Allen D Roses1, Michael W Lutz2, Ann M Saunders2, Dmitry Goldgaber3, Robert Saul4, Scott S Sundseth5, P Anthony Akkari5, Stephanie M Roses2, W Kirby Gottschalk2, Keith E Whitfield6, Alexander A Vostrov3, Michael A Hauser7, R Rand Allingham8, Daniel K Burns9, Ornit Chiba-Falek2, Kathleen A Welsh-Bohmer2. 1. Duke University Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC, USA; Zinfandel Pharmaceuticals Inc, Chapel Hill, NC, USA; Cabernet Pharmaceuticals, Inc., Chapel Hill, NC, USA. Electronic address: allen.roses@duke.edu. 2. Duke University Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC, USA. 3. Department of Psychiatry, State University of New York, Stony Brook, NY, USA. 4. Polymorphic DNA Technologies, Alameda, CA, USA. 5. Cabernet Pharmaceuticals, Inc., Chapel Hill, NC, USA. 6. Department of Psychology, Duke University, Durham, NC, USA. 7. Center for Genetic Diseases, Duke University, Durham, NC, USA. 8. Department of Ophthalmology, Duke University, Durham, NC, USA. 9. Zinfandel Pharmaceuticals Inc, Chapel Hill, NC, USA.
Abstract
BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of Outer Mitochondria Membrane) and APOE depends on accurate TOMM40'523-APOE haplotypes. METHODS: We have compared the APOE and TOMM40'523 phased haplotype frequencies of a 9.5 kb TOMM40/APOE genomic region in West African, Caucasian, and African-American cohorts. RESULTS: African-American haplotype frequency scans of poly-T lengths connected in phase with either APOE ε4 or APOE ε3 differ from both West Africans and Caucasians and represent admixture of several distinct West African and Caucasian haplotypes. A new West African TOMM40'523 haplotype, with APOE ε4 connected to a short TOMM40'523 allele, is observed in African-Americans but not Caucasians. CONCLUSION: These data have therapeutic implications for the age of onset risk algorithm estimates and the design of a prevention trial for African-Americans or other mixed ethnic populations.
BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of Outer Mitochondria Membrane) and APOE depends on accurate TOMM40'523-APOE haplotypes. METHODS: We have compared the APOE and TOMM40'523 phased haplotype frequencies of a 9.5 kb TOMM40/APOE genomic region in West African, Caucasian, and African-American cohorts. RESULTS: African-American haplotype frequency scans of poly-T lengths connected in phase with either APOE ε4 or APOE ε3 differ from both West Africans and Caucasians and represent admixture of several distinct West African and Caucasian haplotypes. A new West African TOMM40'523 haplotype, with APOE ε4 connected to a short TOMM40'523 allele, is observed in African-Americans but not Caucasians. CONCLUSION: These data have therapeutic implications for the age of onset risk algorithm estimates and the design of a prevention trial for African-Americans or other mixed ethnic populations.
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