Search for the elusive haplotype of the APOE polymorphism associated with Alzheimer's disease

The common APOE2/E3/E4 polymorphism is determined by two-site haplotypes: C112R and R158C. Due to strong linkage disequilibrium (LD) between the two sites, three of the four expected haplotypes/alleles (E2, E3, E4) have been observed. Compared to the most common E3 haplotype (C112-R158), E4 (R112-R158) results from a mutation at codon 112, while E2 (C112-C158) results from a mutation at codon 158. The fourth haplotype (E5) having mutations at both sites (R112-C158) has been reported only as an incidental finding in three kindreds. To our knowledge, no systematic search has been done to determine its distribution in the general population. The objective of this study was to search for the elusive haplotype by subcloning a DNA fragment of 177 bp from 355 subjects with the APOE 2/4 genotype followed by sequencing as well as in 11,647 subjects genotyped by TaqMan assays. No example of the E5 haplotype was observed, suggesting it might have a minimum effect, if any, on Alzheimer's disease risk. Under the assumption of strong LD between the two sites, the estimated probability for the occurrence of the E5 haplotype by recombination event is 3.31E-08, which is similar to 5.58E-08 probability obtained by recurrent point mutation.