Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12

Luedecking-Zimmer, Erin; DeKosky, Steven T.; Chen, Qi; Barmada, M. Michael; Kamboh, M. Ilyas

doi:10.1007/s00439-002-0802-7

Cited by 45 publications

(34 citation statements)

References 44 publications

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“…7 We also observed an association between the OLR1 and LOAD which varied by APOE4. Again, this finding indicates that OLR1 is an independent risk factor to LOAD and supports the initial finding by Luedecking-Zimmer et al 8 Interestingly, Bertram et al 26 showed a similar trend, with the APOE4 negative group exhibiting a much smaller P value than other groups (with one or two copies of APOE4). However, since their study only achieved a trend toward significance for association of OLR1 with LOAD in the APOE4 negative group (P=0.074), this finding went unrecognized.…”

Section: Discussionsupporting

confidence: 84%

“…6,7 Another interesting candidate gene is the oxidized lowdensity lipoprotein (LDL) receptor gene (OLR1). 8 Three novel sequence variations in the OLR1 gene (chromosome 12) exhibiting strong association with LOAD have been described in intron 4 (rs391640 [GG]), intron 5 (rs2742113 [TT]) and 3´ untranslated region (rs1050283 [TT]). All three polymorphisms demonstrated significant association with AD after stratification for APOE4 following screening of 800 AD cases and 700 controls (odds ratio Further, CYP46 (chromosome 14q) is the gene encoding cholesterol 24-hydroxylase.…”

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confidence: 99%

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A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

Ghebranious¹,

Mukesh²,

Giampietro³

et al. 2010

Clinical Medicine & Research

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Al zheimer Disease (AD [MIM 104300]) is a common,complex genetic disorder with a prevalence rate of 5% to 10% and an incidence that increases exponentially after the age of 65 years. A majority of AD cases manifest as sporadic late onset form (LOAD [MIM 606626]), typically with onset above the age of 65 years.Clinical manifestations of the disease are associated with alterations in some or all of the following neurotransmitter networks: the forebrain cholinergic system, noradrenergic system, and telencephalon somatostatinergic system. 1 In addition, the interaction of cholesterol metabolism, inflammatory processes, and APOE has been implicated in contributing to the pathogenesis and/or progression of the disease.Because evidence of genomic variation in association with LOAD is increasingly emerging in both mutational and Background: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD. Methods:The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1, and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index. Results:The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46. Conclusions:These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study.

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

Ghebranious¹,

Mukesh²,

Giampietro³

et al. 2010

Clinical Medicine & Research

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“…However, our data indicate that intron 8/C allele is not exclusively associated with increased AD risk because a less common haplotype H5 (intron 6/C-intron 8/C-intron 9/A) containing intron 8/C allele was protective and had an OR of 0.31. Two-site haplotype analysis also confirmed that no single allele at any one 10 transcription factor CP2 (OR = 1.51) 15 and oxidized LDL receptor 1 (OR = 1.52) 16 genes. In addition to disease risk, we also examined the association of UBQLN1 SNPs with quantitative measures of AD progression, including AAO, disease duration and MMSE scores.…”

Section: Discussionmentioning

confidence: 66%

Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures

et al. 2005

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The gene coding for ubiquilin 1 (UBQLN1) is located near a linkage peak on chromosome 9q22.2 and it also impacts the function of presenilin proteins involved in early-onset Alzheimer's disease (AD). Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples. The purpose of this study was to confirm the reported association in a large case-control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-atonset (AAO), disease duration and Mini-Mental State Examination (MMSE) score. We examined the associations of three SNPs in the UBQLN1 gene (intron 6/A > C, intron 8/T > C and intron 9/ A > G) in up to 978 LOAD cases and 808 controls. All SNPs were in significant linkage disequilibrium (P < 0.0001). While modest significant associations were observed in the singlesite regression analysis, 3-site haplotype analysis revealed significant associations (P < 0.0001 for overall haplotype analysis). One common haplotype (H4) defined by intron 6/A-intron 8/Cintron 9/G alleles was associated with AD risk and one less common haplotype (H5) defined by intron 6/C-intron 8/C-intron 9/A alleles was associated with protection. The adjusted odds ratios with potentially one and two copies of risk haplotype H4 were 1.5 (95% CI: 0.99-2.26; P = 0.054) and 3.66 (95% CI: 1.43-9.39; P = 0.007), respectively, and odds ratio for haplotype H5 carriers was 0.31 (95% CI: 0.10-0.95; P = 0.0398). In addition to disease risk, the homozygosity of the risk haplotype was also associated with older AAO, longer disease duration and lower MMSE score. In summary, our data from a large case-control cohort indicate that genetic variation in the UBQLN1 gene has a modest effect on risk, AAO and disease duration of AD. Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9.

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“…Genotyping for the LOX1 intron 4 G/A (14 bp from the 5Јend of exon 5), intron 5 T/G (27 bp from the start of exon 6), and 3ЈUTR T/C (188 bp from the stop codon) polymorphisms was done as previously described. 13 The APOE genotypes were determined as previously described. 15 …”

Section: Genetic Screeningmentioning

confidence: 99%

“…12 Recently, we have identified three common LOX1 polymorphisms in intron 4 (G3 A), intron 5(T3 G), and 3Ј UTR (T3 C). 13 In this study, we have examined the relation between these three polymorphisms and the risk of CAD in the Women's Ischemia Syndrome Evaluation (WISE) study sample.…”

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confidence: 99%

Genetic Variation in Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 (LOX1) Gene and the Risk of Coronary Artery Disease

et al. 2003

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Background-We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women's Ischemia Syndrome Evaluation (WISE) study population. Methods and Results-The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: Ͻ20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and Ն50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G3 A, intron 5/T3 G, and 3Ј UTR/T3 C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3ЈUTR/T allele was significantly higher in whites than blacks (49% versus 19%; PϽ0.0001). Among white women, the frequency of the 3ЈUTR/T allele carriers (TCϩTT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the Ͻ20%, 20% to 49%, and Ն50% stenosis groups, respectively ( 2 trendϭ6.23; Pϭ0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; Pϭ0.007) and LOX1 (odds ratio, 1.67; Pϭ0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3ЈUTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94Ϯ0.20 versus 0.86Ϯ0.16; Pϭ0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3ЈUTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. Conclusions-Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women. (Circulation. 2003;107:3146-3151.)

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Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer's disease on chromosome 12

Cited by 45 publications

References 44 publications

A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures

Genetic Variation in Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 (LOX1) Gene and the Risk of Coronary Artery Disease

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