Dataset Information

APOE ?4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans.

ABSTRACT: Patterns of linkage between the ?4 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 ?4-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-?4 carriers and almost all (94.2%) of the ?4 carriers had '523-L. The classification was highly concordant. Each ?4 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-?4 carriers had '523-L, but only 47.8% of the ?4 carriers had '523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between ?4 and '523-L carriers. Further, both genotypic and allelic data support that among African Americans the ?4-'523-L haplotype had stronger effect on risk of AD dementia than other ?4-'523 haplotypes.

SUBMITTER: Yu L

PROVIDER: S-EPMC5495438 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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APOE ε4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans.

Yu Lei L Lutz Michael W MW Wilson Robert S RS Burns Daniel K DK Roses Allen D AD Saunders Ann M AM Yang Jingyun J Gaiteri Chris C De Jager Philip L PL Barnes Lisa L LL Bennett David A DA

PloS one 20170703 7

Patterns of linkage between the ε4 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 ε4-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 ...[more]

PMID: 28672022

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Project description:African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Dataset Information

APOE ?4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans.

Publications

APOE ε4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans.

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