Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “statistical genetics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 901 records · Page 50Linked to original sources
PubMed2004

Directed enzyme evolution guided by multidimensional analysis of substrate-activity space.

The directed evolution of protein function frequently involves identification of mutants with improved properties from a population of variants obtained by mutagenesis. The selection of clones to parent the subsequent generation is crucial to the continued creation of superior progeny. In the present study, multivariate analysis guided the evolution of human glutathione transferase (GST) T1-1 to 65-fold enhanced alkyltransferase activity. Six alternative substrates monitored the substrate-activity space that characterized a mutant library of enzymes, obtained by recombination of DNA and heterologous expression in Escherichia coli. A subset of mutants was identified by their proximity in the targeted region of six-dimensional factor space. DNA from these mutants was recombined to create a new generation of GST variants from which an improved enzyme was isolated. The multidimensional cluster analysis is applicable to quantitative properties in any population of molecules undergoing evolution and can guide the tailoring of proteins, nucleic acids and other chemical structures to novel and improved functions.

Alkyl and Aryl Transferases↗
PubMed1997

Genetic variants of microsomal metabolism and susceptibility to hydrocarbon-associated glomerulonephritis.

Hydrocarbon (HC) exposure can play a role in the development of chronic glomerulonephritis (GN). Interindividual variations in various metabolizing enzymes may influence HC biotransformation, and hence susceptibility to HC-associated GN. We evaluated the role of human genotypic polymorphism in HC-associated GN, in 41 patients (30 male, 11 female) with primary GN (17 diffuse mesangial proliferative GN, 12 focal segmental GN, 11 membranous GN, one membranoproliferative GN) and 60 (46 male, 14 female) healthy controls. Genotypic polymorphisms of (CYP) P450 2D6 (CYP2D6), glutathione S-transferases mu (GSTM1) and theta (GSTT1) and N-acetyltransferase (NAT-2) were determined using polymerase chain reaction analysis of white-blood-cell DNA. HC exposure scores were determined using a validated questionnaire, and were significantly elevated in GN patients compared to controls. While no significant differences in the various genotypic frequencies were observed in the GN group overall, compared to controls, there was a significant increase in GSTM1 null (n = 10) to GSTM1 wild type (n = 1), and NAT fast (n = 10) to slow (n = 1) acetylators, in the membranous GN group compared to controls (p < 0.05). These results suggest a possible role for GSTM1 null and NAT fast acetylator in the development of HC-associated membranous GN.

Acetyltransferases↗
PubMed1989

Evidence of inherited susceptibility of increased streptococcal adherence to pharyngeal cells of children with rheumatic fever.

The study included the members of 15 families, each having more than one sibling affected by rheumatic fever (RF). All the rheumatic individuals showed the sequelae of rheumatic carditis, but on clinical and laboratory evidence, the disease was inactive. Thirty normal unrelated individuals, having no rheumatic first-degree relatives, were studied as controls. The following investigations were carried out for all members: (1) history and clinical examination, (2) routine investigations of diagnosis, (3) HLA typing using 9-A, 15-B, 6-DR antigens, (4) adherence of group A streptococci to pharyngeal cells, an in vitro adherence assay. There were two types of strains; five RF-associated strains and two RF-unassociated strains. Statistical and genetic analysis revealed: (1) no significant difference between adherence of RF-associated and unassociated strains amongst controls; (2) significant increased avidity for adherence of RF-associated strains amongst rheumatic siblings compared to normal siblings and controls. There was no significant difference between the three groups using RF-unassociated strains; (3) HLA-haplotype concordance and 'N' measure showed that the avidity for adherence is probably inherited; (4) lod scores for linkage suggest a dominant susceptibility gene(s) closely linked to HLA and segregating in multiplex families.

Bacterial Adhesion↗
PubMed2003

The Biomedical Humanities program: merging humanities and science in a premedical curriculum at Hiram College.

The Biomedical Humanities program at Hiram College, established in 1999, engages premedical and other qualified students in ethical and informed decision making, improves their ability to interact with persons of different backgrounds and cultures, provides them an active introduction to basic medical research and clinical practice, and coaches them in communicating across barriers, appreciating that scientists and humanists typically learn and work differently. The program offers both a major and a minor in biomedical humanities topics. The major requires the core biology and chemistry curriculum necessary for further studies in medicine as well as courses in genetics and statistics. The remainder of the major is devoted to four core areas: Communications, Relationships and Cultural Sensitivity, Ethics and Medical Humanities, and a nonacademic core area, Experiential Learning. Many of the ethics and medical humanities options are team-taught interdisciplinary courses. The Experiential Learning area requires students to take two special topics seminars, two service seminars, and two internships-one shadowing a professional in his or her area of interest and one engaging in basic biomedical research. The shadowing internship and service seminars focus not only on career exploration, but also on human interactions. Students reflect on the personal interactions they observe during their various experiences, and on their own strengths and weaknesses. Essays, designed to help students learn more about their roles in these settings, push them to deal with the sociopolitical issues involved in their service. The major, a robust and vital component of Hiram's undergraduate program, has attracted academically gifted students with a diverse array of career goals.

Bioethics↗
PubMed2001

Cytochrome P450 2D6 genotype and methadone steady-state concentrations.

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

Adolescent↗
PubMed2002

Identification and chromosomal localization of ecogenetic components of electrolyte excretion.

OBJECTIVE: To determine to what extent urinary excretion of blood pressure-modulating electrolytes is genetically determined, and to identify their chromosomal localization. DESIGN AND METHODS: Twenty-six rat recombinant inbred strains (RIS) originating from reciprocal crosses of normotensive Brown Norway (BN.Lx) and spontaneously hypertensive rats (SHR) were used. A pilot experiment on a subset of strains determined that fasting decreases the impact of environmental noise and increases that of heritability. Twenty-four-hour urinary collections were obtained from fasting rats aged 6-12 weeks (3-8 rats per strain). Sodium (Na), potassium (K) and calcium (Ca) excretions were measured, and the Na/K ratio calculated. These phenotypes served as quantitative traits for the search of quantitative trait loci (QTLs) by scanning the RIS genome that was mapped with 475 polymorphic markers. RESULTS: Constant Na intake resulted in a low heritability for Na excretion, reflecting the environmental impact (intake = excretion), whereas fasting revealed a gradient among RIS indicative of the genetic component of the traits. In the fasting state, a locus on chromosome 14 was found to be significantly associated with K excretion (Alb, P = 0.00002, r = -0.69, logarithm of the odds score (LOD) 3.9), whereas another locus on chromosome 10 (D10Cebrp97s5, P = 0.0003, r = -0.69, LOD 3.0) and one on chromosome 6 (D6Cebrp97s14, P = 0.0007, r = -0.65, LOD 1.9) were more significantly associated with Na excretion and the Na/K ratio respectively. The observed correlations were all negative for Na, K and Na/K, indicating a higher excretion of Na and K and a greater Na/K ratio in rats bearing BN.Lx alleles at these loci, i.e. salt retention in fasting SHR. These three loci accounted for 47-55% of variance of their associated trait, suggesting that they are the main genetic determinants for these phenotypes in basal fasting conditions. Rats bearing the Y chromosome of SHR origin had significantly higher K excretion that, in turn, led to a significantly lower Na/K ratio. Finally, a locus on chromosome 7 was linked to Ca excretion, explaining 46% of the trait variance (D7Mit10, LOD score 3.0). CONCLUSION: RIS enabled us to determine QTLs for environmentally modulated traits such as Na, K and Ca excretions. We demonstrated that whereas urinary electrolytes are determined mainly by intake (environment) in a steady state, their excretion in an adaptive state (fasting) is predominantly genetically determined by distinct QTL on autosomes as well as the Y chromosome. Furthermore, the loci responsible for Na and K excretions act independently of the locus governing the relative excretion of Na/K. Thus, the salt-retaining aspects of some hypertensives may be, in large part, determined by genes responsible for renal excretion, the impact of which is predominant over the environment under acute challenge.

Age Factors↗
PubMed2002

Epsilon 4 allele of apolipoprotein E gene associates with lower blood pressure in young Japanese subjects: the Suita Study.

OBJECTIVES: The apolipoprotein epsilon 4 allele (APOE/epsilon 4) increases plasma cholesterol level and the risk for the late onset type of Alzheimer's disease. However, the correlation between hypertension and APOE/epsilon 4 has not yet been clarified. To examine the APOE/epsilon 4 effect in the general population of Japan, we performed a large genetic epidemiological survey (the Suita Study). DESIGN AND METHODS: The Suita Study was a cohort study based on a random sample of 14,200 Japanese residents of Suita city. Subjects who gave informed consent for genetic analysis were recruited in the current study ( = 3997). APOE polymorphism was clearly determined by the TaqMan polymerase chain reaction method. RESULTS: Subjects with APOE/epsilon 4 were significantly ( P < 0.03) more frequent (19.7%) in normotensives than in hypertensives (16.9%), the estimated odds ratio for hypertension (with APOE/epsilon 4 versus without APOE/epsilon 4) being 0.83 [95% confidence interval (CI), 0.70-0.98]. The significance of the association (OR = 0.64; 95% CI, 0.48-0.86) was increased in young subjects ( < or = 60 years old) but disappeared in old subjects. APOE/epsilon 4 also significantly contributed to a 2.9% increase of total cholesterol, 11.8% increase of triglyceride and 3.2% of decrease of high-density lipoprotein-cholesterol. CONCLUSIONS: We concluded that APOE/epsilon 4 was associated with an increase of plasma lipid levels and with a decrease of systolic blood pressure. The final conclusion on whether APOE/epsilon 4 contributes to the risk for cardiovascular disease will be clarified by analysis of the cumulative incidence, which will be obtained in the future Suita Study.

Adult↗
PubMed2004

A common polymorphism of uncoupling protein 2 gene is associated with hypertension.

OBJECTIVES: The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. METHODS: A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P<0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. CONCLUSION: These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Adult↗
PubMed2002

Heritability of social anxiety-related concerns and personality characteristics: a twin study.

Negative evaluation fears figure prominently in the cognitive psychology of patients with social phobia. In this study, we examine the heritability of negative evaluation fears by using a twin sample. The authors also examine the relationships between negative evaluation fears and personality dimensions relevant to social phobia. Scores on the brief version of the Fear of Negative Evaluation Scale (BFNE) were examined in a sample of 437 (245 monozygotic and 192 dizygotic) twin pairs. Biometrical model fitting was conducted by using standard statistical methods. Genetic and environmental correlations with personality dimensions (from the Dimensional Assessment of Personality Pathology-Basic Questionnaire) were also calculated. Broad heritability estimate of the BFNE was 48%. Additive genetic effects and unique environmental effects emerged as the primary influences on negative evaluation fears. Genetic correlations between BFNE scores and the submissiveness, anxiousness, and social avoidance facets of the Dimensional Assessment of Personality Pathology-Basic Questionnaire were high (r(g) =.78 to.80). A cognitive dimension central to the phenomenology (and, perhaps, cause) of social phobia, the fear of being negatively evaluated, is moderately heritable. Moreover, the same genes that influence negative evaluation fears appear to influence a cluster of anxiety-related personality characteristics. Implications and limitations of these findings are discussed.

Adult↗
PubMedDate not supplied

Polymorphisms in the estrogen synthesis and metabolism pathways and symptoms during the menopausal transition: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: The purpose of this study was to determine whether polymorphisms in the estrogen synthesis and metabolism pathways are associated with women's vasomotor symptom experiences during the menopausal transition. DESIGN: In 2002, a subset of women enrolled in the Seattle Midlife Women's Health Study since 1990 (N = 174) provided a buccal smear for genotyping. Women were recruited by complete ascertainment of selected multiethnic neighborhoods in 1990. Participants were midlife women with a mean age of 53 years in 2005, well educated, employed, married, and represented a multiethnic population. Genotyping was done for the following polymorphisms: CYP1A1m2; CYP1B1*2 and CYP1B1*3; CYP17 5'UTR; CYP19 3'UTR; CYP19 (TTTA)n; including CYP19 7r and CYP19 7(r-3); CYP19 8r and CYP19 11r; and ESR1PvuII and ESR1XbaI. Women rated their vasomotor symptom severity in diaries on days 5, 6, and 7 of the menstrual cycle or on a constant date each month for women skipping periods. Menopausal transition stage was determined from daily menstrual calendars. First voided urine specimens provided several times each year were assayed for estrone glucuronide. RESULTS: Women with the CYP19 11r polymorphism reported more severe and frequent hot flashes during the middle and late menopausal transition stages and postmenopause and higher E1G levels during middle and late stages. None of the other polymorphisms studied were related to hot flashes or to estrone glucuronide levels. CONCLUSIONS: These findings suggest a possible role for CYP19 polymorphisms in estrogen levels and in vasomotor symptoms during the menopausal transition that warrants further study in larger and more diverse populations of women.

Alleles↗
PubMed2006

The C242T CYBA polymorphism of NADPH oxidase is associated with essential hypertension.

OBJECTIVE: Oxidative stress is implicated in hypertension. The reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main source of superoxide in phagocytic and vascular cells. The C242T polymorphism of CYBA, the human gene that encodes p22phox, has been found to be functionally associated with vascular NADPH oxidase activity in atherosclerotic patients. We investigated the association of the C242T polymorphism with hypertension and its potential impact on NADPH oxidase activity. We also analysed the interaction of C242T polymorphism with the -930A/G CYBA variant. DESIGN: Case-control study in a random sample of 623 subjects (326 hypertensive patients and 297 normotensive controls) from the general population. METHODS: CYBA polymorphisms were determined by restriction fragment length polymorphism (RFLP) or allelic discrimination. NADPH oxidase activity and p22phox expression were quantified in phagocytic cells by chemiluminescence and by northern and western blots, respectively. RESULTS: The prevalence of the CC genotype and the C allele frequency were significantly higher (P < 0.05) in hypertensives than in normotensives. CC genotype remained associated with hypertension after adjusting for potential confounders in a logistic regression analysis. Increased phagocytic NADPH oxidase activity was observed in CC hypertensives compared with CT and TT hypertensives (P < 0.05). Enhanced plasma levels of von Willebrand factor were found in CC hypertensives compared with TT hypertensives (P < 0.05). The C242T polymorphism was not in linkage disequilibrium with the -930A/G CYBA promoter variation, which also associates with hypertension. CONCLUSION: The C242T CYBA polymorphism is associated with essential hypertension. Furthermore, hypertensives carrying the CC genotype of this polymorphism exhibit features of NADPH oxidase-mediated oxidative stress and endothelial damage.

Female↗
PubMed2003

Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics.

Little is known about the impact of cytochrome P450 polymorphisms on the metabolism of trimipramine, which is still widely used as antidepressant due to its positive effect on sleep patterns. A single oral dose of 75 mg trimipramine was given to 42 healthy volunteers selected according to their CYP2D6, CYP2C19, and CYP2C9 genotypes. The reference group included 8 subjects with homozygous active wild-type genotypes of all 3 enzymes (EM). This group was compared with 7 intermediate (IM) with 1 and 7 poor metabolizers (PM) with zero active alleles of CYP2D6 and CYP2C19, respectively, and with 4 subjects with the genotype CYP2C9*3/*3. Pharmacokinetics of trimipramine and its demethylated metabolite strongly depended on the CYP2D6 genotype. Median oral clearance of trimipramine was 276 L/h (range 180-444) in the reference group but only 36 L/h (range 24-48) in CYP2D6 PMs (P < 0.001). These differences could only be explained by an effect of CYP genotypes on both parameters, systemic clearance and bioavailability, the latter being at least 3-fold higher in CYP2D6 PMs than in the reference group. The desmethyltrimipramine area under the concentration-time curve was 40-fold greater in CYP2D6 PMs than in the reference group (1.7 vs. 0.04 mg/L x h in EMs), but below the quantification limit in most carriers of deficiencies of CYP2C19 or CYP2C9. This indicates that both CYP2C enzymes contribute to the demethylation of desmethyltrimipramine and CYP2D6 to further metabolism.

Adult↗
PubMed2004

Genome-wide linkage analysis for hypospadias susceptibility genes.

PURPOSE: Hypospadias, when the urethra opens on the underside of the penis, is a common malformation that occurs in about 1/300 boys. The etiology of hypospadias is unknown but several lines of evidence indicate that it is caused by the combined influence of genetic and environmental factors. To identify chromosomal loci involved in the pathogenesis of hypospadias we performed genome-wide linkage analysis. MATERIALS AND METHODS: A total of 69 families with at least 2 members with hypospadias were genotyped with 360 microsatellite markers and analyzed with a nonparametric affected relative pair method. Of them 58 were of Swedish origin and 11 were from the Middle East. RESULTS: Suggestive linkage was found at the 4 chromosome regions 9q22 (in all families), 2p11, 10p15 and 10q21 (in Swedish families). CONCLUSIONS: These results provide a basis for outlining the genetic background of hypospadias.

Child↗
PubMed2004

Insulin-like growth factor I gene microsatellite repeat, collagen type Ialpha1 gene Sp1 polymorphism, and bone disease in primary biliary cirrhosis.

BACKGROUND: Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Insulin-like growth factor I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies, and collagen-Ialpha1 (COLIA1) Sp1 s allele was associated with lower bone mineral density in primary biliary cirrhosis. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. We investigated IGF-I and COLIA1 gene polymorphisms and bone mineral density in Hungarian primary biliary cirrhosis patients. PATIENTS AND METHODS: Seventy female patients with primary biliary cirrhosis were enrolled (mean age 57.6 years, range 37-76 years; all anti-mitochondrial antibody M2-positive; stage II-IV). One hundred and thirty-nine age-matched female subjects served as controls (mean age 55.9 years, range 43-72 years). COLIA1 and IGF-I polymorphisms were determined by polymerase chain reaction. Bone mineral density was measured by dual-energy X-ray absorptiometry in the lumbar spine and femoral neck. RESULTS: The IGF-I was not different between primary biliary cirrhosis patients and controls. The genotype frequency of COLIA1 polymorphism was also not different between primary biliary cirrhosis patients and controls. However, the s allele was significantly less frequent in patients with primary biliary cirrhosis. Osteoporosis was detected in 22 patients. The IGF-I 192/192 genotype was associated with higher femoral-neck z-scores compared with other genotypes. CONCLUSION: In contrast to previous studies, the s allele was less frequent in patients with primary biliary cirrhosis, and its presence was not associated with bone mineral density. Since IGF-I polymorphism was associated with bone mineral density, it may be hypothesised that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of bone mineral density in primary biliary cirrhosis.

Adult↗
PubMedDate not supplied

TreeDT: tree pattern mining for gene mapping.

We describe TreeDT, a novel association-based gene mapping method. Given a set of disease-associated haplotypes and a set of control haplotypes, TreeDT predicts likely locations of a disease susceptibility gene. TreeDT extracts, essentially in the form of haplotype trees, information about historical recombinations in the population: A haplotype tree constructed at a given chromosomal location is an estimate of the genealogy of the haplotypes. TreeDT constructs these trees for all locations on the given haplotypes and performs a novel disequilibrium test on each tree: Is there a small set of subtrees with relatively high proportions of disease-associated chromosomes, suggesting shared genetic history for those and a likely disease gene location? We give a detailed description of TreeDT and the tree disequilibrium tests, we analyze the algorithm formally, and we evaluate its performance experimentally on both simulated and real data sets. Experimental results demonstrate that TreeDT has high accuracy on difficult mapping tasks and comparisons to other methods (EATDT, HPM, TDT) show that TreeDT is very competitive.

Algorithms↗