Faculty Bibliography
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person:martif02
Total Results:
134
Effects of multiple genetic Loci on age at onset in late-onset Alzheimer disease: a genome-wide association study
IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 x 10-96), with associations in CR1 (rs6701713, P = 7.2 x 10-4), BIN1 (rs7561528, P = 4.8 x 10-4), and PICALM (rs561655, P = 2.2 x 10-3) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R2 = 0.256) over baseline (R2 = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R2 = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.
PMCID:4314944
PMID: 25199842
ISSN: 2168-6149
CID: 1348572
Chemokine-specific relationships to ad biomarkers in CSF in healthy older adults [Meeting Abstract]
Background: An upregulation of monocyte chemoattractant protein-1 (MCP-1) and other chemokines (Interleukin-8 [IL-8] and Interferon gamma-induced protein 10 [IP-10]) has been reported in MCI and mild Alzheimer's disease (AD). MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. In AD, higher CSF MCP-1, and IP-10 have been associated with higher MMSE scores, suggesting potential beneficial effects of chemokine upregulation. This may include possible effects on AD biomarkers (Abeta and tau indices), which are known to be implicated in preclinical AD. This study examined the relationship between CSF chemokine levels and established AD biomarkers in older individuals with Major Depressive Disorder (MDD), which is a risk factor for AD, and in healthy controls. Methods: CSF was obtained from 47 older subjects with intact cognition and a Mini-Mental State Exam score of at least 28; 29 with MDD and 19 controls. MRI scans were performed to rule out structural brain abnormalities. No subject had gross MRI abnormalities other than white matter hyperintensities. CSF MCP-1, IP-10, IL-8, were determined using Luminex Corporation multiplexed beadbased immunoassays. Abeta40, Abeta42, total-tau, and ptau were determined using previously published methods. Results: MCP-1 was negatively correlated with CSF Abeta40 (r=-0.376, p=0.011), total tau (r=-0.361, p=0.014), and p-tau (r=-0.361, p=0.014); IL-8 was positively correlated with t-tau (r=0.357, p=0.015); IP-10 was positively correlated with t-tau (r=0.380, p=0.009) and p-tau (r=0.323, p=0.027). None of the chemokines showed a significant correlation with Abeta42 or significant group differences. Conclusions: Our findings suggest complex and differential associations between these chemokines and CSF AD Abeta and tau indices and highlight the need for further studies to determine their prognostic significance
EMBASE:71278180
ISSN: 0893-133x
CID: 752912
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
PMCID:3896259
PMID: 24162737
ISSN: 1061-4036
CID: 948132
Production of a Functional Human Acid Maltase in Tobacco Seeds: Biochemical Analysis, Uptake by Human GSDII Cells, and In Vivo Studies in GAA Knockout Mice
Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II (GSDII) or Pompe's disease. To investigate whether we could generate a functional recombinant human GAA enzyme (tobrhGAA) in tobacco seeds for future enzyme replacement therapy, we subcloned the human GAA cDNA into the plant expression plasmid-pBI101 under the control of the soybean beta-conglycinin seed-specific promoter and biochemically analyzed the tobrhGAA. Tobacco seeds contain the metabolic machinery that is more compatible with mammalian glycosylation-phosphorylation and processing. We found the tobrhGAA to be enzymatically active was readily taken up by GSDII fibroblasts and in white blood cells from whole blood to reverse the defect. The tobrhGAA corrected the enzyme defect in tissues at 7 days after a single dose following intraperitoneal (IP) administration in GAA knockout (GAA-/-) mice. Additionally, we could purify the tobrhGAA since it bound tightly to the matrix of Sephadex G100 and can be eluted by competition with maltose. These data demonstrate indirectly that the tobrhGAA is fully functional, predominantly proteolytically cleaved and contains the minimal phosphorylation and mannose-6-phosphate residues essential for biological activity.
PMCID:4703872
PMID: 23907679
ISSN: 0273-2289
CID: 472412
Psoriasis and Leprosy are Teaching Us T-Cell Plasticity
PMID: 24085038
ISSN: 1545-9616
CID: 602712
Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)
Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on gamma-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P
PMCID:3669917
PMID: 23673467
ISSN: 2158-3188
CID: 627142
Molecular skin research can impact systemic cancers
PMID: 23652941
ISSN: 1545-9616
CID: 335872
Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4,and the risk of late-onset Alzheimer disease in African Americans
IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 x 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE 4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 x 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
PMCID:3667653
PMID: 23571587
ISSN: 0098-7484
CID: 627152
Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci
Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease.
PMCID:3578142
PMID: 23360175
ISSN: 0003-4800
CID: 335882
The effect of intraoperative infusion of dexmedetomidine on the quality of recovery after major spinal surgery
BACKGROUND: : Surgery induces a variety of metabolic, endocrine, and immune changes collectively known as the "stress response," which may often lead to prolonged postoperative convalescence. Anesthetic management may modulate this physiological response, thus affecting the postoperative course. We hypothesized that the intraoperative administration of dexmedetomidine (DEX), a sympatholytic agent, would reduce the stress response and improve the quality of recovery in patients undergoing major surgery. METHODS: : We conducted a prospective randomized double-blinded study of 54 patients undergoing multilevel spinal fusion. Anesthesia was maintained using either propofol/fentanyl/dexmedetomidine (PFD) or propofol/fentanyl/placebo-saline (PFS). The quality of recovery (a primary endpoint) was assessed using a 40-item quality of recovery questionnaire and a 9-question Fatigue Severity Scores. The tests were carried out preoperatively on postoperative days (POD) 1, 2, 3, and 30. Blood samples were collected at baseline, in the postanesthesia care unit, and at POD 1 and were analyzed for levels of cortisol, C-reactive proteins (CRP), and cytokines interleukin (IL)-1alpha, IL-1beta, IL-1ra, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha. Data were analyzed using SPSS software (version 18) using a multivariate and mixed model approach to test for the effect of surgery and drug group. Pairwise comparisons were assessed by means of the t test or rank tests after correcting for multiple comparisons. RESULTS: : The global 40-item quality of recovery questionnaire scores showed a significant effect of time (F4,114=22.63, P<0.001) and drug (F1,51=4.368, P=0.042), with average scores decreasing to lower values on POD 1 (163.63+/-2.47) and POD 2 (170.94+/-2.38) compared with baseline (180.56+/-1.588, mean+/-SE, 2-tailed t tests, P<0.001). By POD 3, scores were significantly lower (-13.74 point difference, P=0.005) in the PFS group (169.3+/-3.87) than in the PFD group (183.04+/-2.76). All patients reported significantly higher levels of fatigue postoperatively, but intergroup difference in Fatigue Severity Scores was detected on POD 3 only, with scores in the PFS group higher than in the PFD group (50.0+/-4.0 vs. 36.3+/-4.9, P=0.035). In both groups, plasma cortisol levels were highest in the postanesthesia care unit, whereas CRP levels were elevated on POD 1. DEX significantly reduced the levels of cortisol, but not those of CRP. Levels of cytokines IL-6, IL-8, and IL-10 were significantly higher immediately after surgery and at POD 1. Plasma levels of other cytokines were not affected by surgery. DEX delayed postoperative rise in IL-10 but not in IL-6 or IL-8. CONCLUSIONS: : DEX infusion during multilevel spinal fusions moderately improved the quality of recovery and possibly reduced fatigue in the early postoperative period. Moreover, it reduced plasma levels of cortisol and IL-10 in comparison with the control group. Our sample size was not sufficient to detect differences either in the incidence of complications or in clinically relevant outcomes.
PMCID:3557800
PMID: 22824921
ISSN: 0898-4921
CID: 203812
