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PubMed2001

Apolipoprotein E phenotype and the efficacy of intravenous tissue plasminogen activator in acute ischemic stroke.

We used stored plasma samples from 409 patients in the National Institute of Neurological Diseases and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Trial to examine the relationship between an apolipoprotein (Apo) E2 or an Apo E4 phenotype and a favorable outcome 3 months after stroke, the risk of intracerebral hemorrhage, and the response to intravenous t-PA therapy. For the 27 patients with an Apo E2 phenotype who were treated with t-PA, the odds ratio (OR) of a favorable outcome at 3 months was 6.4 [95% confidence interval (CI) 2.7-15.3%] compared to the 161 patients without an Apo E2 phenotype who were treated with placebo. The 190 patients treated with t-PA who did not have an Apo E2 phenotype also had a greater, though less pronounced, likelihood of a favorable outcome (OR 2.0, 95% CI 1.2-3.2%) than patients without an Apo E2 phenotype treated with placebo. For the 31 patients with an Apo E2 phenotype treated with placebo, the OR of a favorable 3 month outcome was 0.8 (95% CI 0.4-1.7%) compared to the 161 patients without an Apo E2 phenotype treated with placebo. This interaction between treatment and Apo E2 status persisted after adjustment for baseline variables previously associated with 3 month outcome, for differences in the baseline variables in the two treatment groups and in the Apo E2-positive and -negative groups, and for a previously reported time-to-treatment x treatment interaction (p = 0.03). Apo E4 phenotype, present in 111 (27%) of the 409 patients, was not related to a favorable 3 month outcome, response to t-PA, 3 month mortality, or risk of intracerebral hemorrhage. We conclude that the efficacy of intravenous t-PA in patients with acute ischemic stroke may be enhanced in patients who have an Apo E2 phenotype, whereas the Apo E2 phenotype alone is not associated with a detectable benefit on stroke outcome at 3 months in patients not given t-PA. In contrast to prior studies of head injury and stroke, we could not detect a relationship between Apo E4 phenotype and clinical outcome.

Aged↗

PubMed2006

Characteristics of COPD phenotypes classified according to the findings of HRCT.

The present study was performed to clarify the clinical characteristics of chronic obstructive pulmonary disease (COPD) patients classified into phenotypes according to the dominancy of emphysema and the presence of bronchial wall thickening evaluated by chest high-resolution computed tomography (HRCT). Eighty-five patients with stable COPD (FEV1 < or = 80%) were examined by chest HRCT. Emphysematous changes and bronchial wall thickening were evaluated visually, and COPD patients were classified into three phenotypes: absence of emphysema, with little emphysema with or without bronchial wall thickening (A phenotype), emphysema without bronchial wall thickening (E phenotype), and emphysema with bronchial wall thickening phenotype (M phenotype). Clinical characteristics were compared among the three phenotypes. The A phenotype group showed a higher prevalence of subjects who had never smoked and patients with wheezing, higher values of body mass index (BMI) and DLco, milder lung hyperinflation, and greater reversibility of airflow limitation responsive to inhaled beta2-agonist as compared with the other phenotypes. The degree of emphysema was significantly associated with Brinkman index, lower BMI, decrease in DLco, lower FEV1/FVC. The presence of bronchial wall thickening in A- and M- phenotype was significantly associated with reversibility responsive to treatment with inhaled corticosteroid and sputum eosinophilia. These findings suggest that the morphological phenotypes of COPD show several clinical characteristics and different responsiveness to treatment with bronchodilators and inhaled corticosteroids.

Administration, Oral↗

PubMed2004

Evolution of expression of cardiac phenotypes over a 4-year period in the beta-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by a diverse array of cardiac phenotypes evolving over several decades. We have developed transgenic rabbits that fully recapitulate the phenotype of human HCM and provide for the opportunity to delineate the sequence of evolution of cardiac phenotypes, and thus, the pathogenesis of HCM. We determined evolution of biochemical, molecular, histological, structural and functional phenotypes at 4 age-periods in 47 beta-myosin heavy chain-glutamine (MyHC-Q)-403 transgenic rabbits. Ca(+2) sensitivity of myofibrillar ATPase activity was reduced very early and in the absence of other discernible phenotypes. Myocyte disarray also occurred early, prior to, and independent of hypertrophy and fibrosis. The latter phenotypes evolved predominantly during puberty in conjunction with activation of stress-related signaling kinases. Myocardial contraction and relaxation velocities were decreased early despite normal global cardiac function and in the absence of histological phenotype. Global cardiac function declined with aging, while left atrial size was increased along with Doppler indices of left ventricular filling pressure. Thus, Ca(+2) sensitivity of myofibrillar ATPase activity is a primary phenotype expressed early and independent of the ensuing phenotypes. Pathogenesis of myocyte disarray, which exhibits age-independent penetrance, differs from those of hypertrophy and fibrosis, which show age-dependent expression. Myocardial dysfunction is an early marker that predicts subsequent development of hypertrophy. These findings in an animal model that recapitulates the phenotype of human HCM, implicate involvement of multiple independent mechanisms in the pathogenesis of cardiac phenotypes in HCM.

Adenosine Triphosphatases↗

PubMed2002

Lipid compositional differences of small, dense low-density lipoprotein particle influence its oxidative susceptibility: possible implication of increased risk of coronary artery disease in subjects with phenotype B.

An increased susceptibility of low-density lipoprotein (LDL) to lipid peroxidative modification may be a key factor in the higher risk of coronary artery disease (CAD) among subjects with phenotype B. Compositional differences in the LDL particle may also be implicated in its atherogenicity and, in particular, may be associated with varying degrees of oxidative susceptibility of LDL, although this remains unclear. We hypothesized that the oxidative susceptibility of small, dense LDL was directly influenced by its lipid composition, which may lead to an increased risk of CAD in subjects with phenotype B. To test this hypothesis, we compared the differences in lipid compositions of LDL particles from subjects with phenotype A and those with phenotype B, and investigated the direct association of lipid composition with susceptibility to lipid peroxidative modification in 102 subjects who underwent a coronary angiographic examination. Subjects with phenotype B (n = 52) had a significantly higher incidence of CAD than subjects with phenotype A (77% v 44%; P <.005). In comparing the oxidative susceptibility of LDL, the lag time was significantly reduced in subjects with phenotype B compared to phenotype A (48.7 +/- 8.6 v 41.5 +/- 5.5 minutes; P <.0001). In addition, the lag time showed a positive correlation with LDL-peak particle diameter (PPD) (r = 0.324, P <.005). Lipid composition per LDL particle was expressed as the ratio of lipid content to apolipoprotein B (apoB) content (wt/wt). Subjects with phenotype B showed a significant depletion in the contents of free-cholesterol (FC), cholesterol ester (CE), and phospholipid (PL) per particle compared to subjects with phenotype A, although there was no significant difference in the triglyceride (TG) content per LDL particle. Except for TG, the lipid content per LDL particle showed a significant positive correlation with lag time in all subjects. Moreover, increased susceptibility of small, dense LDL to lipid peroxidative modification was most strongly associated with a depleted FC content per LDL particle. In conclusion, the greater risk of CAD in subjects with phenotype B may result, in part, from increased susceptibility to lipid peroxidative modification of LDL that is depleted in lipid contents, especially FC content per LDL particle.

Aged↗

PubMedDate not supplied

Measuring the facial phenotype of individuals with prenatal alcohol exposure: correlations with brain dysfunction.

The purpose of this report is to demonstrate how to measure the magnitude of expression of the fetal alcohol syndrome (FAS) facial phenotype using the new 4-Digit Diagnostic Code and the previously developed D-score and to demonstrate how these two measures of the FAS facial phenotype correlate with brain function and structure; correlations that fail to be identified by the older gestalt method of facial measurement. The D-score and the facial component of the 4-Digit Diagnostic Code quantitatively measure the magnitude of expression of the FAS facial phenotype using three facial features (palpebral fissure length, philtrum smoothness, and upper lip thinness). These facial measurement systems were developed by the Washington State FAS Diagnostic and Prevention Network (FAS DPN) of clinics and are used to screen and diagnose the facial component of FAS for all patients evaluated in the network of clinics (1500 to date). The 4-Digit Diagnostic Code is a comprehensive diagnostic system developed by the FAS DPN in 1997 to diagnose the full spectrum of outcomes among patients with prenatal alcohol exposure. The four digits reflect the magnitude of expression of the four key diagnostic features of FAS in the following order: (1) growth deficiency; (2) the FAS facial phenotype; (3) brain dysfunction; (4) gestational alcohol exposure. The 4-Digit Diagnostic Code was developed to overcome the subjective, highly variable gestalt method of diagnosis that has been used as the standard to date, worldwide. Prior to the development of the 4-Digit Diagnostic Code, the first 445 patients evaluated in the FAS DPN were diagnosed using the gestalt method. For research purposes, their gestalt diagnoses were transformed into 4-Digit Diagnostic Codes, presenting a unique opportunity to directly compare the two diagnostic methods. When the facial phenotype was measured using the 4-Digit Diagnostic Code or D-score, the magnitude of expression of the FAS facial phenotype was significantly correlated with structural, neurologic, and functional measures of brain damage, and the phenotype of those receiving a 4-Digit Diagnosis of FAS showed little variability. When the gestalt method of diagnosis was used, the magnitude of expression of the FAS facial phenotype did not correlate with structural, neurologic and functional measures of brain damage, and the facial phenotype of those receiving a gestalt diagnosis of FAS was highly variable. The 4-Digit Diagnostic Code and D-score thus provide more precise and accurate measures of the FAS facial phenotype and reveal important correlations with brain structure and function, suggesting that intermediate expressions of the FAS facial phenotype may serve as important risk factors for brain damage caused by prenatal alcohol exposure.

Adolescent↗

PubMed1998

Assessment of ejaculate quality and sperm characteristics in turkeys: sperm mobility phenotype is independent of time.

Given a pool of genetically superior male turkeys, the subsequent selection of toms as semen donors for artificial insemination should be based upon criteria that are predictive of the tom's fertility and fecundity over the course of a production cycle. Recently, sperm mobility phenotype has been shown to correlate highly with fertility. Therefore, the objectives of this study were to determine: 1) whether sperm mobility phenotypes of individual toms were independent of time, and 2) the extent to which traditional semen quality variables changed as a function of time during the study interval. Sperm mobility phenotype was determined by objectively measuring the ability of sperm to penetrate 2% Accudenz solution at body temperature. During the initial assessments of a flock (n = 94), sperm mobility indexes (SMI) were significantly higher for the High Mobility Phenotype toms (56.61 +/-1.03% SMI) compared to the Low Mobility Phenotype (30.46+/-1.27% SMI, P < or = 0.0001) toms. Over the 5 mo of this study, the High Mobility Phenotype toms consistently had higher (P < or = 0.05) SMI values than the Low Mobility Phenotype toms, with SMI values similar to those of the initial screen. Ejaculate volume, concentration, and plasma membrane integrity showed no significant differences between phenotypes (P > or = 0.05). Sperm viability remained significantly lower (P < or = 0.05) over the course of this study for the High Mobility Phenotype toms than for the Low Mobility Phenotype toms. Because sperm mobility phenotype remained consistent through time, the Sperm Mobility Test provides a potentially important tool for selecting semen donors in turkeys.

Animals↗

PubMed1997

Lipoprotein(a) phenotypes in Japanese children: a cohort study.

BACKGROUND: Elevated serum lipoprotein(a) [Lp(a)] concentrations have been demonstrated to be associated with cardiovascular diseases due to premature atherosclerosis. However, the association of Lp(a) phenotypes with the development of these diseases remains largely unexplored. METHODS: We analyzed the population-based frequencies of serum Lp(a) phenotypes in 269 Japanese children aged 8-13 years in one community. According to the different apolipoprotein(a) [apo(a)] electrophoretic mobilities, Lp(a) was classified into seven single-band and respective double-band phenotypes. Each individual expressed a single (homozygotic) or a double band (heterozygotic). RESULTS: The serum Lp(a) concentration frequency distribution was skewed toward lower levels with a mean +/- SD of 15.5 +/- 18.0 mg/dl and a median of 11.0 mg/dl. The Lp(a) phenotype frequencies revealed that the frequency of double-band phenotype expression (55%) was higher than that of single bands (44%) and that the frequency of phenotypes representative of low molecular weight apo(a) was very low (2%). The mean serum Lp(a) concentration of the double-band-expressing subjects was higher than that of subjects with the single-band phenotype (20.1 +/- 19.9 vs. 10.5 +/- 15.9 mg/dl, p < 0.01). CONCLUSIONS: These findings of Lp(a) phenotypes in children seemed to differ from those in Japanese adults in another study; contrary to expectation, the predominant Lp(a) phenotypes found in children were those frequently associated with cardiovascular diseases in adults. Thus, it is speculated that children whose Lp(a) phenotypes remain unchanged during the transition to adulthood may show an increased susceptibility to cardiovascular disease, although the nutritional effects on the Lp(a) phenotypes cannot be neglected.

Adolescent↗

PubMed2004

Clinical phenotypes of asthma.

PURPOSE OF REVIEW: Asthma is a phenotypically heterogeneous disorder and, over the years, many different clinical subtypes of asthma have been described. A precise definition of asthma phenotypes is now becoming more and more important, not only for a better understanding of pathophysiologic mechanisms, but in particular to ascertain the specific genes associated with these phenotypes. RECENT FINDINGS: In children, three asthma phenotypes are now well defined: transient infant wheezing, nonatopic wheezing of the toddler, and IgE-mediated wheezing/asthma. Recently, a fourth phenotype, late-onset childhood asthma has been added to this list. In adults, asthma persisting from childhood into adulthood should be distinguished from asthma starting in adulthood. The phenotypes of adult-onset asthma are still poorly defined. Until now, phenotypic classification has been based primarily on etiologic factors (eg, aspirin sensitivity, persistent respiratory infections, occupational factors, or toxic exposures) or clinical characteristics of the disease (eg, mild, severe, brittle, near fatal, with fixed airflow obstruction, steroid resistant). Novel noninvasive techniques to assess the type and severity of airway inflammation and dysfunction are increasingly used to identify better the different phenotypes. SUMMARY: The classic phenotype of IgE-mediated asthma starting in childhood is now clearly defined. However, many other phenotypes of asthma in childhood as well in adulthood are being recognized. In particular, asthma starting in adulthood and noneosinophilic asthma constitute an important part of the adult asthma population, and are still poorly defined. A precise definition of these asthma phenotypes is urgently needed because they are likely to be associated with different genotypes, responses to treatment, and prognoses.

Adult↗

PubMed1987

Influence of the catBCE sequence on the phenotypic reversion of a pcaE mutation in Acinetobacter calcoaceticus.

Isofunctional beta-ketoadipate:succinyl coenzyme A transferases I and II are encoded by the pcaE and catE genes, respectively, of Acinetobacter calcoaceticus. The genes are under separate transcriptional control and genetically unlinked. Mutations in the pcaE gene result in a p-hydroxybenzoate-negative (POB-) phenotype, whereas catE mutations cause a benzoate-negative (Ben-) phenotype. A. calcoaceticus ADP125 carries the pcaE3125 mutation and gave rise to POB+ revertants with a frequency of 10(-4). A 5.0-kilobase-pair (kb) EcoRI restriction fragment containing the catBCDE genes possesses two SalI restriction sites separated by 1.5 kb. Removal of the DNA between the SalI sites created a deletion removing the terminal 35 base pairs of the catB gene, the 300-base-pair catC gene, and about 1.1 kb of the 1.2-kb catE gene. Transformation of strain ADP125 with the modified EcoRI fragment lacking the SalI segment produced natural transformants containing this designed deletion with a frequency of 20%. The frequency of POB+ phenotypic reversion of the pcaE3125 mutation in these transformants was more than 300-fold lower than the frequency of phenotypic reversion observed in genetic backgrounds containing the catBCE segment. Alleles created by pcaE phenotypic reversion in a wild-type cat genetic background were unlinked to the cat gene cluster, and revertant transferases were expressed inducibly with the pca genes. Alterations in the restriction pattern of the pca gene cluster in several revertants were observed, indicating that multiple sequence changes have occurred in the pca genes during reversion. Growth of the phenotypic revertants under nonselective conditions resulted in loss of either the POB+ phenotype or both the POB+ and Ben+ phenotypes at high frequency. Southern hybridizations revealed that loss of the POB+ of Ben+ phenotype was due to deletion of the entire pca or cat gene cluster, a loss of at least 16 kb in some strains. Revertants isolated in a catBCE deletion background were stable. These results suggest that enhanced phenotypic reversion of pcaE3125 in wild-type cat background is due to repair of the mutation by recombination between the catBCE and pcaE3125 sequences. Genetic instability of the phenotypic revertants may be attributed to deletion of pca and cat sequences by recombination between regions of homology created as a consequence of pcaE repair.

Acinetobacter↗

PubMed1997

Escherichia coli cells expressing a mutant glyV (glycine tRNA) gene have a UVM-constitutive phenotype: implications for mechanisms underlying the mutA or mutC mutator effect.

Transfection of M13 single-stranded viral DNA bearing a 3,N4-ethenocytosine lesion into Escherichia coli cells pretreated with UV results in a significant elevation of mutagenesis at the lesion site compared to that observed in untreated cells. This response, termed UVM, for UV modulation of mutagenesis, is induced by a variety of DNA-damaging agents and is distinct from known cellular responses to DNA damage, including the SOS response. This report describes our observation, as a part of our investigation of the UVM phenomenon, that E. coli cells bearing a mutA or mutC allele display a UVM-constitutive phenotype. These mutator alleles were recently mapped (M. M. Slupska, C. Baikalov, R. Lloyd, and J. H. Miller, Proc. Natl. Acad. Sci. USA 93:4380-4385, 1996) to the glyV (mutA) and glyW (mutC) tRNA genes. Each mutant allele was shown to arise by an identical mutation in the anticodon sequence such that the mutant tRNAs could, in principle, mistranslate aspartate codons in mRNA as glycine at a low level. Because a UVM-constitutive phenotype resulting from a mutation in a tRNA gene was unexpected, we undertook a series of experiments designed to test whether the phenotype was indeed mediated by the expression of mutant glycine tRNAs. We placed either a wild-type or a mutant glyV gene under the control of a heterologous inducible promoter on a plasmid vector. E. coli cells expressing the mutant glyV gene displayed all three of the following phenotypes: (i) missense suppression of a test allele, (ii) a mutator phenotype measured by mutation to rifampin resistance, and (iii) a UVM-constitutive phenotype. These phenotypes were not associated with cells expressing the wild-type glyV gene or with cells in which the mutant allele was present but was not transcriptionally induced. These observations provide strong support for the idea that expression of mutant tRNA can confer a mutator phenotype, including the UVM-constitutive phenotype observed in mutA and mutC cells. However, our data imply that low-level mistranslation of the epsilon subunit of polymerase III probably does not account for the observed UVM-constitutive phenotype. Our results also indicate that mutA deltarecA double mutants display a normal UVM phenotype, suggesting that the mutA effect is recA dependent. The observations reported here raise a number of intriguing questions and raise the possibility that the UVM response is mediated through transient alteration of the replication environment.

Anticodon↗

PubMed1994

Deletions in the 5' region of dystrophin and resulting phenotypes.

Deletions in the dystrophin gene give rise to both Duchenne and Becker muscular dystrophies. Good correlation is generally found between the severity of the phenotype and the effect of the deletion on the reading frame: deletions that disrupt the reading frame result in a severe phenotype, while in frame deletions are associated with a milder disease course. Rare exceptions to this rule, mainly owing to frameshift mutations in the 5' region of the gene (in particular deletions involving exons 3 to 7) which are associated with a milder than expected phenotype, have been reported previously. In order to characterise better the relationship between genotype and phenotype as a result of mutations arising in the 5' region of the gene, we have studied a large cohort of patients with small in frame and out of frame deletions in the first 13 exons of the dystrophin gene. Fifty-five patients with a deletion in this area were identified; approximately one third of them had a phenotype different from that theoretically expected. Patients were divided into two groups: (1) patients with a severe clinical phenotype despite the presence of a small, in frame deletion and (2) patients with a mild phenotype and an out of frame deletion. Noticeable examples observed in the first group were Duchenne boys with a deletion of exon 5, of exon 3, and of exons 3-13. In the second group we observed several patients with an intermediate or Becker phenotype and out of frame deletions involving not only the usual exons 3-7 but also 5-7 and 3-6. These data indicate that a high proportion of patients with a deletion in the 5' end of the gene have a phenotype that is not predictable on the basis of the effect of the deletion on the reading frame. The N-terminus of dystrophin has at least one actin binding domain that might be affected by the small, in frame deletions in this area. The effect of the in frame deletions of exon 3, 5, and 3-13 on this domain might account for the severe phenotype observed in these patients. Other mechanisms, such as unexpected effect of the deletion on splicing behaviour, might, however, also be implicated in determining the phenotype outcome.

Adolescent↗

PubMed2006

Gastric and intestinal phenotypic marker expression in early differentiated-type tumors of the stomach: clinicopathologic significance and genetic background.

PURPOSE: Gastric and intestinal phenotypic cell markers are expressed in gastric carcinomas, irrespective of their histologic type. In the present study, we determined the clinicopathologic significance of phenotypic marker expression in early-stage gastric differentiated-type tumors and the association between marker expression and genetic alterations. EXPERIMENTAL DESIGN: Phenotypic marker expression was determined by examining the expressions of human gastric mucin (HGM), MUC6, MUC2, and CD10 in 63 gastric adenomas, 133 early differentiated-type carcinomas, and 24 follow-up cases with gastric adenoma. Tumors were classified into gastric, gastric and intestinal mixed, or intestinal phenotypes according to the immunopositivity of the above markers. The presence of mutations in APC, K-ras, and p53 and the microsatellite instability status were also determined in all tumors. RESULTS: The expressions of HGM and MUC6, representing gastric or gastric and intestinal mixed phenotypes, were significantly associated with high-grade atypia in the 63 gastric adenomas. Among the 133 early differentiated-type carcinomas, HGM expression was significantly associated with mixed-type (with an undifferentiated-type component) tumors and lymph node metastasis. MUC2 expression was inversely associated with submucosal invasion. A multivariate analysis revealed that gastric adenomas were significantly associated with the intestinal phenotype and were inversely associated with p53 mutation compared with early differentiated-type carcinomas. Among all 196 tumors, APC mutation was significantly associated with CD10 expression and the intestinal phenotype and was inversely associated with the expressions of HGM and MUC6. The microsatellite instability status was significantly associated with MUC6 expression. Malignant transformation from gastric adenoma to carcinoma was shown in 5 of the 24 follow-up cases of gastric adenoma. The malignant transformation was significantly associated with the gastric and intestinal mixed phenotype and was inversely associated with APC mutation. No malignant transformation was found in intestinal phenotype gastric adenomas with APC mutation. CONCLUSIONS: Our present findings show that phenotypic marker expression is associated with tumor aggressiveness during the early stage of gastric differentiated-type tumors. Differences in the biological behavior of tumors with different phenotypes may result from differences in the genetic backgrounds during the incipient phase of gastric tumorigenesis.

Adenoma↗

PubMed2001

Genotype versus phenotype in families with androgen insensitivity syndrome.

Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.

Adolescent↗

PubMed2006

Diagnosis of alpha-1-antitrypsin deficiency: An algorithm of quantification, genotyping, and phenotyping.

BACKGROUND: Laboratory testing in suspected alpha-1-antitrypsin (A1AT) deficiency involves analysis of A1AT concentrations and identification of specific alleles by genotyping or phenotyping. The purpose of this study was to define and evaluate a strategy that provides reliable laboratory evaluation of A1AT deficiency. METHODS: Samples from 512 individuals referred for A1AT phenotype analysis were analyzed by quantification, phenotype, and genotype. A1AT concentrations were measured by nephelometry. Phenotype analysis was performed by isoelectric focusing electrophoresis. The genotype assay detected the S and Z deficiency alleles by a melting curve analysis. RESULTS: Of the 512 samples analyzed, 2% of the phenotype and genotype results were discordant. Among these 10 discordant results, 7 were attributed to phenotyping errors. On the basis of these data we formulated an algorithm, according to which we analyzed samples by genotyping and quantification assays, with a reflex to phenotyping when the genotype and quantification results were not concordant. Retrospective analyses demonstrated that 4% of samples submitted for genotype and quantitative analysis were reflexed to phenotyping. Of the reflexed samples, phenotyping confirmed the genotype result in 85% of cases. In the remaining 15%, phenotyping provided further information, including identifying rare deficiency alleles and suggesting the presence of a null allele, and allowed for a more definitive interpretation of the genotype result. CONCLUSIONS: The combination of genotyping and quantification, with a reflex to phenotyping, is the optimal strategy for the laboratory evaluation of A1AT deficiency.

Algorithms↗

PubMed2004

[Differentiation of resistance phenotypes among erythromycin-resistant streptococci].

Although macrolide antibiotics have proved to be a valuable alternative to beta-lactam antibiotics in the treatment of respiratory tract infections, resistance to these agents is now becoming established in streptococci, especially among Streptococcus pneumoniae isolates. Of particular concern is the emergence of cross-resistance to 14-, 15- and 16-membered macrolides, licosamides and group B streptogramins (MLSb phenotype). MLS resistance can be expressed either constitutively (cMLS phenotype) or inducibly (iMLS phenotype). MLS resistance is mediated by two classes of methylase genes--the conventional erm(B) and recently described erm(A) determinants. A new macrolide efflux mechanism has been described for streptococci, in which it is associated with a new resistance pattern (M phenotype) characterized by resistance to 14- and 15-membered macrolides, and susceptibility to 16-membered macrolides, lincosamides and streptogramin B. The recognition of the prevalence of M phenotype in streptococci has implications for sensitivity testing and may have an impact on the choice of antibiotic therapy in clinical practice. While M resistance is similar in S. pyogenes and S. pneumoniae being mediated by mef(A) and mef(E), respectively, MLS resistance in both species appears to be genotypically and phenotypically more varied. Differentiation of M and MLS phenotypes of erythromycin-resistant strains can be performed using the erythromycin-clindamycin double-disc method (ECDD). Distinguishing not only M resistance but also constitutively or inducibly MLS phenotype by ECDD in S. pyogenes is easily and reliably achieved. Inducible MLS phenotype S. pyogenes strain is genotypically and phenotypically heterogeneous and is further subdivided into three recently described subtypes, iMLS-A, iMLS-B and iMLS-C, by a triple-disk test with erythromycin plus clindamycin and josamycin. While distinguishing M from MLS resistance in S. pneumoniae by ECDD test is easily and reliably achieved, the differentiation between constitutive and inducible MLS resistance is by far more uncertain. The meaning of inducible MLS resistance appears to be different in S. pneumoniae from that in S. pyogenes. In order to easily differentiate, within erythromycin-resistant pneumococci, not only the strains of the M phenotype from those with MLS resistance but also among the latter, cMLS from iMcLS strains, a triple-disk test has been set up by adding a rokitamycin disk to the conventional

Drug Resistance, Bacterial↗

PubMed1994

Apolipoprotein E phenotypes and serum lipids in newborns and 3-year-old children: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Apolipoprotein E (apoE) phenotype is a genetic determinant of plasma total cholesterol and low density lipoprotein (LDL) cholesterol concentrations, that are classical coronary heart disease risk factors. ApoE appears in three major isoforms E2, E3, and E4, coded by corresponding alleles epsilon 2, epsilon 3, and epsilon 4. These give rise to six different phenotypes. OBJECTIVE: To study the associations of apoE phenotype with cord serum lipids (during minimal enteral nutrition), and with serum lipids of 3-year-old children. SUBJECTS AND METHODS: We determined serum lipid levels and apoE phenotypes in 206 newborns and 259 3-year-old children in connection with a larger follow-up study of atherosclerosis precursors in children and young adults. ApoE phenotyping was done directly from plasma by isoelectric focusing followed by immunoblotting. RESULTS: The effect of apoE phenotype on serum total and LDL cholesterol was significantly different in newborns and 3-year-old children (two-way ANOVA, interaction between apoE phenotype and age group: P < .001 for both). In 3-year-old children, the concentrations of serum total cholesterol and LDL cholesterol increased with apoE phenotype in the order of E3/2, E3/3, E4/3, and E4/4, in both males and females (P < .0001). On the contrary, in neonates total cholesterol and LDL cholesterol concentrations were low and did not differ significantly between apoE phenotypes (P > .05) either in males or in females. The mean serum levels of triglycerides and high density lipoprotein cholesterol did not differ between apoE phenotypes either in 3-year-old children or newborns. CONCLUSIONS: The results show that the differences in serum total and LDL cholesterol levels between apoE phenotypes are formed after birth by the influence of environmental factors and suggest that both genetic and external factors influence the levels of serum cholesterol concentrations during the first years of life.

Adolescent↗

PubMed2025

Optimized phenotyping of complex morphological traits: enhancing discovery of common and rare genetic variants.

Genotype-phenotype (G-P) analyses for complex morphological traits typically utilize simple, predetermined anatomical measures or features derived via unsupervised dimension reduction techniques (e.g. principal component analysis (PCA) or eigen-shapes). Despite the popularity of these approaches, they do not necessarily reveal axes of phenotypic variation that are genetically relevant. Therefore, we introduce a framework to optimize phenotyping for G-P analyses, such as genome-wide association studies (GWAS) of common variants or rare variant association studies (RVAS) of rare variants. Our strategy is two-fold: (i) we construct a multidimensional feature space spanning a wide range of phenotypic variation, and (ii) within this feature space, we use an optimization algorithm to search for directions or feature combinations that are genetically enriched. To test our approach, we examine human facial shape in the context of GWAS and RVAS. In GWAS, we optimize for phenotypes exhibiting high heritability, estimated from either family data or genomic relatedness measured in unrelated individuals. In RVAS, we optimize for the skewness of phenotype distributions, aiming to detect commingled distributions that suggest single or few genomic loci with major effects. We compare our approach with eigen-shapes as baseline in GWAS involving 8246 individuals of European ancestry and in gene-based tests of rare variants with a subset of 1906 individuals. After applying linkage disequilibrium score regression to our GWAS results, heritability-enriched phenotypes yielded the highest SNP heritability, followed by eigen-shapes, while commingling-based traits displayed the lowest SNP heritability. Heritability-enriched phenotypes also exhibited higher discovery rates, identifying the same number of independent genomic loci as eigen-shapes with a smaller effective number of traits. For RVAS, commingling-based traits resulted in more genes passing the exome-wide significance threshold than eigen-shapes, while heritability-enriched phenotypes lead to only a few associations. Overall, our results demonstrate that optimized phenotyping allows for the extraction of genetically relevant traits that can specifically enhance discovery efforts of common and rare variants, as evidenced by their increased power in facial GWAS and RVAS.

Humans↗

PubMed2005

Airborne occupational exposure, ABO phenotype, and risk of obesity.

BACKGROUND: We have previously found a quite strong interplay between occupational airborne pollutants, ABO phenotypes, and risk of ischaemic heart disease (IHD), with long-term exposure being associated with a significantly increased risk among men with phenotype O, and not among men with other ABO phenotypes. We suggested that the biological pathway could be a stronger systemic inflammatory response in men with blood group O. Several inflammatory mediators likely to increase the risk of IHD have recently been linked also to obesity, suggesting that long-term exposure to airborne pollutants might play a role in the aetiology of obesity. Accordingly, we tested the hypothesis that long-term occupational exposure to airborne pollutants would be more strongly associated with obesity in men with phenotype O than in men with other ABO phenotypes. DESIGN: Cross-sectional exposure-response study taking into account potential confounders. SETTING: The Copenhagen Male Study. SUBJECTS: A total of 3290 men aged 53-74 y. MAIN OUTCOME MEASURE: Prevalence of obesity (BMI > or =30 (kg/m2)). RESULTS: Overall, no differences were found in the prevalence of obesity between men with the O phenotype (n=1399) and men with other phenotypes (n=1891), 8.6 and 9.0%. However, only among men with the O phenotype was long-term occupational exposure (at least 5 y of frequent exposure) to various respirable airborne pollutants: dust, asbestos, soldering fumes, welding fumes, organic solvents, fumes from lacquer, paint or varnish, toxic components, breath irritants, stench or strongly smelling products, and irritants (other than breath irritants or contagious components) associated with an increased prevalence of obesity. Statistically, the strongest univariate associations were found for asbestos exposure, welding fumes, and breath irritants. Odds ratios (95% confidence limits) for these factors were 3.7 (1.8-7.6), 2.7 (1.6-4.4), and 2.6 (1.5-4.4), respectively. This particular relationship of airborne exposures with obesity in men with phenotype O was supported in multivariate analysis including interaction terms and taking into account a number of potential confounders. In contrast, no gene-environment interactions with obesity were found with respect to ABO phenotypes and a number of nonrespirable exposures. CONCLUSION: The finding of a quite strong interplay between long-term exposure to airborne pollutants, ABO phenotypes, and risk of obesity may open up new possibilities for clarifying mechanisms underlying the global obesity epidemic.

ABO Blood-Group System↗