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1.
JAMA Neurol ; 72(2): 209-16, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25531812

RESUMO

IMPORTANCE: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. CONCLUSIONS AND RELEVANCE: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fatores de Proteção , Suécia/epidemiologia , Estados Unidos/epidemiologia
2.
BioData Min ; 7(1): 35, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25649863

RESUMO

BACKGROUND: Identifying genetic interactions in data obtained from genome-wide association studies (GWASs) can help in understanding the genetic basis of complex diseases. The large number of single nucleotide polymorphisms (SNPs) in GWASs however makes the identification of genetic interactions computationally challenging. We developed the Bayesian Combinatorial Method (BCM) that can identify pairs of SNPs that in combination have high statistical association with disease. RESULTS: We applied BCM to two late-onset Alzheimer's disease (LOAD) GWAS datasets to identify SNPs that interact with known Alzheimer associated SNPs. We also compared BCM with logistic regression that is implemented in PLINK. Gene Ontology analysis of genes from the top 200 dataset SNPs for both GWAS datasets showed overrepresentation of LOAD-related terms. Four genes were common to both datasets: APOE and APOC1, which have well established associations with LOAD, and CAMK1D and FBXL13, not previously linked to LOAD but having evidence of involvement in LOAD. Supporting evidence was also found for additional genes from the top 30 dataset SNPs. CONCLUSION: BCM performed well in identifying several SNPs having evidence of involvement in the pathogenesis of LOAD that would not have been identified by univariate analysis due to small main effect. These results provide support for applying BCM to identify potential genetic variants such as SNPs from high dimensional GWAS datasets.

3.
Vaccine ; 31(46): 5381-91, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-24075919

RESUMO

The influence of genetic variability within the major histocompatibility complex (MHC) region on variations in immune responses to childhood vaccination was investigated. The study group consisted of 135 healthy infants who had been immunized with hepatitis B (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using Illumina Goldengate MHC panels (Mapping and Exon Centric). At the 1 year post vaccination check-up total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. A number of single nucleotide polymorphisms (SNPs) within MHC Class I and II genes were found to be associated with variations in the vaccine specific antibody responses and serum levels of immunoglobulins (IgG, IgM) and IgG isotypes (IgG1, IgG4) (all at p<0.001). Linkage disequilibrium patterns and functional annotations showed that significant SNPs were strongly correlated with other functional regulatory SNPs. These SNPs were found to regulate the expression of a group of genes involved in antigen processing and presentation including HLA-A, HLA-C, HLA-G, HLA-H, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DOB, and TAP-2. The results suggest that genetic variations within particular MHC genes can influence immune response to common childhood vaccinations, which in turn may influence vaccine efficacy.


Assuntos
Vacinas contra Difteria, Tétano e Coqueluche Acelular/imunologia , Vacinas contra Hepatite B/imunologia , Complexo Principal de Histocompatibilidade , Vacinas Pneumocócicas/imunologia , Polimorfismo de Nucleotídeo Único , Anticorpos Antibacterianos/sangue , Vacinas contra Difteria, Tétano e Coqueluche Acelular/administração & dosagem , Feminino , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Vacina Pneumocócica Conjugada Heptavalente , Humanos , Lactente , Masculino , Vacinas Pneumocócicas/administração & dosagem
4.
Autoimmune Dis ; 2013: 761046, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23509613

RESUMO

Background. The persistent presence of antiphospholipid antibodies (APA) may lead to the development of primary or secondary antiphospholipid syndrome. Although the genetic basis of APA has been suggested, the identity of the underlying genes is largely unknown. In this study, we have performed a genome-wide association study (GWAS) in an effort to identify susceptibility loci/genes for three main APA: anticardiolipin antibodies (ACL), lupus anticoagulant (LAC), and anti- ß 2 glycoprotein I antibodies (anti- ß 2GPI). Methods. DNA samples were genotyped using the Affymetrix 6.0 array containing 906,600 single-nucleotide polymorphisms (SNPs). Association of SNPs with the antibody status (positive/negative) was tested using logistic regression under the additive model. Results. We have identified a number of suggestive novel loci with P < E - 05. Although they do not meet the conservative threshold of genome-wide significance, many of the suggestive loci are potential candidates for the production of APA. We have replicated the previously reported associations of HLA genes and APOH with APA but these were not the top loci. Conclusions. We have identified a number of suggestive novel loci for APA that will stimulate follow-up studies in independent and larger samples to replicate our findings.

5.
J Gerontol A Biol Sci Med Sci ; 68(7): 760-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23213029

RESUMO

This study focuses on the participants of the Long Life Family Study to elucidate whether biogenetic mechanisms underlying relationships among heritable complex phenotypes in parents function in the same way for the same phenotypes in their children. Our results reveal 3 characteristic groups of relationships among phenotypes in parents and children. One group composed of 3 pairs of phenotypes confirms that associations among some phenotypes can be explained by the same biogenetic mechanisms working in parents and children. Two other groups including 9 phenotype pairs show that this is not a common rule. Our findings suggest that biogenetic mechanisms underlying relationships among different phenotypes, even if they are causally related, can function differently in successive generations or in different age groups of biologically related individuals. The results suggest that the role of aging-related processes in changing environment may be conceptually underestimated in current genetic association studies using genome wide resources.


Assuntos
Crianças Adultas , Envelhecimento/genética , Epigênese Genética , Predisposição Genética para Doença , Pais , Idoso , Idoso de 80 Anos ou mais , Meio Ambiente , Feminino , Genótipo , Humanos , Longevidade/genética , Masculino , Pessoa de Meia-Idade , Fenótipo
6.
Am J Neurodegener Dis ; 1(2): 191-8, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22984654

RESUMO

Late-onset Alzheimer's disease (LOAD) is a complex and multifactorial disease. So far ten loci have been identified for LOAD, including APOE, PICALM, CLU, BIN1, CD2AP, CR1, CD33, EPHA1, ABCA7, and MS4A4A/MS4A6E, but they explain about 50% of the genetic risk and thus additional risk genes need to be identified. Amyloid beta (Aß) plaques develop in the brains of LOAD patients and are considered to be a pathological hallmark of this disease. Recently 12 new Aß toxicity modifier genes (ADSSL1, PICALM, SH3KBP1, XRN1, SNX8, PPP2R5C, FBXL2, MAP2K4, SYNJ1, RABGEF1, POMT2, and XPO1) have been identified that potentially play a role in LOAD risk. In this study, we have examined the association of 222 SNPs in these 12 candidate genes with LOAD risk in 1291 LOAD cases and 958 cognitively normal controls. Single site and haplotype analyses were performed using PLINK. Following adjustment for APOE genotype, age, sex, and principal components, we found single nucleotide polymorphisms (SNPs) in PPP2R5C, PICALM, SH3KBP1, XRN1, and SNX8 that showed significant association with risk of LOAD. The top SNP was located in intron 3 of PPP2R5C (P=0.009017), followed by an intron 19 SNP in PICALM (P=0.0102). Haplotype analysis revealed significant associations in ADSSL1, PICALM, PPP2R5C, SNX8, and SH3KBP1 genes. Our data indicate that genetic variation in these new candidate genes affects the risk of LOAD. Further investigation of these genes, including additional replication in other case-control samples and functional studies to elucidate the pathways by which they affect Aß, are necessary to determine the degree of involvement these genes have for LOAD risk.

7.
Neurology ; 79(3): 221-8, 2012 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-22722634

RESUMO

OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.


Assuntos
Doença de Alzheimer/genética , Química Encefálica/genética , Expressão Gênica/fisiologia , Idoso , Alelos , Apolipoproteína E4/genética , Autopsia , Feminino , Dosagem de Genes , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Lineares , Masculino , Polimorfismo de Nucleotídeo Único , RNA/genética , RNA/isolamento & purificação , Fatores de Risco , Lobo Temporal/metabolismo
8.
Am J Respir Crit Care Med ; 186(2): 140-6, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22652028

RESUMO

RATIONALE: Vitamin D insufficiency (a serum 25(OH)D <30 ng/ml) has been associated with severe asthma exacerbations, but this could be explained by underlying racial ancestry or disease severity. Little is known about vitamin D and asthma in Puerto Ricans. OBJECTIVES: To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors. METHODS: A cross-sectional study was conducted of 560 children ages 6-14 years with (n = 287) and without (n = 273) asthma in San Juan, Puerto Rico. We measured plasma vitamin D and estimated the percentage of African racial ancestry among participants using genome-wide genotypic data. We tested whether vitamin D insufficiency is associated with severe asthma exacerbations, lung function, or atopy (greater than or equal to one positive IgE to allergens) using logistic or linear regression. Multivariate models were adjusted for African ancestry, time outdoors, atopy, and other covariates. MEASUREMENTS AND MAIN RESULTS: Vitamin D insufficiency was common in children with (44%) and without (47%) asthma. In multivariate analyses, vitamin D insufficiency was associated with higher odds of greater than or equal to one severe asthma exacerbation in the prior year (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.9; P = 0.001) and atopy, and a lower FEV(1)/FVC in cases. After stratification by atopy, the magnitude of the association between vitamin D insufficiency and severe exacerbations was greater in nonatopic (OR, 6.2; 95% CI, 2-21.6; P = 0.002) than in atopic (OR, 2; 95% CI, 1-4.1; P = 0.04) cases. CONCLUSIONS: Vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, or markers of disease severity or control.


Assuntos
Asma/etiologia , Deficiência de Vitamina D/complicações , Adolescente , Criança , Grupos de Populações Continentais , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Análise Multivariada , Porto Rico , Testes de Função Respiratória , Índice de Gravidade de Doença , Vitamina D/sangue
9.
J Allergy Clin Immunol ; 129(6): 1484-90.e6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22560959

RESUMO

BACKGROUND: Puerto Rican and African American subjects share a significant proportion of African ancestry. Recent findings suggest that African ancestry influences lung function in African American adults. OBJECTIVE: We sought to examine whether a greater proportion of African ancestry is associated with lower FEV(1) and forced vital capacity (FVC) in Puerto Rican children independently of socioeconomic status, health care access, or key environmental/lifestyle factors. METHODS: We performed a cross-sectional case-control study of 943 Puerto Rican children aged 6 to 14 years with (n= 520) and without (n= 423) asthma (defined as physician-diagnosed asthma and wheeze in the prior year) living in Hartford, Connecticut (n= 383), and San Juan, Puerto Rico (n= 560). We estimated the percentage of African racial ancestry in study participants using genome-wide genotypic data. We tested whether African ancestry is associated with FEV(1) and FVC using linear regression. Multivariate models were adjusted for indicators of socioeconomic status and health care and selected environmental/lifestyle exposures. RESULTS: After adjustment for household income and other covariates, each 20% increment in African ancestry was significantly associated with lower prebronchodilator FEV(1) (-105 mL; 95% CI, -159 to -51 mL; P< .001) and FVC (-133 mL; 95% CI, -197 to -69 mL; P< .001) and postbronchodilator FEV(1) (-152 mL; 95% CI, -210 to -94 mL; P< .001) and FVC (-145 mL; 95% CI, -211 to -79 mL; P< .001) in children with asthma. Similar but weaker associations were found for prebronchodilator and postbronchodilator FEV(1) (change for each 20% increment in African ancestry, -78 mL; 95% CI, -131 to -25 mL; P= .004) and for postbronchodilator FVC among children without asthma. CONCLUSIONS: Genetic factors, environmental/lifestyle factors, or both correlated with African ancestry might influence childhood lung function in Puerto Rican subjects.


Assuntos
Grupo com Ancestrais do Continente Africano , Asma/etnologia , Asma/fisiopatologia , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Porto Rico/epidemiologia , Testes de Função Respiratória , Capacidade Vital
10.
Circulation ; 125(18): 2232-42, 2012 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-22499950

RESUMO

BACKGROUND: Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. METHODS AND RESULTS: We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. CONCLUSIONS: Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.


Assuntos
Transtornos da Motilidade Ciliar/epidemiologia , Cardiopatias Congênitas/epidemiologia , Síndrome de Heterotaxia/epidemiologia , Anormalidades do Sistema Respiratório/epidemiologia , Adolescente , Adulto , Dineínas do Axonema/genética , Testes Respiratórios , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/genética , Proteínas do Citoesqueleto , Feminino , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia/genética , Humanos , Lactente , Masculino , Microscopia de Vídeo , Pessoa de Meia-Idade , Mutação , Óxido Nítrico/análise , Prevalência , Proteínas/genética , Anormalidades do Sistema Respiratório/genética , Adulto Jovem
11.
Nat Genet ; 43(5): 436-41, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21460841

RESUMO

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Proteínas do Citoesqueleto/genética , Proteínas de Membrana/genética , Receptor EphA1/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Família Multigênica , Polimorfismo de Nucleotídeo Único , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
12.
Gut ; 60(1): 77-84, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21148579

RESUMO

OBJECTIVE: To compare patients with chronic pancreatitis (CP) with constant pain patterns to patients with CP with intermittent pain patterns. METHODS: This was a prospective cohort study conducted at 20 tertiary medical centers in the USA comprising 540 subjects with CP. Patients with CP were asked to identify their pain from five pain patterns (A-E) defined by the temporal nature (intermittent or constant) and the severity of the pain (mild, moderate or severe). Pain pattern types were compared with respect to a variety of demographic, quality of life (QOL) and clinical parameters. Rates of disability were the primary outcome. Secondary outcomes included: use of pain medications, days lost from school or work, hospitalisations (preceding year and lifetime) and QOL as measured using the Short Form-12 (SF-12) questionnaire. RESULTS: Of the 540 CP patients, 414 patients (77%) self-identified with a particular pain pattern and were analysed. Patients with constant pain, regardless of severity, had higher rates of disability, hospitalisation and pain medication use than patients with intermittent pain. Patients with constant pain had lower QOL (by SF-12) compared with patients who had intermittent pain. Additionally, patients with constant pain were more likely to have alcohol as the aetiology for their pancreatitis. There was no association between the duration of the disease and the quality or severity of the pain. CONCLUSIONS: This is the largest study ever conducted of pain in CP. These findings suggest that the temporal nature of pain is a more important determinant of health-related QOL and healthcare utilisation than pain severity. In contrast to previous studies, the pain associated with CP was not found to change in quality over time. These results have important implications for improving our understanding of the mechanisms underlying pain in CP and for the goals of future treatments and interventions.


Assuntos
Recursos em Saúde/estatística & dados numéricos , Dor/etiologia , Pancreatite Crônica/complicações , Qualidade de Vida , Absenteísmo , Adulto , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Doença Crônica , Avaliação da Deficiência , Métodos Epidemiológicos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Medição da Dor/métodos , Pancreatite Crônica/epidemiologia , Fumar/efeitos adversos , Fumar/epidemiologia , Estados Unidos/epidemiologia
13.
Headache ; 50(6): 955-62, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20412323

RESUMO

INTRODUCTION: Migraine is thought to be genetically complex. There is evidence of an X-linked dominant genetic component. A locus at Xq24-q28 has already been described supporting this hypothesis. METHODS: The X chromosome in 61 migraine families was screened using markers spanning the entire chromosome. Alleles were assigned using the GeneScan Analysis software, analysis for affected relative allele sharing and linkage was performed using Genehunter X and ALLEGRO. For linkage analysis we chose a model based on epidemiological data as well as assumptions drawn on other complex disorders. RESULTS: Linkage analysis of combined families showed a parametric 2-point logarithm of the odds (LOD) of 2.86 at theta 0.1 between markers DXS8051 and DXS1223, as well as excess allele sharing at marker DXS8051 with a non-parametric LOD score of 2.85. CONCLUSION: These results provide suggestive evidence for a susceptibility locus for migraine on Xp22. Families with different types of migraine contributed to this LOD score.


Assuntos
Cromossomos Humanos X/genética , Loci Gênicos , Transtornos de Enxaqueca/genética , Alelos , Família , Ligação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Escore Lod
14.
Mech Ageing Dev ; 131(3): 215-22, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20184914

RESUMO

While there is evidence that longevity runs in families, the study of long-lived families is complicated by the fact that longevity-related information is available only for the oldest old, many of whom may be deceased and unavailable for testing, and information on other living family members, primarily descendents, is censored. This situation requires a creative approach for analyzing determinants of longevity in families. There are likely biomarkers that predict an individual's longevity, suggesting the possibility that those biomarkers which are heritable may constitute valuable endophenotypes for exceptional survival. These endophenotypes could be studied in families to identify human longevity genes and elucidate possible mechanisms of their influence on longevity. In this paper, we analyze data collected in the Long Life Family Study (LLFS) investigating whether indicators of physiological state, cognitive functioning and health/well-being among offspring predict longevity in parents. Good predictors can be used as endophenotypes for exceptional survival. Our analyses revealed significant associations between cumulative indices describing physiological state, as well as a number of offspring phenotypes, and parental lifespan, supporting both their familial basis and relevance to longevity. We conclude that the study of endophenotypes within families is a valid approach to the genetics of human longevity.


Assuntos
Família/psicologia , Longevidade/genética , Pais , Relações Familiares , Serviços de Saúde , Humanos , Masculino , Pesquisa , Sobrevida
15.
AMIA Annu Symp Proc ; 2010: 127-31, 2010 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-21346954

RESUMO

This paper compares the predictive performance and efficiency of several machine-learning methods when applied to a genome-wide dataset on Alzheimer's disease that contains 312,318 SNP measurements on 1411 cases. In particular, a Bayesian algorithm is introduced and compared to several standard machine-learning methods. The results show that the Bayesian algorithm predicts outcomes comparably to the standard methods, and it requires less total training time. These results support the further development and evaluation of the Bayesian algorithm.


Assuntos
Algoritmos , Teorema de Bayes , Genoma , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico
16.
Eur J Hum Genet ; 14(10): 1097-105, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16773128

RESUMO

The gamma-actin gene (ACTG1) encodes a major cytoskeletal protein of the sensory hair cells of the cochlea. Recently, mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing impairment linked to the DFNA20/26 locus on chromosome 17q25.3 in four American families and in one Dutch family. We report here the linkage of autosomal dominant, progressive, sensorineural hearing impairment in a large Norwegian family to the DFNA20/26 locus. Sequencing of ACTG1 identified a novel missense mutation (c.1109T>C; p.V370A) segregating with the hearing loss. Functional analysis in yeast showed that the p.V370A mutation restricts cell growth at elevated temperature or under hyperosmolar stress. Molecular modelling suggested that the p.V370A mutation modestly alters a site for protein-protein interaction in gamma-actin and thereby modestly alters gamma-actin-based cytoskeletal structures. Nineteen Norwegian and Danish families with autosomal, dominant hearing impairment were analyzed for mutations in ACTG1 by sequencing, but no disease-associated mutations were identified. Finally, a long-term follow-up of the hearing loss progression associated with the p.V370A mutation in ACTG1 is provided. The present study expands our understanding of the genotype-phenotype relationship of this deafness gene and provides a sensitive and simple functional assay for missense mutations in this gene, which may assist future molecular diagnosis of autosomal-dominant hearing impairment. Finally, the present results do not indicate that mutations in ACTG1 are a frequent cause of autosomal-dominant postlingual sensorineural hearing impairment in Norway nor Denmark.


Assuntos
Actinas/genética , Perda Auditiva Neurossensorial/genética , Mutação de Sentido Incorreto/genética , Análise Mutacional de DNA , Seguimentos , Genes Dominantes , Noruega , Linhagem , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento
18.
Inflamm Bowel Dis ; 11(1): 1-7, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15674107

RESUMO

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. PATIENTS AND METHODS: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. RESULTS: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P

Assuntos
Cromossomos Humanos Par 14 , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Fumar/efeitos adversos , Adolescente , Adulto , Idade de Início , Estudos de Coortes , Meio Ambiente , Feminino , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Linhagem , Locos de Características Quantitativas , Irmãos
19.
JOP ; 5(6): 457-63, 2004 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-15536282

RESUMO

CONTEXT: Alterations of the renin-angiotensin system have been implicated in the pathogenesis of various diseases. The angiotensin converting enzyme is a key enzyme in the renin-angiotensin system. A deletion polymorphism of a 287-bp fragment of intron 16 of the angiotensin converting enzyme gene allele results in higher levels of circulating enzyme. ACE deletion genotype has been linked to heart diseases, sarcoidosis and liver fibrosis. The pancreatic renin-angiotensin system plays a role in the development of pancreatic fibrosis and ACE inhibitors decrease pancreatic fibrosis in experimental models. OBJECTIVES: We investigated the frequency of the ACE gene insertion/deletion polymorphism in chronic pancreatitis patients and controls. PATIENTS: Subjects with familial pancreatitis (n=51), sporadic chronic pancreatitis (n=104), and healthy controls (n=163) were evaluated. MAIN OUTCOME MEASURE: The presence of ACE insertion/deletion polymorphism. RESULTS: The frequency of the ACE gene deletion allele was similar in familial pancreatitis (49.0%) sporadic pancreatitis (51.0%) and controls (55.8%). Furthermore, there was no significant difference in clinical features between patients with ACE-insertion or insertion/deletion genotypes vs. patients with ACE-deletion genotype. CONCLUSION: We conclude that the ACE deletion genotype does not make a significant contribution to the pathogenesis and the progression of chronic pancreatitis.


Assuntos
Pancreatite/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Alelos , Calcinose/epidemiologia , Calcinose/genética , Doença Crônica , Análise Mutacional de DNA , Progressão da Doença , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Pancreatopatias/epidemiologia , Pancreatopatias/genética , Ductos Pancreáticos/anormalidades , Pseudocisto Pancreático/epidemiologia , Pseudocisto Pancreático/genética , Pancreatite/epidemiologia , Peptidil Dipeptidase A/fisiologia , Sistema Renina-Angiotensina/fisiologia , Deleção de Sequência
20.
Am J Hum Genet ; 73(2): 420-9, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12840782

RESUMO

Hypertensive nephropathy (HN) and focal segmental glomerulosclerosis (FSGS) are significant causes of end-stage renal disease (ESRD), but no genes or loci have been associated with this phenotype among African Americans, a group at high risk. We performed a genomewide linkage scan with approximately 400 microsatellite markers on 23 individuals of a large four-generation African American family with 18 affected individuals (7 with ESRD), in which the 13-year-old proband (also with ESRD) presented with hypertension and proteinuria (2-4 g/day) and underwent a kidney biopsy that revealed FSGS-like lesions with arteriolar thickening. A genomewide scan revealed LOD scores of >2.5 for markers on chromosomes 3 and 9, and fine mapping was performed on 5 additional members (total 28 members) that showed a maximum multipoint LOD score of 5.4 in the 9q31-q32 region, under an autosomal dominant model with 99% penetrance. This 8-cM (6-Mb) region is flanked by markers D9S172 and D9S105, and further candidate gene sequencing studies excluded the coding regions of three genes (ACTL7A, ACTL7B, and CTNNAL1). To our knowledge, this is the first report of a locus, denoted as "HNP1," for the HN/FSGS phenotype in a large African American family with dominantly inherited nephropathy characterized by ESRD, hypertension, and some features of FSGS.


Assuntos
Cromossomos Humanos Par 9/genética , Hipertensão Renal/genética , Afro-Americanos , Sequência de Bases , Mapeamento Cromossômico , DNA/genética , Feminino , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Hipertensão Renal/patologia , Escore Lod , Masculino , Mutação , Linhagem
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