Association of APOE ε2/ε3/ε4 and promoter gene variants with dementia but not cardiovascular mortality in old age

Abstract

The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE epsilon4 allele were associated with a 4.1-fold (95% CI, 2.2-7.7) increased risk of dementia as compared to the epsilon3/epsilon3 genotype in old subjects. Moreover, homozygosity for the -219T allele was found to be associated with a 2.4-fold (95% CI, 1.0-5.8) increased risk independently of epsilon2 and epsilon4; the -491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among epsilon4 carriers (RR, 0.6; 95% CI, 0.4-1.0) or -219T homozygous subjects (RR, 1.1; 95% CI, 0.7-1.7), nor did it decrease among -491T homozygous subjects (RR, 1.4; 95% CI, 0.6-3.1). In conclusion, both the APOE epsilon2/epsilon3/epsilon4 and the -219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age.

Combined association and linkage analysis applied to the APOE locus

“…Previously, the À219G/T polymorphism was associated with apoE plasma levels [Lambert et al, 2000;Stengard et al, 2002]. This SNP is in partial LD with the APOEE2/E3/E4 polymorphism [Fullerton et al;2000;Heijmans et al, 2002], and thus may have contributed to the association we observed.…”

Hardy–Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power

“…Violation of the equilibrium was admitted in only four associations (two data sets) that we found to deviate. 21,24 Among the 163 disease-free controls (124 distinct data sets) where we found no statistically significant deviation from HWE, in three (three distinct data sets) 25,26 the articles reported that HWE was violated, and in 76 (54 distinct data sets) the articles correctly mentioned that HWE was not violated. For the rest of the papers either the authors have not reported anything about testing, or the results were not clear in their report.…”

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

“…In recent years, substantial evidence has confirmed that variants in the promoter of certain genes may underlie the pathogenesis of several neurological diseases, including Parkinson's disease [Wang et al, 2006], Huntington's disease [Coles et al, 1998], and AD [Fallin et al, 2001;Heijmans et al, 2002]. Very recent studies provide strong evidence that an APP promoter polymorphism, which has a higher transcriptional activity, over-expresses APP [Lv et al, 2008].…”