APOE and APOC1 Promoter Polymorphisms and the Risk of Alzheimer Disease in African American and Caribbean Hispanic Individuals

Tycko, Benjamin; Lee, Joseph H.; Ciappa, Alejandra; Saxena, Anjana; Li, Chi-Ming; Feng, Lin; Arriaga, Alex; Stern, Yaakov; Lantigua, Rafael; Shachter, Neil; Mayeux, Richard

Background: The APOE ε4 allele is a genetic risk factor for Alzheimer disease (AD), though the strength of the association varies by ethnic group. Polymorphisms in regulatory sequences of APOE have also been related to AD, but the effects are inconsistent across studies.

Methods: We examined the association between AD and variants in 3 APOE promoters and in the promoter of the adjacent APOC1 gene in African American and Caribbean Hispanic individuals. Polymorphisms tested were the −491A/T, −427T/C, and −219G/T (Th1/E47cs) in the APOE promoter and the HpaI variant in the APOC1 promoter. Using standard research criteria for AD, overall odds ratios were computed and repeated stratified by presence or absence of APOE ε4.

Results: The APOC1 HpaI+ variant was associated with AD in Caribbean Hispanic individuals, but strong linkage disequilibrium with the APOE ε4 allele indicated that this was not an independent effect. No promoter variant in APOE or APOC1 was associated with AD before or after adjusting for age, education, sex, and multiple comparisons. Estimated haplotypes including −219G/T, APOE, and APOC1 differed significantly in Caribbean Hispanic patients and controls but not in African American participants. This effect was primarily owing to the −219G/T-APOE haplotype, but we did not detect significant allele-specific differences in promoter activity comparing reporter constructs containing the APOE −219G and −219 T alleles.

Conclusion: These findings exclude a strong or independent influence of APOE or APOC1 promoter polymorphisms on the variation in APOE-related risk of AD in African American and Caribbean Hispanic individuals.

The ε4 variant of the APOE gene is a well-established risk factor for sporadic and familial Alzheimer disease (AD),1,2 although risk appears less consistent among African American and Caribbean Hispanic individuals with sporadic AD.2,3 An attractive hypothesis has been that genetic polymorphisms in regulatory sequences of the APOE locus, either in the immediate upstream promoter region or in the downstream enhancer regions, or a nearby gene might modify the APOE-associated risk. Thus, overexpression of the ε4 allele in the aging brain may be detrimental, possibly by promoting the extracellular aggregation of amyloid-β peptide, whereas overexpression of the ε3 or ε2 alleles may be neutral or protective. Data from transgenic mice that express human APOE protein have tended to support this hypothesis.4,5 An association between 1 or more APOE promoter polymorphisms and AD has been reported.6-15 Promoter polymorphisms associated with AD in 1 or more of these studies are, numbered relative to the transcriptional start site: −491A/T, −427T/C, and −219G/T (also known as Th1/E47cs). However, for each of these markers there are conflicting data.13,16-22 The HpaI+ variant in the promoter of the APOC1 gene, located closely downstream of APOE, has also been associated with AD.23-25 It is not clear whether this is an independent association or due to linkage disequilibrium with the APOE ε4 allele. Herein we report the allele frequencies of each of these polymorphisms in a large sample of African American and Caribbean Hispanic patients with AD and elderly controls, and we test for APOE promoter activity of 1 variant, −219G/T.



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Archives of Neurology

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February 11, 2022