Dataset Information

Comprehensive search for Alzheimer disease susceptibility loci in the APOE region.

ABSTRACT: OBJECTIVE:To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523). DESIGN:Conditional logistic regression models and survival analysis. SETTING:Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. PARTICIPANTS:Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. MAIN OUTCOME MEASURES:Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. RESULTS:In models adjusting for APOE ?4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ?3/?3 subjects. CONCLUSIONS:APOE alleles ?2, ?3, and ?4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

SUBMITTER: Jun G

PROVIDER: S-EPMC3579659 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Comprehensive search for Alzheimer disease susceptibility loci in the APOE region.

Jun Gyungah G Vardarajan Badri N BN Buros Jacqueline J Yu Chang-En CE Hawk Michele V MV Dombroski Beth A BA Crane Paul K PK Larson Eric B EB Mayeux Richard R Haines Jonathan L JL Lunetta Kathryn L KL Pericak-Vance Margaret A MA Schellenberg Gerard D GD Farrer Lindsay A LA

Archives of neurology 20121001 10

<h4>Objective</h4>To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).<h4>Design</h4>Conditional logistic regression models and survival analysis.<h4>Setting</h4>Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.<h4>Participants</h4>Eleven th ...[more]

PMID: 22869155

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Project description:This research was aimed to explore correlation of gene polymorphisms of CD36 and ApoE with susceptibility of Alzheimer disease (AD).This study was a case-control study. Two hundred eleven AD hospitalized patients were selected as the AD group and 241 subjects were selected as the control group. PCR-RFLP was used to detect three loci (rs7755, rs3211956, and rs10499859) of CD36 gene and ApoE genotype. Chi-square test and univariate nonconditional logistic regression analysis were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI). The haplotypes were constructed using SHEsis online software and the correlation between haplotypes and AD was analyzed. Meanwhile, differences of 3 alleles of ApoE and 6 genotypes (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4) were compared between AD and control groups.The frequencies of rs7755 genotype (??=?10.780, P?=?.005) and allele (??=?10.549, P?=?.001) were statistically different between 2 groups. The genotype frequency of rs3211956 was statistically different between AD and control groups (??=?10.119, P?=?.006). For the rs7755 locus, GG genotype (OR: 2.013, 95% CI: 1.098-3.699) was an independent risk factor for AD compared with AA genotype. In the dominant model, the risk to develop AD in AG/GG genotype was 1.686 times higher than AA genotype. For the rs3211956 locus, compared with TT genotype, GT genotype (OR: 0.536, 95% CI: 0.340-0.846) was a protective factor for AD after adjusting various physiological and biochemical factors. In the dominant model, the risk of GT/GG genotype to develop AD was reduced by 41.6%. For ApoE gene, the distribution differences of E2/E3 (??=?9.216, P?=?.002), E3/E4 (??=?7.728, P?=?.005), and E4/E4 had statistical significance between the 2 groups. The frequencies of allele E2 (??=?9.359, P?=?.002) and E4 (??=?13.995, P?<?.001) were statistically significant between AD and control groups.The rs7755 and rs3211956 loci polymorphisms of CD36 gene and genotype E2/E3, E3/E4, E4/E4 of ApoE gene, and E2 and E4 alleles were statistically related with AD.

Project description:Importance:The ?2 and ?4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 near the APOC1 gene, it is unknown whether these associations are independent of the ?2 and ?4 alleles. Objective:To assess whether variants near APOE are associated with AD independently of the ?2/?3/?4 genotype. Design, Setting, and Participants:In this genetic association study of the Alzheimer's Disease Genetics Consortium imputed genotype at data, 14?415 variants near APOE (±500 kilobase) for 18?795 individuals with European ancestry were tested for association with AD using 4 logistic mixed models adjusting for sex, cohort, population structure, and relatedness. Model 1 had no APOE adjustment, and model 2 adjusted for the count of ?2 and ?4 alleles. Model 3 was restricted to ?3 homozygotes, and model 4 was restricted to ?4 homozygotes. Data were downloaded from May 31, 2018, to June 3, 2018, and analyzed from November 1, 2018, to June 24, 2020. Main Outcomes and Measures:Alzheimer disease affectation status was defined by clinicians using standard National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria. Association was evaluated using Score tests; results with P?<?.05 divided by the number of independent tests per model were considered statistically significant. Results:Among the 18?795 individuals in the study, 9704 were affected by AD and 9066 were control individuals; the median age at onset/evaluation was 76 (interquartile range, 70-82) years; and 11 167 were female (59.4%). Associations with AD were found for rs2075650 (odds ratio [OR], 2.59; 95% CI, 2.45-2.75; P?=?3.19?×?10-228) and rs4420638 (OR, 2.77; 95% CI, 2.62-2.94; P?=?2.99?×?10-254) without APOE adjustment. Although rs2075650 was nominally associated with AD among the ?4 homozygotes (OR, 1.33; 95% CI, 1.00-1.77; P?=?.047), the association between rs4420638 and AD was eliminated by APOE adjustment (model 2 OR, 1.06 [95% CI, 0.96-1.18; P?=?.24]; model 3 OR, 1.13 [95% CI, 0.95-1.34; P?=?.18]; model 4 OR, 0.90 [95% CI, 0.56-1.45; P?=?.66]). There was a significant association between rs192879175 and AD among ?3 homozygotes (OR, 0.50; 95% CI, 0.37-0.68; P?=?8.30?×?10-6). Conclusions and Relevance:The results of this genetic association study suggest that ?2/?3/?4 alleles are not the only variants in the APOE region that are associated with AD risk. Additional work with independent data is needed to replicate these results.

Project description:ImportanceThere are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)-negative (Aβ-) suspected non-Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts.ObjectiveTo examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts.Design, setting, and participantsA longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ- and neurodegeneration-positive [Aβ-N+]) subtypes and their Aβ+N+ counterparts.Main outcomes and measuresParticipants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]).ResultsThe study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were Aβ-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were Aβ+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their Aβ+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: Aβ-N+, 1.25 [0.11] vs Aβ+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ε4 (Aβ-N+, 18.7% vs Aβ+N+, 70.6%) and disproportionately high APOE ε2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (Aβ-N+, 6.5% vs Aβ+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their Aβ+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between Aβ-N+ and Aβ+N+ cases.Conclusions and relevanceIn MCI with SNAP, low APOE ε4 and high APOE ε2 carrier prevalence may account for differences in neurodegeneration patterns between Aβ-N+ and Aβ+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

Project description:Gallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0-5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD >or=1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans.

Dataset Information

Comprehensive search for Alzheimer disease susceptibility loci in the APOE region.

Publications

Comprehensive search for Alzheimer disease susceptibility loci in the APOE region.

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