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1.
BMC Public Health ; 19(1): 1039, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375074

RESUMO

BACKGROUND: Interventions in India to improve menstrual health and hygiene management (MHHM) have been implemented at the national, state, district and school level. However, evaluations of these interventions have been scarce. The objective of the study was to determine if a social and behavioral change communication (SBCC) intervention (GARIMA) had a relationship with knowledge, attitudes, interpersonal communication, restrictions and MHHM using a comparison group post-test only design among 2206 adolescent girls. METHODS: Intervention villages and adolescent girls were selected through stratified random sampling based on where GARIMA was implemented. Villages and adolescent girls in comparison villages were matched socio-demographically to intervention villages and adolescent girls. Multi-level logistic regressions assessed the relationship between the encoded exposure, mediators and MHHM. RESULTS: The results showed that the encoded exposure predicted all behaviors corresponding to MHHM. Additionally, adolescent girls in the high encoded exposure group had significantly higher knowledge about puberty and reproductive parts (AOR: 2.03 (95% CI: 1.31 - 3.15)), positive attitudes towards gender (AOR: 1.48 (95% CI: 1.02 - 2.16)) and higher levels of some discussion and dialogue (AOR: 1.41 (95% CI: 1.04 - 1.92)). CONCLUSIONS: Future programs should use SBCC to improve MHHM behavior but involve families, peers and community members to a greater extent in order to improve attitudes towards menstruation, attitudes towards restrictions, attitudes towards absorbent use and reduce restrictions within the community.

2.
Genet Med ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30293986

RESUMO

PURPOSE: Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test. METHODS: We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases. RESULTS: We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs. CONCLUSION: Robust identification of CNVs by GS is possible within a clinical testing environment.

3.
Front Pharmacol ; 9: 305, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29674966

RESUMO

The CYP2D6 gene encodes an enzyme important in the metabolism of many commonly used medications. Variation in CYP2D6 is associated with inter-individual differences in medication response, and genetic testing is used to optimize medication therapy. This report describes a retrospective study of CYP2D6 allele frequencies in a large population of 104,509 de-identified patient samples across all regions of the United States (US). Thirty-seven unique CYP2D6 alleles including structural variants were identified. A majority of these alleles had frequencies which matched published frequency data from smaller studies, while eight had no previously published frequencies. Importantly, CYP2D6 structural variants were observed in 13.1% of individuals and accounted for 7% of the total variants observed. The majority of structural variants detected (73%) were decreased-function or no-function alleles. As such, structural variants were found in approximately one-third (30%) of CYP2D6 poor metabolizers in this study. This is the first CYP2D6 study to evaluate, with a consistent methodology, both structural variants and single copy alleles in a large US population, and the results suggest that structural variants have a substantial impact on CYP2D6 function.

4.
Hum Mutat ; 39(2): 281-291, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29193635

RESUMO

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.

5.
Circ Cardiovasc Genet ; 10(6)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29237685

RESUMO

BACKGROUND: Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. METHODS AND RESULTS: Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; P=3.5×10-11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ≈7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in APOC3 (rs147210663) and 3 established functional SNPs in APOA5. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (ß=-0.92±0.059 SD unit; P=9.6×10-55 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 APOA5 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null. CONCLUSIONS: APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants.


Assuntos
Apolipoproteína C-III/genética , Efeito Fundador , Estudo de Associação Genômica Ampla , Índios Norte-Americanos/genética , Mutação , Triglicerídeos/sangue , Apolipoproteína A-V/genética , Cromossomos Humanos Par 11/genética , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único
6.
J Health Commun ; 22(1): 66-74, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28060582

RESUMO

Entertainment-education is an effective health communication strategy that combines or embeds educational messages into entertainment programs to bring about social and behavior change. For years, scholars have considered how entertainment-education works. Some contemporary theories posit that entertainment-education does not engender behavior change directly but does so through mediating variables. This study adds to the literature on this topic by exploring the direct relationship between exposure and social norms instead of their relationship through behavior as a mediator. Novel to this study is the use of encoded exposure, a continuous and recognition-based measure of exposure that includes ever watching, recall, involvement, and dose in its operationalization. Using cross-sectional data from Kyunki … Jeena Issi Ka Naam Hai, an entertainment-education program in India, this exploratory analysis indicates a positive and significant relationship between encoded exposure and social norms. How can this finding be applied to future programs? Questions remain, and replication is needed, but if it is not essential to go through behavior in order to change social norms, then implications emerge for the theory and practice of entertainment-education.


Assuntos
Comunicação em Saúde/métodos , Educação em Saúde/métodos , Normas Sociais , Televisão/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Índia , Inquéritos e Questionários
7.
PLoS Genet ; 11(8): e1005352, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26305897

RESUMO

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.


Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Afro-Americanos/genética , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Índios Norte-Americanos/genética , Proteínas de Ligação a RNA/genética , Estados Unidos
9.
PLoS One ; 9(7): e102544, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25014012

RESUMO

BACKGROUND: Genotype imputation is commonly used in genetic association studies to test untyped variants using information on linkage disequilibrium (LD) with typed markers. Imputing genotypes requires a suitable reference population in which the LD pattern is known, most often one selected from HapMap. However, some populations, such as American Indians, are not represented in HapMap. In the present study, we assessed accuracy of imputation using HapMap reference populations in a genome-wide association study in Pima Indians. RESULTS: Data from six randomly selected chromosomes were used. Genotypes in the study population were masked (either 1% or 20% of SNPs available for a given chromosome). The masked genotypes were then imputed using the software Markov Chain Haplotyping Algorithm. Using four HapMap reference populations, average genotype error rates ranged from 7.86% for Mexican Americans to 22.30% for Yoruba. In contrast, use of the original Pima Indian data as a reference resulted in an average error rate of 1.73%. CONCLUSIONS: Our results suggest that the use of HapMap reference populations results in substantial inaccuracy in the imputation of genotypes in American Indians. A possible solution would be to densely genotype or sequence a reference American Indian population.


Assuntos
Genoma Humano , Genótipo , Índios Norte-Americanos , Polimorfismo de Nucleotídeo Único , Software , Algoritmos , Mapeamento Cromossômico , Frequência do Gene , Estudo de Associação Genômica Ampla , Projeto HapMap , Humanos , Desequilíbrio de Ligação , Estados Unidos
10.
Hum Mol Genet ; 22(21): 4438-49, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23825110

RESUMO

To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10(-7) and 8.1 × 10(-7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10(-2)-10(-5)), and the combined P-values across both American Indians and Caucasian were P = 10(-4)-10(-9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation.


Assuntos
Índice de Massa Corporal , Hipotálamo/metabolismo , Inflamação/genética , MAP Quinase Quinase 3/genética , MAP Quinase Quinase 3/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Peso Corporal , Linhagem Celular , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hipotálamo/citologia , Hipotálamo/embriologia , Índios Norte-Americanos/genética , Estudos Longitudinais , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
11.
Obesity (Silver Spring) ; 21(1): 193-202, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23505186

RESUMO

OBJECTIVE: A genome-wide association study (GWAS) was recently completed in 1120 Pima Indians to identify loci that influence BMI. Among the top 100 signals were three variants that mapped within the lysophosphatidylglycerol acyltransferase 1 (LPGAT1) gene. LPGAT1 belongs to a large family of acyltransferases, which are involved in a variety of biological processes including pathways that regulate energy homeostasis and body weight. Therefore LPGAT1 was analyzed as a candidate gene for obesity in Pima Indians. DESIGN AND METHODS: Variants (n = 26) located within and adjacent to LPGAT1 including a novel 27bp deletion in the 5'-untranslated region identified by sequencing were genotyped in a population-based sample of 3,391 full-heritage Pima Indians living in the Gila River Indian Community. Replication of selected variants was assessed in a second sample of 3,327 mixed-heritage Native Americans from the same community. RESULTS: Variants with nominal associations with BMI in each of the two independent samples (tagged by rs112662024 and rs12058008) had associations of P = 1-4 × 10(-5) in the combined sample (n = 6718). A haplotype that includes the novel 27bp deletion, which does not occur in Caucasians, showed the strongest association with BMI in the full-heritage Pima Indians. In vitro functional studies provided suggestive evidence that this 27bp deletion may affect transcriptional or posttranscriptional regulation. Analysis of LPGAT1 cDNA from human preadipocytes identified an additional exon whose sequence could potentially serve as a mitochondrial targeting peptide. CONCLUSIONS: LPGAT1 is a novel gene that influences BMI in Native Americans.


Assuntos
Aciltransferases/genética , Tecido Adiposo , Índice de Massa Corporal , Índios Norte-Americanos/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Deleção de Sequência , Composição Corporal/genética , Peso Corporal , DNA Complementar , Metabolismo Energético , Éxons , Regulação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Íntrons , Mitocôndrias , Obesidade/etnologia , Peptídeos/genética , Transdução de Sinais
12.
Obesity (Silver Spring) ; 19(10): 2102-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21701565

RESUMO

Numerous studies have been done to understand genetic contributors to BMI, but only a limited number of studies have been done in nonwhite groups such as American Indians. A genome-wide association study (GWAS) for BMI was therefore performed in Pima Indians. BMI measurements from a longitudinal study of 1,120 Pima Indians and 454,194 single-nucleotide polymorphisms (SNPs) from the 1 million Affymetrix SNP panel were used (35% of SNPs were excluded due to minor allele frequency <0.05). Data included BMI measured at multiple examinations collected from 1965 to 2004, as well as the maximum BMI at one of these visits. General and within-family tests were performed using a maximum-likelihood based mixed model procedure. No SNP reached a genome-wide significance level (estimated at P < 4.94 × 10(-7)). For repeated measures analyses, the strongest associations for general and within-family tests mapped to two different regions on chromosome 6 (rs9342220 (P = 1.39 × 10(-6)) and rs7758764 (P = 2.51 × 10(-6)), respectively). For maximum BMI, the strongest association for the general tests mapped to chromosome 4 (rs17612333; P = 1.98 × 10(-6)) and to chromosome 3 (rs11127958; P = 1.53 × 10(-6)) for the within-family tests. Further analysis is important because only a few of these regions have been previously implicated in a GWAS and genetic susceptibility may differ by ethnicity.


Assuntos
Índice de Massa Corporal , Cromossomos Humanos , Genoma Humano , Índios Norte-Americanos/genética , Obesidade/etnologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Família , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Adulto Jovem
13.
Diabetes Metab Res Rev ; 25(8): 740-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19795399

RESUMO

BACKGROUND: Previous studies have shown that in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations. METHODS: Phenotypic and genotypic data were obtained from African American (AA; total number of individuals [N] = 1004), American Indian (AI; N = 883), European American (EA; N = 537), and Mexican American (MA; N = 1634) individuals from the Family Investigation of Nephropathy and Diabetes. Non-parametric linkage analysis, using an average of 4404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM. RESULTS: Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 regions showed suggestive evidence for linkage (estimated at LOD > 1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD = 2.02) and 22q12.3 (LOD = 2.38) in AA, 2p11.1 (LOD = 2.23) in AI, 6p12.3 (LOD = 2.77) in EA, and 13q21.1 (LOD = . 2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD > 1.71 have been identified in previously published studies. CONCLUSIONS: The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA; 6p in EA; 2p in AI; and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 4/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Adulto , Idoso , Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/etiologia , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Grupos Populacionais/genética , Estatística como Assunto
14.
Genet Epidemiol ; 31 Suppl 1: S43-50, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18046764

RESUMO

The complexity of data available in human genetics continues to grow at an explosive rate. With that growth, the challenges to understanding the meaning of the underlying information also grow. A currently popular approach to dissecting such information falls under the broad category of data mining. This can apply to any approach that tries to extract relevant information from large amounts of data, but often refers to methods that deal, in a non-linear fashion, with very large numbers of variables that cannot be simultaneously handled by more conventional statistical methods. To explore the usefulness of some of these approaches, 13 groups applied a variety of strategies to the first dataset provided to GAW 15 participants. With the extensive microarray and SNP data provided for 14 CEPH families, these groups explored multistage analyses, machine learning methods, network construction, and other techniques to try to answer questions about gene-gene interaction, functional similarities, co-regulated gene expression and the mapping of gene expression determinants, among others. In general, the methods offered strategies to provide a better understanding of the complex pathways involved in gene expression and function. These are still "works in progress," often exploratory in nature, but they provide insights into ways in which the data might be interpreted. Despite the still preliminary nature of some of these methods and the diversity of the approaches, some common themes emerged. The collection of papers and methods offer a starting point for further exploration of complex interactions in human genetic data now readily available.


Assuntos
DNA/genética , Genética Médica , RNA/genética , Teorema de Bayes , Ligação Genética , Impressão Genômica , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único
15.
Diabetes ; 56(3): 890-6, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17327462

RESUMO

Dyslipidemia is a major risk factor for coronary heart disease, which is the predominant cause of mortality in individuals with type 2 diabetes. To date, nine linkage studies for quantitative lipid traits have been performed in families ascertained for type 2 diabetes, individually yielding linkage results that were largely nonoverlapping. Discrepancies in linkage findings are not uncommon and are typically due to limited sample size and heterogeneity. To address these issues and increase the power to detect linkage, we performed a meta-analysis of all published genome scans for quantitative lipid traits conducted in families ascertained for type 2 diabetes. Statistically significant evidence (i.e., P < 0.00043) for linkage was observed for total cholesterol on 7q32.3-q36.3 (152.43-182 cM; P = 0.00004), 19p13.3-p12 (6.57-38.05 cM; P = 0.00026), 19p12-q13.13 (38.05-69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53-101.1 cM; P = 0.00033), as well as LDL on 19p13.3-p12 (P = 0.00041). Suggestive evidence (i.e., P < 0.00860) for linkage was also observed for LDL on 19p12-q13.13, triglycerides on 7p11-q21.11 (63.72-93.29 cM), triglyceride/HDL on 7p11-q21.11 and 19p12-q13.13, and LDL/HDL on 16q11.2-q24.3 (65.2-130.4 cM) and 19p12-q13.13. Linkage for lipid traits has been previously observed on both chromosomes 7 and 19 in several unrelated studies and, together with the results of this meta-analysis, provide compelling evidence that these regions harbor important determinants of lipid levels in individuals with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Ligação Genética/genética , Genoma Humano , Locos de Características Quantitativas/genética , Grupos de Populações Continentais , Feminino , Humanos , Masculino , Linhagem
16.
BMC Proc ; 1 Suppl 1: S160, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18466506

RESUMO

We performed a multipoint linkage analysis for rheumatoid arthritis (RA) using high-density single-nucleotide polymorphism (SNP) data for chromosome 6 and chromosome 21 using Genetic Analysis Workshop 15 (GAW15) data. These regions were previously shown to have high LOD scores, not accounting for linkage disequilibrium (LD). We propose three novel methods to control for LD in a linkage analysis: allow for LD between markers using graphical modeling, eliminate high-LD markers by principal-component analysis (PCA) using haplotype data, and eliminate high-LD markers by PCA using genotype data. All three novel methods were compared to the previously published SNPLINK high-LD elimination method. Although all four methods verified the previous results, differences in linkage peak height and position were observed across methods. Additional work is required to further understand the effects of LD on linkage results and explore LD control methodology.

17.
BMC Proc ; 1 Suppl 1: S48, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18466547

RESUMO

Extensive studies have been performed to analyze variation in gene expression data by using multistage approaches, including a combination of microarray and linkage analysis. Such a method was recently used in the analysis of normal variation in gene expression by Cheung et al. (Nat. Genet. 2003, 33: 422-425) and Morley et al. (Nature 2004, 430: 743-747). Using these data, we also explored a multistage method by first performing non-hierarchical clustering for 3554 genes, which identified 114 clusters with number of genes ranging from 2 to 113. Heritabilities of the first principal component of each cluster were then estimated and 29 highly heritable clusters (i.e., h2 > 0.35) were further analyzed using variance components linkage analysis. The highest LOD score was observed on chromosome 1 (LOD = 5.36, 111.71 cM) for a cluster containing two genes [glutathione S-transferase M1 (GSTM1) and glutathione S-transferase M2 (GSTM2)] that are both located on chromosome 1p13.3. These results show the method followed in our analysis of performing cluster analysis followed by linkage analysis is another useful approach to identify chromosomal locations for genes affecting expression levels of multiple transcripts.

18.
Hum Mol Genet ; 14(24): 3955-62, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16301214

RESUMO

Genetic influences on lipid traits have been suggested by numerous studies. In addition to heritability studies, over 50 genome scans have been performed to identify regions of linkage for quantitative lipid levels. Five of these scans have been performed in African Americans (four univariate and one bivariate linkage analysis), but with results that have been largely inconclusive. Linkage analyses are often limited by both sample size and heterogeneity, which may lead to nominal LOD scores or lack of evidence for linkage; the use of meta-analysis to combine linkage results from populations with similar ethnic backgrounds may help overcome some of these limitations. Thus, we performed a meta-analysis using data from four genome scans conducted in African American families to identify chromosomal regions showing evidence of linkage for total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL) and high density lipoprotein cholesterol (HDL). Significant evidence (i.e. P<0.00042) for linkage was found for LDL on chromosome 1q32.1-q41 (Pweighted=0.00014 and Punweighted=0.00007) and 1q41-q44 (Pweighted=0.00017 and Punweighted=0.00014). We found suggestive evidence (i.e. P<0.00847) for TG on 16p12.1-q11.2 and for HDL on 4p15.1-p11. We also assessed heterogeneity between studies and found significant evidence for low heterogeneity for both regions on chromosome 1q (P=0.0300 and P=0.0279, respectively) for LDL and chromosome 16 (P=0.0429) for TG. Statistically significant evidence for linkage and low heterogeneity on chromosome 1q therefore suggest that this region may harbor a gene underlying the inheritance of LDL in African Americans.


Assuntos
Afro-Americanos/genética , Ligação Genética , Genoma Humano , Lipídeos/genética , Grupo com Ancestrais do Continente Africano/genética , Colesterol/genética , HDL-Colesterol/genética , LDL-Colesterol/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 16 , Heterogeneidade Genética , Humanos , Locos de Características Quantitativas , Triglicerídeos/genética
19.
Diabetes ; 54(10): 3007-14, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16186406

RESUMO

Coronary heart disease (CHD) is the leading cause of death among individuals with type 2 diabetes. Dyslipidemia contributes significantly to CHD in diabetic patients, in whom lipid abnormalities include hypertriglyceridemia, low HDL cholesterol, and increased levels of small, dense LDL particles. To identify genes for lipid-related traits, we performed genome-wide linkage analyses for levels of triglycerides and HDL, LDL, and total cholesterol in Caucasian, Hispanic, and African-American families from the Genetics of NIDDM (GENNID) study. Most lipid traits showed significant estimates of heritability (P < 0.001) with the exception of triglycerides and the triglyceride/HDL ratio in African Americans. Variance components analysis identified linkage on chromosome 3p12.1-3q13.31 for the triglyceride/HDL ratio (logarithm of odds [LOD] = 3.36) and triglyceride (LOD = 3.27) in Caucasian families. Statistically significant evidence for linkage was identified for the triglyceride/HDL ratio (LOD = 2.45) on 11p in Hispanic families in a region that showed suggestive evidence for linkage (LOD = 2.26) for triglycerides in this population. In African Americans, the strongest evidence for linkage (LOD = 2.26) was found on 19p13.2-19q13.42 for total cholesterol. Our findings provide strong support for previous reports of linkage for lipid-related traits, suggesting the presence of genes on 3p12.1-3q13.31, 11p15.4-11p11.3, and 19p13.2-19q13.42 that may influence traits underlying lipid abnormalities associated with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Hiperlipidemias/genética , Característica Quantitativa Herdável , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 3/genética , Doença das Coronárias/etiologia , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Ligação Genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Humanos , Hiperlipidemias/complicações , Escore Lod , Masculino , Pessoa de Meia-Idade , Fenótipo , Sistema de Registros , Triglicerídeos/sangue
20.
J Hum Genet ; 50(2): 69-75, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15682273

RESUMO

Quantitative trait phenotypes and linked marker genotypes were simulated for a range of models with different sets of assumptions based on displacement, prevalence, and heritability of the trait in 30 Utah Centre d'Etude du Polymorphisme Humain (CEPH) families. The gain in power by the addition of 15 families was also estimated by extrapolation. Power was evaluated using both parametric single locus (PSL) models and variance components (VC) methods for two situations: (1) a single marker with 75% heterozygosity and a recombination fraction of 0.05, and (2) a fully informative marker as an approximation to multipoint analysis. When the simulation and analysis models were both dominant with the same prevalence, power > or =80% for lod >3 was estimated when quantitative trait locus variance was > or =40% with a displacement of 2.5 or 3. Power was 5-15% lower for recessive models compared to dominant models. With the addition of 15 families, an average increase in power of 17% and 22% was estimated for the dominant and recessive models, respectively. In PSL analyses, power was estimated at < or =20% when the dominance was misspecified. This investigation delineates parameter conditions under which this unique sample affords adequate power to detect linkage using both PSL and VC methods.


Assuntos
Ligação Genética , Genética Populacional , Modelos Teóricos , Genótipo , Humanos , Linhagem , Fenótipo , Característica Quantitativa Herdável , Sensibilidade e Especificidade , Utah
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