LETTER TO JMG No association between a previously reported OLR1 39 UTR polymorphism and Alzheimer’s disease in a large family sample

Abstract

R ecently, two studies 2 reported independent evidence of genetic association between a 39 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 a2-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 Tanzi and Saunders et al). For OLR1, Luedecking-Zimmer and colleagues first reported evidence of association with the 39 UTR SNP (rs1050283) in a white North American case-control sample of more than 1500 subjects. This association showed a strong interaction with APOE (apolipoprotein E) e4-genotype, and led to opposite effects in subgroups stratified by APOE e4. Specifically, APOE e4-positive carriers of the TT-genotype had a 1.7-fold increased AD risk, whereas APOE e4-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. However, no APOE e4-dependence was observed in either of the samples investigated in the latter study. Furthermore, these authors also saw a significant under-representation of the TT-genotype v the CC/CT-genotypes, and this finding was interpreted as a risk effect in carriers of the C-allele v noncarriers. Similar to the previous analyses, these genetic results were also supported by some functional data suggesting reduced binding of the T-allele to nuclear and cytoplasmic proteins as compared to the C-allele as determined by EMSA. While no correlation between this polymorphism and cerebral Ab or tau load was observed in this study, there was evidence of a significantly reduced expression of OLR1 in carriers of the C-allele carriers v non-carriers. Our laboratory has previously tested several AD candidate genes on chromosome 12 for association with AD in one of the largest AD family samples collected to date, the NIMH Genetics Initiative Study sample. Of these, the strongest and most consistent signals observed were obtained with polymorphisms in A2M, which show a strong effect on AD risk, predominantly in families with late-onset AD. 5 Although A2M maps about 1 Mb pter of OLR1, it is conceivable that at least part of the independent association signals observed across our and the OLR1-positive studies is due to polymorphisms in linkage disequilibrium (LD) with genetic variants in these two genes. Thus, we have tested the OLR1 SNP in the full NIMH sample, which is comprised of 1439 of individuals from 437 families in which all affected individuals had disease onset at .50 years. These include 994 affected individuals (mean age of onset 72.4¡7.7 years, range 50–97), 411 unaffecteds, and 34 with phenotype unknown. Pedigrees were classified as ‘‘late-onset’’ (320 pedigrees) when all sampled affecteds in each pedigree had onset ages of .65 years, and ‘‘early/mixed’’ otherwise. APOE genotyping was performed as described previously, and pedigrees were classified as ‘‘APOE-e4/4 positive’’ when at least one affected individual per pedigree carried the e4/4 genotype (120 pedigrees), and as ‘‘APOE-e4/4 negative’’ otherwise, and as ‘‘APOE-e4 positive’’ when at least one affected individual per pedigree carried the e4-allele (358

2 Figures and Tables

Cite this paper

@inproceedings{Bertram2004LETTERTJ, title={LETTER TO JMG No association between a previously reported OLR1 39 UTR polymorphism and Alzheimer’s disease in a large family sample}, author={Lars Bertram and Michele Parkinson and Kristina Mullin and Ramsekhar Menon and Dina Blacker and Rudolph E. Tanzi}, year={2004} }