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1.
Bone Joint J ; 103-B(9): 1552, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34465161
2.
Bone Joint J ; 101-B(7_Supple_C): 48-54, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31256639

RESUMO

AIMS: The outcomes of total knee arthroplasty (TKA) depend on many factors. The impact of implant design on patient-reported outcomes is unknown. Our goal was to evaluate the patient-reported outcomes and satisfaction after primary TKA in patients with osteoarthritis undergoing primary TKA using five different brands of posterior-stabilized implant. PATIENTS AND METHODS: Using our institutional registry, we identified 4135 patients who underwent TKA using one of the five most common brands of implant. These included Biomet Vanguard (Zimmer Biomet, Warsaw, Indiana) in 211 patients, DePuy/Johnson & Johnson Sigma (DePuy Synthes, Raynham, Massachusetts) in 222, Exactech Optetrak Logic (Exactech, Gainesville, Florida) in 1508, Smith & Nephew Genesis II (Smith & Nephew, London, United Kingdom) in 1415, and Zimmer NexGen (Zimmer Biomet) in 779 patients. Patients were evaluated preoperatively using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lower Extremity Activity Scale (LEAS), and 12-Item Short-Form Health Survey questionnaire (SF-12). Demographics including age, body mass index, Charlson Comorbidity Index, American Society of Anethesiologists status, sex, and smoking status were collected. Postoperatively, two-year KOOS, LEAS, SF-12, and satisfaction scores were compared between groups. RESULTS: Outcomes were available for 4069 patients (98%) at two years postoperatively. In multiple regression analysis, which separately compared each implant group with the aggregate of all others, there were no clinically significant differences in the change of KOOS score from baseline to two-year follow-up between any of the groups. More than 80% of patients in each group were satisfied at this time in all domains. In a multivariate regression model, patients in the NexGen group were the most likely to be satisfied (odds ratio (OR) 1.63; p = 0.006) and Optetrak Logic patients were the least likely to be satisfied (OR 0.60; p < 0.001). CONCLUSION: TKA provides improvement in function and satisfaction regardless of the type of implant. We could not demonstrate superiority of one design above others across these groups of implants, and any price premium for one above the other systems may not be justified. Healthcare administrators may find these similarities in outcomes helpful when negotiating purchasing contracts. Cite this article: Bone Joint J 2019;101-B(7 Supple C):48-54.


Assuntos
Artroplastia do Joelho/métodos , Articulação do Joelho/cirurgia , Prótese do Joelho , Osteoartrite do Joelho/cirurgia , Medidas de Resultados Relatados pelo Paciente , Amplitude de Movimento Articular/fisiologia , Recuperação de Função Fisiológica/fisiologia , Idoso , Feminino , Seguimentos , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/fisiopatologia , Desenho de Prótese , Sistema de Registros , Estudos Retrospectivos , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
3.
Bone Joint J ; 101-B(6_Supple_B): 68-76, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31146558

RESUMO

AIMS: Custom flange acetabular components (CFACs) are a patient-specific option for addressing large acetabular defects at revision total hip arthroplasty (THA), but patient and implant characteristics that affect survivorship remain unknown. This study aimed to identify patient and design factors related to survivorship. PATIENTS AND METHODS: A retrospective review of 91 patients who underwent revision THA using 96 CFACs was undertaken, comparing features between radiologically failed and successful cases. Patient characteristics (demographic, clinical, and radiological) and implant features (design characteristics and intraoperative features) were collected. There were 74 women and 22 men; their mean age was 62 years (31 to 85). The mean follow-up was 24.9 months (sd 27.6; 0 to 116). Two sets of statistical analyses were performed: 1) univariate analyses (Pearson's chi-squared and independent-samples Student's t-tests) for each feature; and 2) bivariable logistic regressions using features identified from a random forest analysis. RESULTS: Radiological failure and revision rates were 23% and 12.5%, respectively. Revisions were undertaken at a mean of 25.1 months (sd 26.4) postoperatively. Patients with radiological failure were younger at the time of the initial procedure, were less likely to have a diagnosis of primary osteoarthritis (OA), were more likely to have had ischial screws in previous surgery, had fewer ischial screw holes in their CFAC design, and had more proximal ischial fixation. Random forest analysis identified the age of the patient and the number of locking and non-locking screws used for inclusion in subsequent bivariable logistic regression, but only age (odds ratio 0.93 per year) was found to be significant. CONCLUSION: We identified both patient and design features predictive of CFAC survivorship. We found a higher rate of failure in younger patients, those whose primary diagnosis was not OA, and those with more proximal ischial fixation or fewer ischial fixation options. Cite this article: Bone Joint J 2019;101-B(6 Supple B):68-76.


Assuntos
Acetábulo/cirurgia , Artroplastia de Quadril/métodos , Acetábulo/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/instrumentação , Parafusos Ósseos , Feminino , Prótese de Quadril , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/cirurgia , Desenho de Prótese , Falha de Prótese , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
4.
Oncogene ; 33(10): 1258-64, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-23503461

RESUMO

Epstein-Barr virus (EBV) has evolved exquisite controls over its host cells, human B lymphocytes, not only directing these cells during latency to proliferate and thereby expand the pool of infected cells, but also to survive and thereby persist for the lifetime of the infected individual. Although these activities ensure the virus is successful, they also make the virus oncogenic, particularly when infected people are immunosuppressed. Here we show, strikingly, that one set of EBV's microRNAs (miRNAs) both sustain Burkitt's lymphoma (BL) cells in the absence of other viral oncogenes and promote the transformation of primary B lymphocytes. BL cells were engineered to lose EBV and found to die by apoptosis and could be rescued by constitutively expressing viral miRNAs in them. Two of these EBV miRNAs were found to target caspase 3 to inhibit apoptosis at physiological concentrations.


Assuntos
Linfoma de Burkitt/patologia , Herpesvirus Humano 4/fisiologia , MicroRNAs/genética , Interferência de RNA , Apoptose , Linfócitos B/enzimologia , Linfócitos B/fisiologia , Linfócitos B/virologia , Sequência de Bases , Sítios de Ligação , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/virologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Antígenos Nucleares do Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos
5.
Hum Genet ; 128(5): 501-13, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20725740

RESUMO

To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex-genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype-sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.


Assuntos
Povo Asiático/genética , Obesidade/genética , Caracteres Sexuais , Adulto , Índice de Massa Corporal , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Havaí/epidemiologia , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Razão de Chances , Fenótipo , São Francisco/epidemiologia , Fatores Sexuais , Taiwan/epidemiologia
6.
Diabetologia ; 50(8): 1631-40, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17579830

RESUMO

AIMS/HYPOTHESIS: Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely. METHODS: We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Study. RESULTS: We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p = 0.0006); (2) fasting insulin and homeostasis model assessment of beta cell function (HOMA-beta) (empirical p = 0.0051); and (3) HOMA of insulin resistance (IR) and HOMA-beta (empirical p = 0.0044). In addition, the peak logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait for the pair fasting insulin and HOMA-IR rose to 5.10 (equivalent LOD score in univariate analysis, LOD([1]) = 4.01, empirical p = 8.0 x 10(-5)) from 3.67 and 3.42 respectively for these two traits in univariate analysis. Additional significant linkage evidence, not shown in single-trait analysis, was identified at 45 cM on chromosome 16 for the pair 1 h insulin and the AUC for insulin, with a LOD score of 4.29 (or LOD([1]) = 3.27, empirical p = 2.0 x 10(-4)). This new locus is also likely to harbour the common genes regulating these two traits (p = 1.73 x 10(-6)). CONCLUSIONS/INTERPRETATION: These data help provide a better understanding of the genomic structure underlying the metabolic syndrome.


Assuntos
Povo Asiático/genética , Genoma Humano , Hipertensão/genética , Resistência à Insulina/genética , Adulto , Análise de Variância , Glicemia/metabolismo , Índice de Massa Corporal , HDL-Colesterol/genética , Cromossomos Humanos Par 20/genética , Saúde da Família , Jejum , Feminino , Ligação Genética/genética , Genótipo , Humanos , Hipertensão/sangue , Escore Lod , Masculino , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Fenótipo , Locos de Características Quantitativas/genética
7.
Hum Genet ; 120(4): 501-18, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16953426

RESUMO

Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2-5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright's fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6-WNT10A and COL4A3-COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.


Assuntos
Cromossomos Humanos Par 2 , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Saúde da Família , Feminino , Frequência do Gene , Ligação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Maryland , Análise Multivariada , Núcleo Familiar , Singapura , Taiwan
8.
Mol Psychiatry ; 7(6): 658-64, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12140791

RESUMO

Information from multiple genome scans and collaborative efforts suggests that schizophrenia is a heterogeneous, complex disorder with polygenic and environmental antecedents. In a previous paper we demonstrated that stratification of families on the basis of co-segregating phenotypes (psychotic affective disorders (PAD) and schizophrenia spectrum personality disorders (SSPD) in first-degree relatives of schizophrenic probands increased linkage evidence in the chromosome 8p21 region (D8S1771) among families with co-segregating SSPD. We have now applied a method of conditional analysis of sib-pairs affected with schizophrenia, examining shared alleles identical-by-descent (IBD) at multiple loci. The method yields enhanced evidence for linkage to the chromosome 8p21 region conditioned upon increased allele sharing at a chromosome 14 region. The method produces a more refined estimate of the putative disease locus on chromosome 8p21, narrowing the region from 18 cM (95% confidence interval) in our previous genome scan, to approximately 9.6 cM. We have also shown that the affected siblings sharing two alleles IBD at the chromosome 8p21 region and one allele IBD at the chromosome 14 region differ significantly in clinical symptoms from non-sharing affected siblings. Thus the analysis of allele sharing at a putative schizophrenia susceptibility locus conditioned on allele sharing at other loci provides another important method for dealing with heterogeneity.


Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Heterogeneidade Genética , Esquizofrenia/genética , Distribuição de Qui-Quadrado , Mapeamento Cromossômico , Intervalos de Confiança , Delusões/genética , Ligação Genética , Marcadores Genéticos , Alucinações/genética , Humanos , Funções Verossimilhança , Razão de Chances , Irmãos
9.
J Biol Chem ; 276(45): 42259-67, 2001 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-11533059

RESUMO

Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis.


Assuntos
Neoplasias da Mama/genética , Estrogênios/farmacologia , Proteínas de Ligação ao GTP/genética , Genes ras , Inibidores do Crescimento/genética , Células 3T3 , Sequência de Aminoácidos , Animais , Neoplasias da Mama/patologia , Feminino , GTP Fosfo-Hidrolases/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Células Tumorais Cultivadas
10.
Genet Epidemiol ; 21(2): 105-22, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11507720

RESUMO

In this paper, we proposed a multipoint method to assess evidence of linkage to one region by incorporating linkage evidence from another region. This approach uses affected sib pairs in which the number of alleles shared identical by descent (IBD) is the primary statistic. This generalized estimating equation (GEE) approach is robust in that no assumption about the mode of inheritance is required, other than assuming the two regions being considered are unlinked and that there is no more than one susceptibility gene in each region. The method proposed here uses data from all available families to simultaneously test the hypothesis of statistical interaction between regions and to estimate the location of the susceptibility gene in the target region. As an illustration, we have applied this GEE method to an asthma sib pair study (Wjst et al. [1999] Genomics 58:1-8), which earlier reported evidence of linkage to chromosome 6 but showed no evidence for chromosome 20. Our results yield strong evidence to chromosome 20 (P value = 0.0001) after incorporating linkage information from chromosome 6. Furthermore, it estimates with 95% certainty that the map location of the susceptibility gene is flanked by markers D20S186 and D20S101, which are approximately 16.3 cM apart.


Assuntos
Asma/genética , Mapeamento Cromossômico/métodos , Ligação Genética , Cromossomos Humanos Par 20 , Cromossomos Humanos Par 6 , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Modelos Estatísticos , Núcleo Familiar
11.
Am J Psychiatry ; 158(8): 1258-64, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11481160

RESUMO

OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Delusões/diagnóstico , Delusões/genética , Família , Alucinações/diagnóstico , Alucinações/genética , Adulto , Transtornos Psicóticos Afetivos/diagnóstico , Transtornos Psicóticos Afetivos/epidemiologia , Transtornos Psicóticos Afetivos/genética , Biomarcadores , Transtorno Bipolar/epidemiologia , Análise por Conglomerados , Comorbidade , Delusões/epidemiologia , Feminino , Predisposição Genética para Doença , Alucinações/epidemiologia , Humanos , Masculino , Linhagem , Fenótipo , Índice de Gravidade de Doença
12.
Ann Epidemiol ; 11(6): 434-42, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11454503

RESUMO

PURPOSE: Isolated, nonsyndromic oral clefts cases (n = 171) and unaffected controls (n = 182) were used to identify both genetic and environmental risk factors. METHODS: Infants born in Maryland between 1992 to 1998 with an isolated, nonsyndromic oral cleft [cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP)] were recruited and exposure plus family history data were collected. Controls were unaffected infants. DNA was collected from all cases and their parents, plus controls. RESULTS: No statistically significant association was found between any of the following: maternal smoking, vitamin use, urinary tract infection, or recreational drug use in either univariate analysis or after adjusting for maternal age and education. More control mothers reported alcohol use during the critical time period of pregnancy (one month before conception through the first trimester) as compared to case mothers. There was a 10-fold increase in risk to siblings of cases as compared to siblings of controls. Markers at four candidate genes were examined: transforming growth factor alpha (TGF alpha), transforming growth factor beta 3 (TGF beta 3), MSX1, and BCL3. Only MSX1 showed significant differences in allele frequencies between CP cases and controls. MSX1 also showed significant evidence of linkage disequilibrium with a susceptibility gene controlling risk for CP. CONCLUSION: Most environmental risk factors examined here gave little evidence of association with risk to isolated, nonsyndromic oral clefts, although any alcohol consumption seemed protective. MSX1 showed evidence of linkage disequilibrium in both case-control and case-parent trio analysis.


Assuntos
Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Fenda Labial/etiologia , Fenda Labial/genética , Fissura Palatina/etiologia , Fissura Palatina/genética , Genótipo , Humanos , Recém-Nascido , Modelos Logísticos , Maryland/epidemiologia , Método de Monte Carlo , Fatores de Risco
13.
Hum Hered ; 51(1-2): 64-78, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11096273

RESUMO

Multipoint linkage analysis is a powerful tool to localize susceptibility genes for complex diseases. However, the conventional lod score method relies critically on the correct specification of mode of inheritance for accurate estimation of gene position. On the other hand, allele-sharing methods, as currently practiced, are designed to test the null hypothesis of no linkage rather than estimate the location of the susceptibility gene(s). In this paper, we propose an identity-by-descent (IBD)-based procedure to estimate the location of an unobserved susceptibility gene within a chromosomal region framed by multiple markers. Here we deal with the practical situation where some of the markers might not be fully informative. Rather the IBD statistic at an arbitrary within the region is imputed using the multipoint marker information. The method is robust in that no assumption about the genetic mechanism is required other than that the region contains no more than one susceptibility gene. In particular, this approach builds upon a simple representation for the expected IBD at any arbitrary locus within the region using data from affected sib pairs. With this representation, one can carry out a parametric inference procedure to locate an unobserved susceptibility gene. In addition, here we derive a sample size formula for the number of affected sib pairs needed to detect linkage with multiple markers. Throughout, the proposed method is illustrated through simulated data. We have implemented this method including exploratory and formal model-fitting procedures to locate susceptibility genes, plus sample size and power calculations in a program, GENEFINDER, which will be made available shortly.


Assuntos
Mapeamento Cromossômico/métodos , Doenças Genéticas Inatas/genética , Ligação Genética , Modelos Genéticos , Predisposição Genética para Doença , Humanos , Modelos Estatísticos , Núcleo Familiar
15.
Genet Epidemiol ; 21 Suppl 1: S55-60, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11793735

RESUMO

Using a recently developed multipoint parametric method, which tests for linkage in the presence of heterogeneity, we performed a genome-wide search for linkage using the German asthma data. Both dominant and recessive models were assumed in this parametric approach. Identity-by-descent (IBD) sharing for affected sibs was also calculated to help identify an appropriate genetic model and localize the trait locus. The strongest evidence for linkage was on chromosome 6 (p-value = 0.00006) under the dominant model with heterogeneity. Using both linkage and IBD sharing information for D6S422 (36.55 cM) on chromosome 6, we conducted exploratory analyses to locate additional trait loci that might explain the linkage heterogeneity. We found evidence of heterogeneity between D6S422 and D11S4111 based on a test of association (p-value = 0.0015).


Assuntos
Asma/genética , Mapeamento Cromossômico , Heterogeneidade Genética , Genoma , Adulto , Alelos , Criança , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , Feminino , Predisposição Genética para Doença/genética , Genética Populacional , Alemanha , Humanos , Masculino , Modelos Genéticos , Estados Unidos
16.
Am J Psychiatry ; 157(12): 2048-50, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11097977

RESUMO

OBJECTIVE: This study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder. METHOD: In 71 families ascertained for a genetic linkage study, 337 subjects with major affective disorder were assessed by using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. RESULTS: Subjects with bipolar disorder and alcoholism had a 38.4% lifetime rate of attempted suicide, whereas those without alcoholism had a 21.7% rate. Attempted suicide among subjects with bipolar disorder and alcoholism clustered in a subset of seven families. Families with alcoholic and suicidal probands had a 40.7% rate of attempted suicide in first-degree relatives with bipolar disorder, whereas other families had a 19.0% rate. CONCLUSIONS: Comorbid alcoholism was associated with a higher rate of attempted suicide among family members with bipolar disorder. Attempted suicide and alcoholism clustered in a subset of families. These relationships may have a genetic origin and may be mediated by intoxication, mixed states, and/or temperamental instability.


Assuntos
Alcoolismo/diagnóstico , Transtorno Bipolar/diagnóstico , Família , Tentativa de Suicídio/estatística & dados numéricos , Intoxicação Alcoólica/epidemiologia , Intoxicação Alcoólica/psicologia , Alcoolismo/epidemiologia , Alcoolismo/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Comorbidade , Predisposição Genética para Doença , Humanos , Comportamento Impulsivo/epidemiologia , Comportamento Impulsivo/psicologia , Razão de Chances , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Fatores de Risco , Temperamento/classificação
17.
J Allergy Clin Immunol ; 104(2 Pt 1): 485-91, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10452776

RESUMO

BACKGROUND: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease. OBJECTIVE: To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG ) and one of the signal transducers and activators of transcription (STAT6 ), we conducted further linkage studies among 33 multiplex families. METHODS: We characterized 528 subjects from Barbados for asthma; 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning approximately 79 centimorgan) was performed. RESULTS: Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P <.05 to.002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P =.002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P =.01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric linkage analysis score at D12S326 (nonparametric linkage score = 3.8, P =.0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P =.036). CONCLUSIONS: Our findings suggest that (1) one or more loci in the chromosome 12q13. 12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.


Assuntos
Asma/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Ligação Genética , Hipersensibilidade Imediata/genética , Adulto , Alelos , Cromossomos Humanos Par 12/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
J Allergy Clin Immunol ; 102(3): 436-42, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9768585

RESUMO

BACKGROUND: Dermatophagoides pteronyssinus (Der p) is one of the most frequently implicated allergens in atopic diseases. Although HLA could play an important role in the development of the IgE response to the Der p allergens, genetic regulation by non-HLA genes influences certain HLA-associated IgE responses to complex allergens. OBJECTIVE: To clarify genetic control for the expression of Der p-specific IgE responsiveness, we conducted a genome-wide search for genes influencing Der p-specific IgE antibody levels by using 45 Caucasian and 53 African American families ascertained as part of the Collaborative Study on the Genetics of Asthma (CSGA). METHODS: Specific IgE antibody levels to the Der p crude allergen and to the purified allergens Der p 1 and Der p 2 were measured. Multipoint, nonparametric linkage analysis of 370 polymorphic markers was performed with the GENEHUNTER program. RESULTS: The best evidence of genes controlling specific IgE response to Der p was obtained in 2 novel regions: chromosomes 2q21-q23 (P = .0033 for Caucasian subjects) and 8p23-p21 (P = .0011 for African American subjects). Three regions previously proposed as candidate regions for atopy, total IgE, or asthma also showed evidence for linkage to Der p-specific IgE responsiveness: 6p21 (P = .0064) and 13q32-q34 (P = 0.0064) in Caucasian subjects and 5q23-q33 (P = 0.0071) in African American subjects. CONCLUSIONS: No single locus generated overwhelming evidence for linkage in terms of established criteria and guidelines for a genome-wide screening, which supports previous assertions of a heterogeneous etiology for Der p-specific IgE responsiveness. Two novel regions, 2q21-q23 and 8p23-p21, that were identified in this study merit additional study.


Assuntos
Asma/genética , Asma/imunologia , Mapeamento Cromossômico , Genoma Humano , Glicoproteínas/imunologia , Imunoglobulina E/genética , Ácaros/imunologia , Adulto , Animais , Especificidade de Anticorpos , Antígenos de Dermatophagoides , População Negra/genética , Criança , Saúde da Família , Feminino , Ligação Genética , Genótipo , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Masculino , Fenótipo , Polimorfismo Genético , Testes Cutâneos , População Branca/genética
19.
J Allergy Clin Immunol ; 102(3): 449-53, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9768587

RESUMO

BACKGROUND: We have recently conducted a genome-wide screening for genes influencing Dermatophagoides pteronyssinus-specific IgE responsiveness as a part of the Collaborative Study on the Genetics of Asthma (CSGA), which showed evidence for linkage in some regions, including chromosomes 5131-q33 and 11q13 in African American families. OBJECTIVES: To clarify relative contributions of these regions to atopy in the same African American population, we have conducted further genetic linkage studies of specific IgE responses toward common inhaled allergens. METHODS: We studied 328 individuals in 58 African American families participating in the CSGA. Specific IgE responses toward Dermatophagoides farinae, cat, dog, American cockroach, rye grass, and Bermuda grass, as measured by skin tests, were used for multipoint linkage analysis with polymorphic markers on chromosomes 5q31-q33 and 11q13. RESULTS: Specific IgE response toward American cockroach showed evidence for linkage to chromosomes 5q31-q33 (P = .0050) and 11q13 (P = .017). Specific IgE response toward dog showed evidence for linkage with chromosome 5q31-q33 (P = .0043). Evidence for linkage with chromosome 11q13 was obtained for specific IgE responses toward Dermatophagoides farinae (P = .012), cat (P = .035), and Bermuda grass (P = .017). The presence of a positive ST response for at least 1 of 30 common allergens showed evidence for linkage to chromosomes 5q31-q33 (P = .017) and 11q13 (P = .00058). CONCLUSIONS: These data support that genes on both chromosomes 5q31-q33 and 11q13 confer susceptibility to upregulated IgE-mediated immune responses in this African American population. The putative genes on chromosomes 5q31-q33 and 11q13, however, showed contrasting effects on atopy, which may result from strong gene-environmental interactions.


Assuntos
Alérgenos/imunologia , População Negra/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 5 , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Administração por Inalação , Animais , Especificidade de Anticorpos , Gatos , Cães , Feminino , Marcadores Genéticos , Humanos , Masculino
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