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1.
Nutrients ; 13(10)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34684365

RESUMO

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state. Participants were recruited as lean (n = 55, aged 8-17 years, BMI percentile 5-85%) and overweight and obese (OVOB, n = 228, aged 8-17 years, BMI percentile ≥ 85%). Untargeted metabolomics profiled 246 annotated metabolites in plasma at t0 and t60 min during the OGTT. Our results suggest that obesity and IR influence the switch from fatty acid (FA) to glucose oxidation in response to the OGTT. Obesity was associated with a blunted decline of acylcarnitines and fatty acid oxidation intermediates. In females, metabolites from the Fasted and Random-Fed OGTT were associated with HOMA-IR, including diacylglycerols, leucine/isoleucine, acylcarnitines, and phosphocholines. Our results indicate that at an early age, obesity and IR may influence the metabolome dynamics in response to a glucose challenge.


Assuntos
Jejum/metabolismo , Comportamento Alimentar , Resistência à Insulina , Metaboloma , Obesidade/metabolismo , Caracteres Sexuais , Adolescente , Glicemia/metabolismo , Criança , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Cinética , Masculino , Obesidade/sangue
2.
Metabolites ; 10(12)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255384

RESUMO

Modern analytical methods allow for the simultaneous detection of hundreds of metabolites, generating increasingly large and complex data sets. The analysis of metabolomics data is a multi-step process that involves data processing and normalization, followed by statistical analysis. One of the biggest challenges in metabolomics is linking alterations in metabolite levels to specific biological processes that are disrupted, contributing to the development of disease or reflecting the disease state. A common approach to accomplishing this goal involves pathway mapping and enrichment analysis, which assesses the relative importance of predefined metabolic pathways or other biological categories. However, traditional knowledge-based enrichment analysis has limitations when it comes to the analysis of metabolomics and lipidomics data. We present a Java-based, user-friendly bioinformatics tool named Filigree that provides a primarily data-driven alternative to the existing knowledge-based enrichment analysis methods. Filigree is based on our previously published differential network enrichment analysis (DNEA) methodology. To demonstrate the utility of the tool, we applied it to previously published studies analyzing the metabolome in the context of metabolic disorders (type 1 and 2 diabetes) and the maternal and infant lipidome during pregnancy.

3.
Bioinformatics ; 36(6): 1801-1806, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31642507

RESUMO

MOTIVATION: When metabolites are analyzed by electrospray ionization (ESI)-mass spectrometry, they are usually detected as multiple ion species due to the presence of isotopes, adducts and in-source fragments. The signals generated by these degenerate features (along with contaminants and other chemical noise) obscure meaningful patterns in MS data, complicating both compound identification and downstream statistical analysis. To address this problem, we developed Binner, a new tool for the discovery and elimination of many degenerate feature signals typically present in untargeted ESI-LC-MS metabolomics data. RESULTS: Binner generates feature annotations and provides tools to help users visualize informative feature relationships that can further elucidate the underlying structure of the data. To demonstrate the utility of Binner and to evaluate its performance, we analyzed data from reversed phase LC-MS and hydrophilic interaction chromatography (HILIC) platforms and demonstrated the accuracy of selected annotations using MS/MS. When we compared Binner annotations of 75 compounds previously identified in human plasma samples with annotations generated by three similar tools, we found that Binner achieves superior performance in the number and accuracy of annotations while simultaneously minimizing the number of incorrectly annotated principal ions. Data reduction and pattern exploration with Binner have allowed us to catalog a number of previously unrecognized complex adducts and neutral losses generated during the ionization of molecules in LC-MS. In summary, Binner allows users to explore patterns in their data and to efficiently and accurately eliminate a significant number of the degenerate features typically found in various LC-MS modalities. AVAILABILITY AND IMPLEMENTATION: Binner is written in Java and is freely available from http://binner.med.umich.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Metabolômica , Espectrometria de Massas em Tandem , Cromatografia Líquida , Humanos , Íons , Espectrometria de Massas por Ionização por Electrospray
4.
Nat Commun ; 10(1): 4052, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492856

RESUMO

Metabolites are active controllers of cellular physiology, but their role in complex behaviors is less clear. Here we report metabolic changes that occur during the transition between hunger and satiety in Drosophila melanogaster. To analyze these data in the context of fruit fly metabolic networks, we developed Flyscape, an open-access tool. We show that in response to eating, metabolic profiles change in quick, but distinct ways in the heads and bodies. Consumption of a high sugar diet dulls the metabolic and behavioral differences between the fasted and fed state, and reshapes the way nutrients are utilized upon eating. Specifically, we found that high dietary sugar increases TCA cycle activity, alters neurochemicals, and depletes 1-carbon metabolism and brain health metabolites N-acetyl-aspartate and kynurenine. Together, our work identifies the metabolic transitions that occur during hunger and satiation, and provides a platform to study the role of metabolites and diet in complex behavior.


Assuntos
Drosophila melanogaster/fisiologia , Fome/fisiologia , Redes e Vias Metabólicas/fisiologia , Metaboloma/fisiologia , Saciação/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Dieta , Drosophila melanogaster/metabolismo , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Humanos , Metabolômica/métodos
5.
Bioinformatics ; 33(10): 1545-1553, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28137712

RESUMO

MOTIVATION: Recent technological advances in mass spectrometry, development of richer mass spectral libraries and data processing tools have enabled large scale metabolic profiling. Biological interpretation of metabolomics studies heavily relies on knowledge-based tools that contain information about metabolic pathways. Incomplete coverage of different areas of metabolism and lack of information about non-canonical connections between metabolites limits the scope of applications of such tools. Furthermore, the presence of a large number of unknown features, which cannot be readily identified, but nonetheless can represent bona fide compounds, also considerably complicates biological interpretation of the data. RESULTS: Leveraging recent developments in the statistical analysis of high-dimensional data, we developed a new Debiased Sparse Partial Correlation algorithm (DSPC) for estimating partial correlation networks and implemented it as a Java-based CorrelationCalculator program. We also introduce a new version of our previously developed tool Metscape that enables building and visualization of correlation networks. We demonstrate the utility of these tools by constructing biologically relevant networks and in aiding identification of unknown compounds. AVAILABILITY AND IMPLEMENTATION: http://metscape.med.umich.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Redes e Vias Metabólicas , Metabolômica/métodos , Modelos Biológicos , Adulto , Feminino , Humanos , Espectrometria de Massas/métodos , Pessoa de Meia-Idade
6.
Bioinformatics ; 30(15): 2239-41, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24713438

RESUMO

MOTIVATION: In recent years, metabolomics has emerged as an approach to perform large-scale characterization of small molecules in biological systems. Metabolomics posed a number of bioinformatics challenges associated in data analysis and interpretation. Genome-based metabolic reconstructions have established a powerful framework for connecting metabolites to genes through metabolic reactions and enzymes that catalyze them. Pathway databases and bioinformatics tools that use this framework have proven to be useful for annotating experimental metabolomics data. This framework can be used to infer connections between metabolites and diseases through annotated disease genes. However, only about half of experimentally detected metabolites can be mapped to canonical metabolic pathways. We present a new Cytoscape 3 plug-in, MetDisease, which uses an alternative approach to link metabolites to disease information. MetDisease uses Medical Subject Headings (MeSH) disease terms mapped to PubChem compounds through literature to annotate compound networks. AVAILABILITY AND IMPLEMENTATION: MetDisease can be downloaded from http://apps.cytoscape.org/apps/metdisease or installed via the Cytoscape app manager. Further information about MetDisease can be found at http://metdisease.ncibi.org CONTACT: akarnovs@med.umich.edu SUPPLEMENTARY INFORMATION: Supplementary Data are available at Bioinformatics online.


Assuntos
Doença/genética , Metabolômica/métodos , Bases de Dados de Compostos Químicos , Genoma Humano/genética , Humanos , Medical Subject Headings , Redes e Vias Metabólicas , Software
7.
Diabetes ; 57(11): 3136-44, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18678618

RESUMO

OBJECTIVE: Type 2 diabetes is a common complex disorder with environmental and genetic components. We used a candidate gene-based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to type 2 diabetes. RESEARCH DESIGN AND METHODS: In a case-control study of 1,161 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also from Finland. RESULTS: Using SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in PPARG, KCNJ11, and SLC2A2; identified significant SNPs in genes with previously reported associations (ENPP1 [rs2021966, P = 0.00026] and NRF1 [rs1882095, P = 0.00096]); and implicated novel genes, including RAPGEF1 (rs4740283, P = 0.00013) and TP53 (rs1042522, Arg72Pro, P = 0.00086), in type 2 diabetes susceptibility. CONCLUSIONS: Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Adulto , Idoso , Feminino , Finlândia , Frequência do Gene , Genes p53/genética , Genótipo , Transportador de Glucose Tipo 2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fator 1 Nuclear Respiratório/genética , Diester Fosfórico Hidrolases/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Pirofosfatases/genética
8.
J Clin Invest ; 118(7): 2620-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18521185

RESUMO

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Glicemia/análise , Glucose-6-Fosfatase/genética , Polimorfismo de Nucleotídeo Único , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Adulto , Idoso , Análise de Variância , Jejum/sangue , Finlândia , Seguimentos , Frequência do Gene , Genótipo , Humanos , Itália , Desequilíbrio de Ligação , Pessoa de Meia-Idade , População Branca/genética
9.
Nat Genet ; 40(5): 638-45, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18372903

RESUMO

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único
10.
Nat Genet ; 40(2): 161-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18193043

RESUMO

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Doença da Artéria Coronariana/genética , Lipídeos/genética , Triglicerídeos/genética , Alelos , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Simulação por Computador , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Frequência do Gene , Variação Genética , Genoma Humano , Haplótipos , Humanos , Funções Verossimilhança , Lipídeos/sangue , Cadeias de Markov , Polimorfismo de Nucleotídeo Único , Probabilidade , Fatores de Risco , Triglicerídeos/sangue
11.
Science ; 316(5829): 1341-5, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17463248

RESUMO

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Genoma Humano , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , DNA Intergênico , Feminino , Finlândia , Genes p16 , Genótipo , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Íntrons , Modelos Logísticos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade
12.
Diabetes ; 56(1): 256-64, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17192490

RESUMO

More than 120 published reports have described associations between single nucleotide polymorphisms (SNPs) and type 2 diabetes. However, multiple studies of the same variant have often been discordant. From a literature search, we identified previously reported type 2 diabetes-associated SNPs. We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium (r(2) > 0.8) with another typed SNP. Of the 114 SNPs examined, we followed up the 20 most significant SNPs (P < 0.10) on an additional 384 case subjects and 366 control subjects from a population-based study in Finland. In the combined data, we replicated association (P < 0.05) for 12 SNPs: PPARG Pro12Ala and His447, KCNJ11 Glu23Lys and rs5210, TNF -857, SLC2A2 Ile110Thr, HNF1A/TCF1 rs2701175 and GE117881_360, PCK1 -232, NEUROD1 Thr45Ala, IL6 -598, and ENPP1 Lys121Gln. The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association (P = 0.012). We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample (P = 0.03), although we also replicated 4 of 58 SNPs from genes that had only one previous report of association.


Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Polimorfismo de Nucleotídeo Único , Idoso , Glicemia/análise , Índice de Massa Corporal , Jejum , Feminino , Humanos , Lactente , Insulina/sangue , Masculino , Pessoa de Meia-Idade
13.
Hum Hered ; 63(1): 17-25, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17179727

RESUMO

OBJECTIVES: The purpose of this study was to examine carefully heterogeneity underlying evidence for linkage to type 2 diabetes (T2DM) on chromosome 6q from two sets of FUSION families. METHODS: Ordered subsets analysis (OSA) was performed on two sets of FUSION families. For OSA results showing significant improvement in evidence for linkage, T2DM-related phenotypes were compared between individuals with T2DM within the subset versus the complement. RESULTS: OSA analysis revealed 105 families with the highest average HDL to total cholesterol ratio (HDL ratio) that had strongly increased evidence for linkage (MLS = 7.91 at 78.0 cM; uncorrected p = 0.00002). Subjects with T2DM within this subset were significantly leaner, had lower fasting glucose, insulin, and C-peptide, and more favorable cardiovascular risk profile compared to the complement set of subjects with T2DM. OSA also revealed 33 families with the lowest average fasting insulin that had increased evidence for linkage at a second locus (MLS = 3.45 at 128 cM; uncorrected p = 0.017) coincident with quantitative trait locus linkage analysis results for fasting and 2-hour insulin in subjects without T2DM. CONCLUSIONS: These results suggest two diabetes susceptibility loci on chromosome 6q that may affect subsets of individuals with a milder form of T2DM.


Assuntos
HDL-Colesterol/sangue , Colesterol/sangue , Cromossomos Humanos Par 6/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Ligação Genética , Idoso , Feminino , Finlândia , Genótipo , Humanos , Insulina/sangue , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Locos de Características Quantitativas
14.
Diabetes ; 55(9): 2534-40, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16936201

RESUMO

Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r(2)< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Diabetes Mellitus Tipo 2/etiologia , Feminino , Finlândia , Glucoquinase/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transativadores/genética
15.
Diabetes ; 55(9): 2649-53, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16936217

RESUMO

Transcription factor 7-like 2 (TCF7L2) is part of the Wnt signaling pathway. Genetic variants within TCF7L2 on chromosome 10q were recently reported to be associated with type 2 diabetes in Icelandic, Danish, and American (U.S.) samples. We previously observed a modest logarithm of odds score of 0.61 on chromosome 10q, approximately 1 Mb from TCF7L2, in the Finland-United States Investigation of NIDDM Genetics study. We tested the five associated TCF7L2 single nucleotide polymorphism (SNP) variants in a Finnish sample of 1,151 type 2 diabetic patients and 953 control subjects. We confirmed the association with the same risk allele (P value <0.05) for all five SNPs. Our strongest results were for rs12255372 (odds ratio [OR] 1.36 [95% CI 1.15-1.61], P = 0.00026) and rs7903146 (1.33 [1.14-1.56], P = 0.00042). Based on the CEU HapMap data, we selected and tested 12 additional SNPs to tag SNPs in linkage disequilibrium with rs12255372. None of these SNPs showed stronger evidence of association than rs12255372 or rs7903146 (OR < or =1.26, P > or = 0.0054). Our results strengthen the evidence that one or more variants in TCF7L2 are associated with increased risk of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Fatores de Transcrição TCF/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteína 2 Semelhante ao Fator 7 de Transcrição
16.
Exp Eye Res ; 82(6): 1068-74, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16298363

RESUMO

Open angle glaucoma (OAG) is a complex disorder with varying etiologies due to multiple genes and environmental effects. This genetic heterogeneity can confound efforts to map loci. Increased homogeneity in a sample can be achieved using either ordered subset analysis (OSA) which groups families, or individual OSA (IOSA), which groups individuals based on disease related covariates. Recently, GLC1I was mapped to 15q11-13 in families with early adult onset of OAG. We tested for linkage to GLC1I in an independent sample of 167 individuals in 25 multiplex OAG families of European descent. We carried out nonparametric linkage analysis on the complete set of 25 families and obtained a maximum LOD score of 1.00 at 9.0 cM. Using mean age at diagnosis (AAD) across the affected individuals within each family to order the families as a proxy for age at onset, we found a maximum OSA LOD score of 2.09 (p=0.021) at 26.1 cM. The mean (+/-s.d.) AAD across the 14 earlier AAD families that contributed to the OSA LOD score was 50.6 years (+/-5.38); the mean AAD for the other 1210 later AAD families that did not contribute to the OSA LOD score (the high-AAD) was 61.7 years (+/-3.50). We also ran IOSA on our families using AAD as our covariate on which to subset affected individuals. The maximum LOD score was 1.01 at 14.3 cM when ordering subjects from early to late AAD. Ordered subset analysis of this sample has provided evidence of linkage close to the previously identified GLC1I glaucoma locus on 15q11-13 in families with middle-aged mean age at diagnosis.


Assuntos
Cromossomos Humanos Par 15/genética , Saúde da Família , Glaucoma/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico/métodos , Heterogeneidade Genética , Ligação Genética/genética , Marcadores Genéticos , Genótipo , Glaucoma/epidemiologia , Glaucoma de Ângulo Aberto/epidemiologia , Glaucoma de Ângulo Aberto/genética , Humanos , Escore Lod , Pessoa de Meia-Idade , Estatísticas não Paramétricas
17.
Genet Epidemiol ; 27(1): 53-63, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15185403

RESUMO

Etiologic heterogeneity is a fundamental feature of complex disease etiology; genetic linkage analysis methods to map genes for complex traits that acknowledge the presence of genetic heterogeneity are likely to have greater power to identify subtle changes in complex biologic systems. We investigate the use of trait-related covariates to examine evidence for linkage in the presence of heterogeneity. Ordered-subset analysis (OSA) identifies subsets of families defined by the level of a trait-related covariate that provide maximal evidence for linkage, without requiring a priori specification of the subset. We propose that examining evidence for linkage in the subset directly may result in a more etiologically homogeneous sample. In turn, the reduced impact of heterogeneity will result in increased overall evidence for linkage to a specific region and a more distinct lod score peak. In addition, identification of a subset defined by a specific trait-related covariate showing increased evidence for linkage may help refine the list of candidate genes in a given region and suggest a useful sample in which to begin searching for trait-associated polymorphisms. This method provides a means to begin to bridge the gap between initial identification of linkage and identification of the disease predisposing variant(s) within a region when mapping genes for complex diseases. We illustrate this method by analyzing data on breast cancer age of onset and chromosome 17q [Hall et al., 1990, Science 250:1684-1689]. We evaluate OSA using simulation studies under a variety of genetic models.


Assuntos
Mapeamento Cromossômico/métodos , Heterogeneidade Genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Modelos Genéticos , Neoplasias da Mama/genética , Simulação por Computador , Fatores de Confusão Epidemiológicos , Feminino , Humanos , Escore Lod , Masculino , Modelos Estatísticos , Núcleo Familiar , Sensibilidade e Especificidade
18.
Diabetes ; 53(3): 821-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14988269

RESUMO

The aim of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genes that predispose to type 2 diabetes or are responsible for variability in diabetes-related traits via a positional cloning and positional candidate gene approach. In a previously published genome-wide scan of 478 Finnish affected sibling pair (ASP) families (FUSION 1), the strongest linkage results were on chromosomes 20 and 11. We now report a second genome-wide scan using an independent set of 242 Finnish ASP families (FUSION 2), a detailed analysis of the combined set of 737 FUSION 1 + 2 families (495 updated FUSION 1 families), and fine mapping of the regions of chromosomes 11 and 20. The strongest FUSION 2 linkage results were on chromosomes 6 (maximum logarithm of odds score [MLS] = 2.30 at 95 cM) and 14 (MLS = 1.80 at 57 cM). For the combined FUSION 1 + 2 families, three results were particularly notable: chromosome 11 (MLS = 2.98 at 82 cM), chromosome 14 (MLS = 2.74 at 58 cM), and chromosome 6 (MLS = 2.66 at 96 cM). We obtained smaller FUSION 1 + 2 MLSs on chromosomes X (MLS = 1.27 at 152 cM) and 20p (MLS = 1.21 at 20 cM). Among the 10 regions that showed nominally significant evidence for linkage in FUSION 1, four (on chromosomes 6, 11, 14, and X) also showed evidence for linkage in FUSION 2 and stronger evidence for linkage in the combined FUSION 1 + 2 sample.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Idade de Início , Idoso , Sequência de Bases , Constituição Corporal , Primers do DNA , Família , Feminino , Finlândia , Marcadores Genéticos , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Irmãos
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