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- A2M, α2-macroglobulin
- AD, Alzheimer’s disease
- APOE, apolipoprotein E
- CLR, conditional logistic regression
- EMSAs, electrophoretic mobility shift assays
- LD, linkage disequilibrium
- LRP1, low density lipoprotein-related protein 1
- OLR1, oxidised LDL receptor 1
Recently, two studies1,2 reported independent evidence of genetic association between a 3′ UTR single nucleotide polymorphism (SNP; rs1050283, also known as “+1073”) in the oxidised LDL receptor 1 gene (OLR1) on chromosome 12p13.2 and risk for Alzheimer’s disease (AD). The implied chromosomal area is a highly promising AD candidate region because both genetic linkage and association studies have reported significant signals to two different locations separated by about 40 Mb (about 44 cM): the more proximal region is located near 10 Mb, on 12p13, and contains OLR1 as well as the gene encoding α2-macroglobulin (A2M), while the more distal region near 50 Mb, on 12q13, maps close to the genes encoding LRP1 (low density lipoprotein-related protein 1) and TFCP2 (transcription factor CP2). All four of these genes have shown independent associations with AD risk, although the results for A2M and LRP1 have been controversial (for recent reviews see Bertram and Tanzi3 and Saunders et al4).
For OLR1, Luedecking-Zimmer and colleagues first reported evidence of association with the 3′ UTR SNP (rs1050283) in a white North American case-control sample of more than 1500 subjects.1 This association showed a strong interaction with APOE (apolipoprotein E) ε4-genotype, and led to opposite effects in subgroups stratified by APOE ε4. Specifically, APOE ε4-positive carriers of the TT-genotype had a 1.7-fold increased AD risk, whereas APOE ε4-negative carriers of the same genotype showed a significantly reduced (OR = 0.7) risk for AD. Performing electrophoretic mobility shift assays (EMSAs) indicated reduced binding of nuclear proteins related to the T-allele of this variant.
The more recently published results by Lambert et al were obtained on a large French case-control sample and a considerably smaller North American family-based sample, and also showed significant effects with this polymorphism.2 However, no APOE ε4-dependence was …