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:BackgroundAfrican Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease.MethodsWe selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch.ResultsWe observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001).ConclusionsOverall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive ('cold') tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.

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.

Similar Datasets

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