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PubMed2006

Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation.

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO. OBJECTIVES: The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date. DESIGN AND SETTING: This study was primarily a retrospective cross-sectional analysis of individuals with a ClCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied. PATIENTS AND INTERVENTIONS: We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistry), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a ClCN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/or self-reported responses on a questionnaire that was completed by all subjects. MAIN OUTCOME MEASURES: The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype. RESULTS: Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P < 0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) and osteomyelitis (16 vs. 0.9%; P < 0.0001). Severe fractures (defined as > or =10 fractures of any type and/or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time. CONCLUSIONS: ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.

Adolescent↗

PubMed1998

Role of HIV-1 phenotype in viral pathogenesis and its relation to viral load and CD4+ T-cell count.

The predictive value of HIV-1 phenotype in peripheral blood mononuclear cell (PBMC) coculture and the relation among viral phenotype, viral load, and CD4+ T-cell count were examined in two studies. In study A, 132 HIV-1-infected individuals were examined retrospectively for the relation between the result of their initial HIV cultivation in PBMC coculture and survival rate 6 years later. In study B, 176 patients were examined since 1994 for markers of HIV disease progression. HIV-1 phenotype was determined by PBMC cocultivation, viral load by NASBA HIV RNA QT System, and CD4+ T-cell count by flow cytometry. In study A, the percentage of survival for patients with initial negative virus culture was significantly higher (95%) than in patients with nonsyncytia-inducing (NSI) isolates (78%) and syncytia-inducing (SI) isolates (21%) (P < 0.05 and P< 0.0001, respectively). When SI phenotype was subdivided into moderately cytopathogenic and highly cytopathogenic, significant differences in the rate of survival between these subgroups could be observed (45% vs. 14%; P < 0.05). In study B, progression from negative virus culture to the isolation of NSI variants was associated with increasing viral load (P < 0.0001) but did not affect CD4+ T-cell count significantly (P> 0.07), whereas the switch from NSI to SI virus was accompanied by significant decline of CD4+ T-cells (P < 0.0001) but no change in viral load (P > 0.21). Thus, isolation and phenotyping of HIV represents an additional striking predictive marker for progression of HIV infection.

CD4 Lymphocyte Count↗

PubMedDate not supplied

Somatotype of children with gonadal dysgenesis and structural anomalies of genitalia.

The somatotype of 92 children with sexual structural anomalies of whom 28 with female Turner's syndrome, 22 with Klinefelter's syndrome, 20 with adreno-genital syndrome, 14 with hypospadias, 2 with Reinfenstein's syndrome and 6 with feminizing testis was established on the basis of biometric and genetically determined morphologic characteristics (dermatoglyphics, pigment complex). A morphogram utilizing 12 anthropometric and 5 dermatoglyphic parameters was constructed; it can be used in phenotypical differentiation of the anatomo-clinical variants of structural anomalies of the genitalia and gonads. The 12 anthropometric parameters were: weight, stature, height of the head + neck segment, the sternum-symphysis distance, length of arms and legs, the biacromial and bitrochanterian diameters, the circumference of the thorax, abdomen, hips and head. The dermatoglyphic parameters were: the digital delta index, TFRC, a-b ridge count, the ATD angle and the A line obliquity. For longitudinal assessment of the phenotype of children with structural anomalies of genitalia and gonads, the authors propose utilization of the percentile diagrams regarding weight, stature, pubes to floor distance, and the biacromial and bitrochanterian diameters.

Adolescent↗

PubMed2026

Dynamic Alterations in the Blood Transcriptome Characterize Drug Use Behavior and Co-Morbidities in Cocaine Use Disorder: A Preliminary Study.

Individuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse that can benefit from multimodal treatment monitoring. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome are not only limited but also computationally complex. Therefore, we developed an analytical pipeline to investigate the connection between drug use behaviors during abstinence and change in the blood transcriptome. We conducted a longitudinal study with CUD (n = 12 subjects) and collected behavioral metrics and blood RNA-seq at baseline, 3, 6, and 9 months. Our analytical pipeline of the high-dimensional data encompasses hierarchical k-means clustering to classify subjects to responder groups based on behavioral scores and abstinence duration, in silico cell deconvolution, differential analysis with correlated multivariate testing over time, gene set enrichment analysis, and gene co-expression with time splines and RNA-seq data. The pipeline captured dynamic changes in behavioral scores and abstinence duration in responder groups. Genes showing differential transcript-level expression were enriched in substance use and cardiovascular disease-associated genetic risk loci in responder groups. Lastly, time-dependent gene co-expression revealed dynamic changes related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence. This is a preliminary investigation, providing an innovative and scalable pipeline for blood-based longitudinal RNA-seq studies in CUD, potentially applicable to other substance use disorders. It outlines a data-driven approach for analyzing composite longitudinal drug use behavioral phenotypes with blood-based transcriptomics. We also demonstrate changes in drug use behaviors and the blood transcriptome during drug abstinence.

Humans↗

PubMed2001

A longitudinal assessment of diverging verbal and non-verbal abilities in the Williams syndrome phenotype.

Jarrold et al. (1998) presented evidence to suggest that verbal and non-verbal abilities develop at different rates in individuals with the Williams syndrome phenotype. However, this evidence was derived from cross-sectional rather than longitudinal data. The current report presents data from a series of follow up assessments which examine the development of vocabulary and pattern construction abilities in 15 of the original sample of 16 individuals, over a 40 month period. The results confirm the original predictions, as mental age equivalent scores for vocabulary increase more rapidly than scores for the pattern construction test; a finding, which appears unlikely to be due to practice effects.

Adolescent↗

PubMedDate not supplied

Phenotypic effects of apolipoprotein structural variation on lipid profiles. III. Contribution of apolipoprotein E phenotype to prediction of total cholesterol, apolipoprotein B, and low density lipoprotein cholesterol in the healthy women study.

The apolipoprotein (apo) E structural locus has been shown to influence concentrations of total cholesterol, apo B, and low density lipoprotein (LDL) cholesterol in population studies. Apo E has six phenotypes resulting from three common alleles at this locus. In the present study, we have typed 473 healthy white women for apo E. At baseline in 1984, all women were premenopausal. To date, 109 of these women have become postmenopausal and are not on hormone therapy. Statistical analyses were done on both pre- and postmenopausal groups to assess the influence of menopausal status in combination with the apo E locus on lipid profile. Nine lipoprotein lipids and apolipoproteins were categorized by three apo E phenotypes: apo E3-2, apo E3-3, and apo E4-3. These were compared in analysis of variance. At baseline, the apo E3-2 phenotype showed the lowest average concentrations of total cholesterol (170 mg/dl), apo B (80 mg/dl), and LDL cholesterol (91 mg/dl), while the apo E4-3 phenotype demonstrated the highest average concentrations of total cholesterol (192 mg/dl), apo B (104 mg/dl), and LDL cholesterol (116 mg/dl) (p less than or equal to 0.0004). Apo E3-3 homozygotes were intermediate on all three quantitative variables. The postmenopausal subset showed the same trends by phenotype, with overall increases in total cholesterol, apo B, LDL cholesterol, and triglycerides, regardless of phenotype. Women who remained premenopausal generally showed smaller increases in these same measures. Our results suggest that, on average, the lower lipoprotein values for the apo E3-2 phenotype are maintained through early menopause despite a worsening of lipid profiles for all women as they age.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1994

A model of developmental change in hierarchical phenotypes with application to specific cognitive abilities.

A hierarchical longitudinal path model is described for analysis of twin and sibling data. The model combines multivariate and longitudinal methodologies for assessment of continuity and change in the relationships among characters over time. Additionally, the model permits assessment of shared and independent etiologies for groups of measures at single and multiple occasions. The procedure is illustrated by application to specific cognitive ability data from 103 adopted and 109 nonadopted sibling pairs at ages 3, 4, 7, and 9 years, and 50 pairs of monozygotic and dizygotic twins at ages 3 and 4 years. The results suggest that much of the observed continuity in general intelligence measures is attributable to genetic influences common to specific abilities and indicate differential etiologies for specific abilities at different occasions in childhood.

Adoption↗

PubMed2002

Genetic contribution to rate of change in functional abilities among Danish twins aged 75 years or more.

In a previous cross-sectional study of twins, the authors found evidence of a substantial genetic influence on functional abilities among elderly women. It has been suggested that rate of change in functional abilities over time could underlie such findings and that rate-of-change phenotypes may have an even larger genetic component than "level" phenotypes (e.g., functional abilities per se). If so, rate-of-change phenotypes could be more powerful than level phenotypes in studies aimed at identifying specific polymorphisms of importance for aging. In 1995, the authors assessed a population-based sample of 2,401 Danish twins aged 75 years or more. The survivors were recontacted after 2 years and again after 4 years. Consistent mean-level declines, high within-person correlations over time, and substantial heritability in the female sample were observed for functional abilities. Nonetheless, structural-equation analyses revealed only a very modest and nonsignificant heritability for rate of change in functional abilities: 16% (95% confidence interval: 0, 35) for women and 9% (95% confidence interval: 0, 44) for men. This study had a large initial sample size, high participation rates, and a valid and reliable measure of rate of change in a phenotype that had previously shown substantial heritability in cross-sectional analyses in the same twin population. Still, the present study revealed only a modest and nonsignificant genetic influence on rate of change, which suggests that detection of polymorphisms influencing rate of change in functional abilities among the elderly may prove to be difficult.

Activities of Daily Living↗

PubMed1993

Human CD4+ cytolytic T lymphocyte responses to a human immunodeficiency virus type 1 gp160 subunit vaccine.

The development of an effective vaccine against human immunodeficiency virus type 1 (HIV-1) may require immunization protocols that elicit cytolytic T lymphocytes (CTL) in addition to neutralizing antibodies. This report demonstrates that vaccination of 4 HIV-1-seronegative volunteers with a recombinant HIV-1 gp160 vaccine produced in mammalian cells elicited a CTL response in 3. The observed CTL activity was not mediated by classic CD8+ CTL but rather by cells of the CD4+ phenotype. The level of CTL activity varied over time, did not correlate with the proliferative response to gp160, and was not increased by repeated immunization. At the clonal level, the vaccine was shown to elicit a functionally heterogeneous CD4+ T cell response that included clones with antigen-specific, major histocompatibility complex-restricted cytolytic activity. These clones were capable of lysing target cells expressing the HIV-1 env gene and thus might be active against HIV-1-infected cells in vivo.

AIDS Vaccines↗

PubMed1991

HLA disease association and protection in HIV infection among African Americans and Caucasians.

In a previous investigation, we demonstrated an increased progression of overt AIDS in the African American population compared to the Caucasian population as reflected by the significantly lower absolute number of CD4+ lymphocytes detected in the African American population in an earlier study. The present study elucidates some of the possible genetic factors which may contribute to disease association or protection against HIV infection. The HLA phenotypes expressed as A, B, C, DR and DQw antigens were revealed by the Amos-modified typing procedure. NIH scoring was utilized to designate positive cells taking up trypan blue. A test of proportion equivalent to the chi 2 approximation was used to compare the disease population (n = 62; 38 African Americans, 24 Caucasians) to race-matched normal heterosexual local controls (323 African Americans, 412 Caucasians). Significant p values were corrected for the number of HLA antigens tested. HLA markers associated with possible protection from infection for African Americans were Cw4 and DRw6, whereas Caucasians expressed none. Disease association markers present in the African American population were A31, B35, Cw6, Cw7, DR5, DR6, DRw11, DRw12, DQw6 and DQw7, whereas in the Caucasian population A28, Aw66, Aw48, Bw65, Bw70, Cw7, DRw10, DRw12, DQw6 and DQw7 were demonstrated. The highest phenotypic frequency for a disease association marker in the study was for HLA-DR5 (62.9%) in the HIV-infected African American population without Kaposi's sarcoma compared to a frequency of 28.9% for the regional control group (p = 0.0012). We conclude that genetic factors do have a role in HIV infection since only 50-60% of those exposed to the AIDS virus will become infected.

Black People↗

PubMed2005

An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans.

In the previous OCTO longitudinal study, we identified an immune risk phenotype (IRP) of high CD8 and low CD4 numbers and poor proliferative response. We also demonstrated that cognitive impairment constitutes a major predictor of nonsurvival. In the present NONA longitudinal study, we simultaneously examine in a model of allostatic load IRP and compromised cognition in 4-year survival in a population-based sample (n = 138, 86-94 years). Immune system measurements consisted of determinations of T-cell subsets, plasma interleukin 6 and cytomegalovirus and Epstein-Barr virus serology. Interleukin 2 responsiveness to concanavalin A, using data from the previous OCTO (octogenarians) immune study, hereafter OCTO immune, was also examined. Cognitive status was rated using a battery of neuropsychological tests. Logistic regression indicated that the IRP and cognitive impairment together predicted 58% of observed deaths. IRP was associated with late differentiated CD8+CD28-CD27- cells (p < .001), decreased interleukin 2 responsiveness (p < .05) and persistent viral infection (p < .01). Cognitive impairment was associated with increased plasma interleukin 6 (p < .001). IRP individuals with cognitive impairment were all deceased at the follow-up, indicating an allostatic overload.

Aged↗

PubMed1993

Serial phenotypic, cytogenetic and molecular genetic studies in Richter's syndrome: demonstration of lymphoma development from the chronic lymphocytic leukaemia cells.

In this report we describe a unique longitudinal study on the clinical, phenotypic, cytogenetic and molecular genetic features of malignant cells from diagnosis of chronic lymphocytic leukaemia (CLL) to the development of lymphoma and lymphomatous meningitis. CLL cells at diagnosis were CD5+, CD19+, surface IgG+, kappa+, were karyotypically abnormal and showed clonal rearrangements in the immunoglobulin heavy (IgH) and kappa light chain genes. Phenotypically leukaemic cells and lymphoma cells at RS resembled CLL at diagnosis, but showed cytogenetic evolution. Geometrically leukaemic cells and lymphoma cells retained the initial clonal rearrangements in IGH and kappa genes, but showed additional supervening clonal rearrangements in both of these genes as the disease progressed to RS. Furthermore, the c-lambda DNA showed clonal rearrangements in the leukaemic cells and lymphoma cells at RS. This complete phenotypic and genotypic analysis of tumour cells during the course of the disease demonstrates the origin of lymphoma from CLL cells through progressive cytogenetic and molecular genetic changes in CLL cells.

Blotting, Southern↗

PubMed2003

[Smoking, asthma and associated phenotypes. An epidemiological approach].

INTRODUCTION: The relationship between the respiratory tract and the environment is complex and is based on the dynamic interaction between genetically determined host-defence mechanisms and the toxicity of inhaled pollutants. STATE OF ART: Although the World Health Organisation has decreed that smoking is an avoidable cause of premature death, the epidemiological evaluation of the effects of smoking remains problematical. Indeed, basing assessment on duration of habit and quantity smoked may be miscalculating the true burden of the effects of smoking. Smoking, as a risk factor, is all too often perceived to be confined to development of chronic obstructive pulmonary disease. The consequences of passive smoking on children respiratory health have been established. In adults, active smoking has been related to asthma severity. Recent data demonstrate an effect of passive smoking on the incidence of asthma in adults. PERSPECTIVES: Objective markers of smoking are rarely used in epidemiological studies of asthma. CONCLUSIONS: However, the paucity of published studies linking smoking with asthma should not immediately lead to the conclusion that there is not a causal relationship.

Air Pollutants↗

PubMed2004

Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype.

OBJECTIVE: Transmission of the brain-derived neurotrophic factor (BDNF) Val66 allele in children with a prepubertal and early adolescent bipolar disorder phenotype was examined. METHOD: The prepubertal and early adolescent bipolar disorder phenotype was defined as current DSM-IV bipolar I disorder (manic or mixed phase) with at least one cardinal mania criterion (i.e., euphoria and/or grandiosity) to ensure differentiation from attention deficit hyperactivity disorder. Probands (mean age=10.7 years, SD=2.7) were obtained by consecutive new case ascertainment from designated pediatric and psychiatric venues. Parents and probands were interviewed separately by research nurses who were blind to the probands' diagnoses. Genotyping was done with TaqMan Assay-on-Demand. Analysis was done with the Family Based Association Test program. RESULTS: There were 53 complete, independent trios. The BDNF Val66 allele was preferentially transmitted (Family Based Association Test: chi(2)=6.0, df=1, p=0.014). CONCLUSIONS: This finding in child bipolar disorder is consistent with data for adults with bipolar disorder that show preferential transmission of the Val66 allele.

Adolescent↗

PubMed2002

Longitudinal use of a line probe assay for human immunodeficiency virus type 1 protease predicts phenotypic resistance and clinical progression in patients failing highly active antiretroviral therapy.

An observational study assessed the longitudinal use of a new line probe assay for the detection of protease mutations. Probe assays for detection of reverse transcriptase (Inno-LiPA HIV-1 RT; Innogenetics) and protease (prototype kit Inno-LiPA HIV Protease; Innogenetics) mutations gave results for 177 of 199 sequential samples collected over 2 years from 26 patients failing two nucleoside reverse transcriptase inhibitors and one protease inhibitor (first line: indinavir, n = 6; ritonavir, n = 10; and saquinavir, n = 10). Results were compared to recombinant virus protease inhibitor susceptibility data (n = 87) and to clinical and virological data. Combinations of protease mutations (M46I, G48V, I54V, V82A or -F, I84V, and L90M) predicted phenotypic resistance to the protease inhibitor and to nelfinavir. The sum of protease mutations was associated with virological and clinical outcomes from 6 and 3 months on, respectively. Moreover, a poorer clinical outcome was linked to the sum of reverse transcriptase mutations. In conclusion, despite the limited number of patients studied and the restricted number of codons investigated, probe assay-based genotyping correlates with phenotypic drug resistance and predicts new Centers for Disease Control and Prevention stage B and C clinical events and virological outcome. Line probe assays provide additional prognostic information and should be prospectively investigated for their potential for treatment monitoring.

Antiretroviral Therapy, Highly Active↗

PubMed1986

Alpha-thalassemia in premature newborns.

In this study we have carried out alpha-globin gene mapping, hemoglobin (Hb) Bart's quantitation serum bilirubin, and red blood cell indices determination in a group of Sardinian appropriate for gestational age premature infants (from 32 to 35 wk gestation) in order to define the incidence in this population of the different alpha-thalassemia syndromes, their expression rate, and the correlation between the alpha-globin genotype and phenotype at this developmental stage. The gene frequencies of deletion (-alpha) and nondeletion (alpha alpha th) alpha-thalassemia were 0.29 and 0.04, respectively, and thus not different from those found in full-term newborns from the same population. The majority of premature newborns with a single alpha-globin gene deletion [(-alpha/alpha alpha) genotype] were hematologically silent. Those who manifested increased Hb Bart's (1.2 to 3.4%) had slightly reduced Hb levels (17.4 +/- 2.6 g/dl), mean corpuscular volume (102.6 +/- 6.3 fl), and mean corpuscular Hb (34.8 +/- 2.0 pg) values. Those infants with the deletion of two alpha-globin structural genes (-alpha/-alpha) showed without exception moderate amount of Hb Bart's in the 3.5-8.1% range and an obvious decrease of Hb levels (16.1 +/- 1.6 g/dl) mean corpuscular Hb (30.6 +/- 3.5 pg), and mean corpuscular volume (88.5 +/- 11.5 fl) values. The only infant with the deletion of 3 alpha-globin structural genes had 25% Hb Bart's associated with a moderate microcytic anemia at birth and developed the clinical picture of Hb H disease. Carriers of nondeletion alpha-thalassemia (alpha alpha/alpha alpha th) showed variable amount of Hb Bart's always associated with thalassemia-like red cell indices.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗

PubMed2000

Distribution of geriatric disease-related genotypes in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA).

Phenotypes of various genes related to geriatric diseases and the aging process were assessed in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA). The subjects were 1,297 participants in the NILS-LSA. They were community-living males and females aged 40 to 79 years who were randomly selected from the area of the NILS. Genotypic and allelic frequencies of genes in the subjects were analyzed. Age and gender differences in the distribution of genotypes were also tested. The genotypic frequencies were as follows: (1) Angiotensin I-converting enzyme (ACE) genotype was I/I 46.2%, I/D 38.3% and D/D 15.5%. (2) alpha 1-adrenoreceptor genotype was C/C 84.4%, C/T 12.7%, and T/T 3.0%. (3) Apolipoprotein E genotype was epsilon 2/epsilon 2 0%, epsilon 2/epsilon 3 7.9%, epsilon 3/epsilon 3 70.0%, epsilon 3/epsilon 4 20.8%, epsilon 2/epsilon 4 0%, and epsilon 4/epsilon 4 1.4%. (4) Cholecystokinin type-A receptor (CCKAR) nucleotide-81 (nt-81) genotype was A/A 59.1%, A/G 35.1%, and G/G 5.9%. The CCKAR nucleotide-128 genotype (nt-128) was G/G 74.3%, G/T 23.6%, and T/T 2.2%. The combination of nucleotide (nt-81, nt-128) was (A/A, G/G) 59.1%, (A/G, G/G) 14.1%, (G/G, G/G) 1.1%, (A/G, G/T) 21.0%, (G/G, G/T) 2.6%, and (G/G, T/T) 2.1%. There were no subjects with (A/A, G/T), (A/A, T/T) or (A/G, T/T) genotypic combinations. (5) beta 3-adrenoreceptor genotype was T/T 66.8%, T/A 28.5%, and A/A 4.7%. (6) Dihydrolipoamide succinyltransferase (DLST) nucleotide 19117 genotype was A/A 25.1%, A/G 49.7%, and G/G 25.1%. The DLST nucleotide 19183 genotype was C/C 55.8%, C/T 38.2%, and T/T 5.9%. The combination of nucleotide (nt19117, nt19183) was (A/A, C/C) 6.7%, (A/G, C/C) 24.1%, (G/G, C/C) 25.1%, (A/G, C/T) 25.6%, (A/A, T/T) 5.9%, and (A/A, C/T) 12.6%. There were no subjects with (A/G, T/T), (G/G, T/T) or (G/G, T/C) genotypic combinations. (7) Transforming growth factor-beta 1 genotype T/T 35.2%, T/C 44.6%, and C/C 20.2%. (8) The platelet-activating factor acetylhydrolase genotype was M/M 71.7%, M/m 27.2%, and m/m 1.2%. The mitochondria DNA 5178 genotype A was 42.1% and C was 57.9%. There were no significant gender or age differences in tested genotypic and allelic distribution except for the DLST and apolipoprotein E. Differences in the genotypic frequencies of distribution using the Hardy-Weinberg equilibrium were significant in the ACE and alpha 1-adrenoreceptor genotypes.

Adult↗

PubMed2005

Genome scans with gene-covariate interaction.

Genetic models for gene-covariate interactions are described. Methods of linkage analysis that utilize special features of these models and the corresponding score statistics are derived. Their power is compared with that of simple genome scans that ignore these special features, and substantial gains in power are observed when the gene-covariate interaction is strong. Quantitative trait mapping in randomly ascertained sibships and affected sibpair mapping are discussed. For the latter case, a simpler statistic is proposed that has similar performance to the score statistic, but does not require the estimation of nuisance parameters. Since the nuisance parameters are not estimable solely from affected sib-pair data, this statistic would be much easier to apply in practice. Similarities with linkage analysis of models for longitudinal data and multivariate phenotypes are also briefly discussed. Approximations for the P-value and power are derived under the framework of local alternatives.

Chromosome Mapping↗