Association between variants in IDE-KIF11-HHEX and plasma amyloid ? levels.
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ABSTRACT:
SUBMITTER: Reitz C
PROVIDER: S-EPMC3117070 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
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Association between variants in IDE-KIF11-HHEX and plasma amyloid β levels.
Reitz Christiane C Cheng Rong R Schupf Nicole N Lee Joseph H JH Mehta Pankaj D PD Rogaeva Ekaterina E St George-Hyslop Peter P Mayeux Richard R
Neurobiology of aging 20100817 1
Genetic linkage and association studies in late-onset Alzheimer's disease (LOAD) or its endophenotypes have pointed to several regions on chromosome 10q, among these the ∼ 250 kb linkage disequilibrium (LD) block harboring the genes IDE, KIF1, and HHEX. We explored the association between variants in the genomic region harboring the IDE-KIF11-HHEX complex with plasma Aβ40 and Aβ42 levels in a case-control cohort of Caribbean Hispanics. First, we performed single marker linear regression analysis ...[more]
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Project description:Genome-wide association studies (GWAS) in populations of European ancestry have mapped a type 2 diabetes susceptibility region to chromosome 10q23.33 containing IDE, KIF11 and HHEX genes (IDE-KIF11-HHEX), which has also been replicated in Chinese populations. However, the functional relevance for genetic variants at this locus is still unclear. It is critical to systematically assess the relationship of genetic variants in this region with the risk of type 2 diabetes.A fine-mapping study was conducted by genotyping fourteen tagging single-nucleotide polymorphisms (SNPs) in a 290-kb linkage disequilibrium (LD) region using a two-stage case-control study of type 2 diabetes in a Chinese Han population. Suggestive associations (P<0.05) observed from 1,200 cases and 1,200 controls in the first stage were further replicated in 1,725 cases and 2,081 controls in the second stage. Seven tagging SNPs were consistently associated with type 2 diabetes in both stages (P<0.05), with combined odds ratios (ORs) ranging from 1.14 to 1.33 in the combined analysis. The most significant locus was rs7923837 [OR?=?1.33, 95% confidence interval (CI): 1.21-1.47] at the 3'-flanking region of HHEX gene. SNP rs1111875 was found to be another partially independent locus (OR?=?1.23, 95% CI: 1.13-1.35) in this region that was associated with type 2 diabetes risk. A cumulative effect of rs7923837 and rs1111875 was observed with individuals carrying 1, 2, and 3 or 4 risk alleles having a 1.27, 1.44, and 1.73-fold increased risk, respectively, for type 2 diabetes (P for trend?=?4.1E-10).Our results confirm that genetic variants of the IDE-KIF11-HHEX region at 10q23.33 contribute to type 2 diabetes susceptibility and suggest that rs7923837 may represent the strongest signal related to type 2 diabetes risk in the Chinese Han population.
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Project description:Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism.Twenty-one single nucleotide polymorphisms (SNPs) from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12). But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090). The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006).The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively.
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Project description:OBJECTIVE: Herpes simplex virus (HSV) reactivation has been identified as a possible risk factor for Alzheimer's disease (AD) and plasma amyloid-beta (A?) levels might be considered as possible biomarkers of the risk of AD. The aim of our study was to investigate the association between anti-HSV antibodies and plasma A? levels. METHODS: The study sample consisted of 1222 subjects (73.9 y in mean) from the Three-City cohort. IgM and IgG anti-HSV antibodies were quantified using an ELISA kit, and plasma levels of A?(1-40) and A?(1-42) were measured using an xMAP-based assay technology. Cross-sectional analyses of the associations between anti-HSV antibodies and plasma A? levels were performed by multi-linear regression. RESULTS: After adjustment for study center, age, sex, education, and apolipoprotein E-e4 polymorphism, plasma A?(1-42) and A?(1-40) levels were specifically inversely associated with anti-HSV IgM levels (??=?-20.7, P=0.001 and ??=?-92.4, P=0.007, respectively). In a sub-sample with information on CLU- and CR1-linked SNPs genotyping (n=754), additional adjustment for CR1 or CLU markers did not modify these associations (adjustment for CR1 rs6656401, ??=?-25.6, P=0.002 for A?(1-42) and ??=?-132.7, P=0.002 for A?(1-40;) adjustment for CLU rs2279590, ??=?-25.6, P=0.002 for A?(1-42) and ??=?-134.8, P=0.002 for A?(1-40)). No association between the plasma A?(1-42)-to-A?(1-40) ratio and anti-HSV IgM or IgG were evidenced. CONCLUSION: High anti-HSV IgM levels, markers of HSV reactivation, are associated with lower plasma A?(1-40) and A?(1-42) levels, which suggest a possible involvement of the virus in the alterations of the APP processing and potentially in the pathogenesis of AD in human.
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Project description:OBJECTIVE:The objectives of this study were to investigate whether the plasma levels of oligomeric amyloid-β (OAβ) were affected in Alzheimer's disease (AD) and to examine the associations (or possible correlations) between plasma OAβ levels and memory performance. METHOD:Thirty subjects with AD and 28 cognitively normal controls were recruited in the study. The multimer detection system (MDS) was used to measure the levels of OAβ in the plasma. In addition to assessing the general cognitive function with the Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), and Alzheimer's Disease Assessment Scale-cognitive portion (ADAS-Cog), the common objects memory test (COMT) was used to examine the episodic memory performance. Pearson's and partial correlation analyses were conducted to explore the associations between cognitive performance and OAβ levels in the plasma. A receiving operating curve (ROC) analysis was used to discriminate between the AD and control groups. RESULTS:The plasma OAβ levels in the AD group were significantly higher than those in the control group [1.88 (0.38) ng/ml vs 1.20 (0.40) ng/ml, p < 0.001]. The elevated levels of plasma OAβ showed a strong correlation with cognitive performance in patients with AD, including an inverse correlation with scores on the MMSE (r = - 0.43, p = 0.02), CASI (r = - 0.56, p < 0.01), and the immediate recall (r = - 0.45, p = 0.01), 5-min delayed recall (r = - 0.56, p < 0.01), and 30-min delayed recall (r = - 0.71, p < 0.001) tests of the COMT, and a positive correlation with the ADAS-Cog scores (r = 0.59, p < 0.001). The EDTA plasma Aβ oligomer optical density (OD) value measured using the MDS could discriminate between the AD and control groups with an area under the curve (AUC) of 0.89. The optimal sensitivity and specificity were 82.1% and 90.0%, respectively. CONCLUSION:The elevated levels of OAβ in the plasma distinguished the AD and control groups and were associated with the severity of symptoms, especially memory performance, in patients with AD. Our results suggested that plasma OAβ could potentially be a simple and non-invasive blood-based biomarker for AD diagnosis. Furthermore, longitudinal studies are warranted to explore the application of plasma OAβ levels as a valid diagnostic biomarker in patients with AD.
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Project description:BACKGROUND:The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). METHODOLOGY/PRINCIPAL FINDINGS:We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. CONCLUSIONS:Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.
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Project description:BACKGROUND:A relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus. Relationship quantitative trait loci (rQTL) are often involved in gene-by-gene (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G. METHODS:We performed genome-wide association studies to identify rQTL between tau and A?42 and ptau and A?42 with over 3000 individuals using age, gender, series, APOE ?2, APOE ?4, and two principal components for population structure as covariates. Each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model. Parametric bootstrapping was used to assess significance. RESULTS:We found four significant tau/A?42 rQTL from three unique locations and six ptau/A?42 rQTL from five unique locations. G×G screens with these rQTL produced four significant G×G interactions (one A?42, two ptau, and one tau) with four rQTL where each second locus was from a unique location. On follow-up, rs1036819 and rs74025622 were associated with Alzheimer's disease (AD) case/control status; rs15205 and rs79099429 were associated with rate of decline. CONCLUSIONS:The two most significant rQTL (rs8027714 and rs1036819) for ptau/A?42 are on different chromosomes and both are strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/A?42 relationship but may suggest that these two loci share a pathway. In addition to a ptau/A?42 rQTL and association with AD case/control status, rs1036819 is a strong rQTL for case/control status/A?42 and for tau/A?42. It resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/A?42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a ?-secretase enzyme that initiates production of the ?-amyloid peptide involved in AD and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important AD endophenotypes and some are due to interactions with other loci. Some affect the risk of AD and/or rate of progression.
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