Apostolova1, 1UCLA, Los Angeles, California, United States; 2University of Wisconsin, Madison, Wisconsin, United States; 3 Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, United States. Background: ApolipoproteinE4 (APOE4) is the most established sporadic Alzheimer’s disease (AD) susceptibility gene. TOMM40, a gene adjacent to APOE4, has been postulated to increase one’s risk of AD. TOMM40 polyT polymorphism has been implicated in modulating AD age of onset among APOE4-negative subjects. Methods: Genotyping for APOE4, TOMM40 rs2075650 and rs157580, and TOMM40 polyT polymorphism analyses were performed on 44 cognitively normal elderly (NC) and 48 mild cognitive impairment (MCI) subjects. A novel automated ventricular segmentation technique and the radial distance mapping approach were applied to the subjects’ T1-weighted magnetic resonance imaging data. Multiple linear regression with a permutations threshold of p < 0.01 was used to measure the effect of TOMM40 rs2075650 and TOMM40 rs157580 on ventricular radial distance while correcting for APOE4 genotype. We also analyzed associations between the short (S ¼ 20) and very long (VL ¼ 30) polyT repeat length, and ventricular enlargement in our 59 APOE4-negative individuals:
Figure: 3D statistical maps show the effect of VL repeats on ventricular radial distance (left), and the S/VL vs. S/S group comparison (right). 10 were S/S, 28 were S/VL and 21 were VL/VL carriers. The S/S, S/VL and VL/VL groups were compared. Results: TOMM40 rs2075650 and TOMM40 rs157580 failed to show significant associations with ventricular radial distance. Presence of VL showed significant association with the right temporal (pcorrected ¼ 0.039) and left occipital horns (pcorrected ¼ 0.014) in ApoE4-negative subjects. Trend level effects were detected in the right occipital (pcorrected ¼ 0.085) and frontal (pcorrected ¼ 0.094) horns. In betweengroup comparisons, S/VL carriers showed significantly smaller occipital horns than S/S carriers (left pcorrected ¼ 0.014; right pcorrected ¼ 0.015). Conclusions: Among APOE4-negative subjects, presence of VL repeats associates with smaller lateral ventricles. These data are in agreement with our previous report of VL repeat being associated with larger hippocampi. P1-210
SEARCHING FOR NOVEL KOREAN ALZHEIMER’S DISEASE MUTATIONS
Eva Bagyinszky1, Mino Kang1, Younghee Jang2, Youngcheol Youn3, Hae R. I. NA4, Youngsoon Yang5, SeongSoo A. An2, SangYun Kim3, 1 Kyungwon University, Seongnam-si, South Korea; 2Seoul National University, Seongnam-si, South Korea; 3Chungang University, College of Medicine Seoul, South Korea; 4Bobath Memorial Hospital, Seongnam-si, Kyungki-do, South Korea; 5Hyoja Geriatric Hospital, Yongin, South Korea. Background: The AD can be categorized into two groups, the early onset AD (EOAD) from mostly autosomal dominant genetic mutations, and the late onset AD (LOAD) from both genetic and non-genetic factors. EOAD has three main risk factor genes, the APP (amyloid precursor protein), the presenilin 1 and 2 (PSEN1-2), where higher SNPs were found from PSEN1. PSEN1 mutations are the most frequent. The main risk gene for LOAD is the Apolipoprotein E (APOE) E4 allele. The goal of this study was to perform AD genetic analysis in Korean dementia patients, searching for novel SNPs. Methods: The PCR primers from previous studies were used to amplify 6 PSEN1 (intronic flanking) exons: 4, 5, 6, 7, 8 and 11 (Cruts et al. 1998). For APP exon 16 and 17, the primers from Tanzi et al. and Schellenberg et al. were used. Two PCR based methods were performed. The SSCP (single stradned conformation polymorphism), utilizing the different mobility of single stranded DNA conformations after denaturation in native PAGE gel. The Surveyor Mutation detection kit (Transgenomic)is based on the cleavage of mismatches from hybridization by specific nuclease. To confirm the SNPs, the PCR amplicons were sequenced. APOE genotypings were carried out by specific multiplex PCR Results: A novel mutation was found on PSEN1 exon 6. A CAT->CCT exchange (coding strand) was found for substituting His163 with Pro from a female patient under 40. This patient seems to be heterozygous for this mutation. The APP sequencing, APOE analysis and other mutation searches in other patient’s DNA are in process. Conclusions: In Korea, 4 EOAD mutations were found, one substitution on APP, three on PSEN1. The 163 His->Pro mutation is a novel substitution, a possible AD risk factor. The rigid structure of the Pro could perturb the generation of A-beta. Two other reported mutations at His163 for EOAD were His163Arg and the His163Tyr. The genetic analysis with SSCP and Surveyor mutation detection methods will be adapted to screen larger number of samples to find other novel AD polymorphisms in Korea.
Poster Presentations P1
Australia, Randwick-Sydney, Australia; 7Neuroscience Research Australia; School of Medical Science, University of New South Wales, Sydney, Australia, Randwick-Sydney, Australia; 8Brain & Ageing Research Program, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, the Prince of Wales Hospital, Sydney, Australia, Randwick-Sydney, Australia. Background: White matter lesions (WMLs), seen as hyperintensities on T2-weighted MRI brain scans of older individuals, are thought to be related to cerebral small vessel disease and are often associated with subtle cognitive and functional impairments. WMLs also show a strong correlation with a wide range of neurodegenerative and neuropsychiatric disorders including Alzheimer’s disease and dementia. In addition to age and vascular risk factors, genetic factors have been implicated for WMLs. As oxidative stress is linked to cerebral ischemia and has been shown to play a role in the aetiology of WMLs, genes involved in oxidative stress pathways are candidates for the genetic basis of WMLs. We examined whether a common polymorphism in paraoxonase 2 (PON2)gene is associated with the presence of WMLs. This polymorphism leads to the substitution of serine (Ser) to cysteine (Cys) at codon 311 (Ser311Cys, rs7493) and results in decreased antioxidant activity of the paraoxonase 2 enzyme. Methods: A sample of 445 Australians aged 60-65 was drawn from a larger longitudinal study, the Personality and Total Health (PATH) Through Life Project. PON2 genotyping was determined using a Taqman assay and participants were classified as either PON2 311Cys carriers or non-carriers. The associations between PON2Ser311Cys polymorphism and WMLs were determined using analysis of covariance, controlling for intracranial volume, sex and age. Sex-specific analyses were carried out using the same ANCOVA model, when the sample was stratified by sex. Results: PON2 Ser311Cys polymorphism was not associated with any of WML measures in whole-sample analyses. When the sample was stratified by sex, the Cys allele was associated with total WMLs (p ¼ 0.019), deep WMLs (p ¼ 0.023) and periventricular lesions (p ¼ 0.022) in females only. None of the WML measures showed association with PON2Ser311Cys polymorphism in males. Conclusions: PON2 Ser311Cyspolymorphism is associated with WMLs, but in females only. Our results are in line with prior findings that women are more susceptible to the carcinogenic effects of free radicals compared to men. Our study suggests that women are more prone to the destructive effects of impairments in antioxidant enzymes activities, which might consequently result in brain lesions in the setting of ischemia. P1-209
TOMM40 RS2075650, TOMM40 RS157580 AND TOMM40 POLYT POLYMORPHISM EFFECTS ON VENTRICULAR ENLARGEMENT IN INDIVIDUALS WITH AND WITHOUT MILD COGNITIVE IMPAIRMENT
Sona Babakchanian1, Kristy Hwang1, Giovanni Coppola1, Erick Klein1, Jessica Lane1, Sterling Johnson2, Paul Thompson1, Jason Lee1, Jeffrey Cummings3, Liana Apostolova1, 1UCLA, Los Angeles, California, United States; 2University of Wisconsin, Madison, Wisconsin, United States; 3 Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, United States. Background: ApolipoproteinE4 (APOE4) is the most established sporadic Alzheimer’s disease (AD) susceptibility gene. TOMM40, a gene adjacent to APOE4, has been postulated to increase one’s risk of AD. TOMM40 polyT polymorphism has been implicated in modulating AD age of onset among APOE4-negative subjects. Methods: Genotyping for APOE4, TOMM40 rs2075650 and rs157580, and TOMM40 polyT polymorphism analyses were performed on 44 cognitively normal elderly (NC) and 48 mild cognitive impairment (MCI) subjects. A novel automated ventricular segmentation technique and the radial distance mapping approach were applied to the subjects’ T1-weighted magnetic resonance imaging data. Multiple linear regression with a permutations threshold of p < 0.01 was used to measure the effect of TOMM40 rs2075650 and TOMM40 rs157580 on ventricular radial distance while correcting for APOE4 genotype. We also analyzed associations between the short (S ¼ 20) and very long (VL ¼ 30) polyT repeat length, and ventricular enlargement in our 59 APOE4-negative individuals:
Figure: 3D statistical maps show the effect of VL repeats on ventricular radial distance (left), and the S/VL vs. S/S group comparison (right). 10 were S/S, 28 were S/VL and 21 were VL/VL carriers. The S/S, S/VL and VL/VL groups were compared. Results: TOMM40 rs2075650 and TOMM40 rs157580 failed to show significant associations with ventricular radial distance. Presence of VL showed significant association with the right temporal (pcorrected ¼ 0.039) and left occipital horns (pcorrected ¼ 0.014) in ApoE4-negative subjects. Trend level effects were detected in the right occipital (pcorrected ¼ 0.085) and frontal (pcorrected ¼ 0.094) horns. In betweengroup comparisons, S/VL carriers showed significantly smaller occipital horns than S/S carriers (left pcorrected ¼ 0.014; right pcorrected ¼ 0.015). Conclusions: Among APOE4-negative subjects, presence of VL repeats associates with smaller lateral ventricles. These data are in agreement with our previous report of VL repeat being associated with larger hippocampi. P1-210
SEARCHING FOR NOVEL KOREAN ALZHEIMER’S DISEASE MUTATIONS
Eva Bagyinszky1, Mino Kang1, Younghee Jang2, Youngcheol Youn3, Hae R. I. NA4, Youngsoon Yang5, SeongSoo A. An2, SangYun Kim3, 1 Kyungwon University, Seongnam-si, South Korea; 2Seoul National University, Seongnam-si, South Korea; 3Chungang University, College of Medicine Seoul, South Korea; 4Bobath Memorial Hospital, Seongnam-si, Kyungki-do, South Korea; 5Hyoja Geriatric Hospital, Yongin, South Korea. Background: The AD can be categorized into two groups, the early onset AD (EOAD) from mostly autosomal dominant genetic mutations, and the late onset AD (LOAD) from both genetic and non-genetic factors. EOAD has three main risk factor genes, the APP (amyloid precursor protein), the presenilin 1 and 2 (PSEN1-2), where higher SNPs were found from PSEN1. PSEN1 mutations are the most frequent. The main risk gene for LOAD is the Apolipoprotein E (APOE) E4 allele. The goal of this study was to perform AD genetic analysis in Korean dementia patients, searching for novel SNPs. Methods: The PCR primers from previous studies were used to amplify 6 PSEN1 (intronic flanking) exons: 4, 5, 6, 7, 8 and 11 (Cruts et al. 1998). For APP exon 16 and 17, the primers from Tanzi et al. and Schellenberg et al. were used. Two PCR based methods were performed. The SSCP (single stradned conformation polymorphism), utilizing the different mobility of single stranded DNA conformations after denaturation in native PAGE gel. The Surveyor Mutation detection kit (Transgenomic)is based on the cleavage of mismatches from hybridization by specific nuclease. To confirm the SNPs, the PCR amplicons were sequenced. APOE genotypings were carried out by specific multiplex PCR Results: A novel mutation was found on PSEN1 exon 6. A CAT->CCT exchange (coding strand) was found for substituting His163 with Pro from a female patient under 40. This patient seems to be heterozygous for this mutation. The APP sequencing, APOE analysis and other mutation searches in other patient’s DNA are in process. Conclusions: In Korea, 4 EOAD mutations were found, one substitution on APP, three on PSEN1. The 163 His->Pro mutation is a novel substitution, a possible AD risk factor. The rigid structure of the Pro could perturb the generation of A-beta. Two other reported mutations at His163 for EOAD were His163Arg and the His163Tyr. The genetic analysis with SSCP and Surveyor mutation detection methods will be adapted to screen larger number of samples to find other novel AD polymorphisms in Korea.