Human Genetics

Biography

Biography: Ramon Cacabelos

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular disorders, stroke and dementia (Alzheimer’s disease, vascular dementia). Many different genes are involved in lipid metabolism responsible for the cholesterolemic phenotype. Genes potentially associated with pathogenic lipid metabolism dysfunction in dementia include the following: APOB (OMIM 107730; rs693 [7545C>T], APOEC3 (OMIM 107720; rs5128 [3175G>C, S1/S2], APOE (OMIM 107741; rs429358/rs7412 [112T>C/158T>C, E2, E3, E4], CETP (OMIM 118470; rs708272 [+279G>A, B1/B2] and LPL (OMIM 609708; rs328 [1421C>G, S474X]. In a selected group of 933 Alzheimer’s disease (AD) patients, we constructed a pentagenic haplotype integrating all possible variants of the APOE+APOB+EPOC3+CETP+LPL genes and identified 111 haplotypes (H) with differential basal cholesterol (CHO) levels. About 75% of these haplotypes in the AD population have a frequency below 1%, 10% have a frequency between 1% and 2%, 8% have a frequency between 2% and 5% and only 4% of the haplotypes are present in more than 5% of AD patients. The haplotypes most frequently found are H55 (33-CT-CC-AG-CC (8.79%), H58 (33-CT-CC-GG-CC) and H37 (33-CC-CC-AG-CC) (7.07%). Haplotypes H104 (44-CC-CC-AA-CC) (0.11%), H110 (44-TT-CC-AG-CG) (0.11%) and H98 (34-TT-CC-AA-CG) (0.11%) showed the highest CHO levels and the lowest levels corresponded to haplotypes H26 (23-TT-CG-AG-CC) (0.11%), H8 (23-CC-CG-AG-CC) (0.21%), H50 (33-CC-GG-AG-CC) (0.21%) and H63 (33-CT-CG-AA-GG) (0.11%). These haplotypes have been used for pharmacogenetic studies in hypercholesterolemic patients with AD.