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PubMed1999

Associations among serum lipoprotein(a) levels, apolipoprotein(a) phenotypes, and myocardial infarction in patients with extremely low and high levels of serum lipoprotein(a).

A high serum lipoprotein(a) [Lp(a)] level, which is genetically determined by apolipoprotein(a) [apo(a)] size polymorphism, is an independent risk factor for coronary atherosclerosis. However, the associations among Lp(a) levels, apo(a) phenotypes, and myocardial infarction (MI) have not been studied. Patients with MI (cases, n = 101, M/F: 86/15, age: 62+/-10y) and control subjects (n = 92, M/F: 53/39, age: 58+/-14y) were classified into quintile groups (Groups I to V) according to Lp(a) levels. Apo(a) isoform phenotyping was performed by a sensitive, high-resolution technique using sodium dodecyl sulfate-agarose/gradient polyacrylamide gel electrophoresis (3-6%), which identified 26 different apo(a) phenotypes, including a null type. Groups with higher Lp(a) levels (Groups II, III, and V) had higher percentages of MI patients than that with the lowest Lp(a) levels (Group I) (54%, 56%, or 75% vs. 32%, p<0.05). Groups with different Lp(a) levels had different frequency distributions of apo(a) isoprotein phenotypes: Groups II, III, IV, and V, which had increasing Lp(a) levels, had increasingly higher percentages of smaller isoforms (A1-A4, A5-A9) and decreasingly lower percentages of large isoforms (A10-A20, A21-A25) compared to Group I. An apparent inverse relationship existed between Lp(a) and the apo(a) phenotype. Subjects with the highest Lp(a) levels (Group V) had significantly (p<0.05) higher serum levels of total cholesterol, apo B, and Lp(a). Patients with MI and the controls had different distributions of apo(a) phenotypes: i.e., more small isoforms and more large size isoforms, respectively (A1-A4/A5-A9/A10-A20/A21-A25: 35.7%/27.7%/20.8%/15.8% and 22.8%/23.9%/29.4%/23.9%, respectively). Lp(a) (parameter estimate +/- standard error: 0.70+/-0.20, Wald chi2 = 12.4, p = 0.0004), apo(a) phenotype (-0.43+/-0.15, Wald chi2 = 8.17, p = 0.004), High-density lipoprotein-cholesterol, apo A-I, and apo B were significantly associated with MI after adjusting for age, gender, and conventional risk factors, as assessed by a univariate logistic regression analysis. The association between Lp(a) and MI was independent of the apo(a) phenotype, but the association between the apo(a) phenotype and MI was not independent of Lp(a), as assessed by a multivariate logistic regression analysis. This association was not influenced by other MI- or Lp(a)-related lipid variables. These results suggest that apo(a) phenotype contributes to, but does not completely explain, the increased Lp(a) levels in MI. A stepwise logistic regression analysis with and without Lp(a) in the model identified Lp(a) and the apo(a) phenotype as significant predictors for MI, respectively.

Apolipoproteins A↗
PubMed2026

Genetic Correlation Between Brain Imaging Phenotypes and Externalizing Behavior: A Large-Scale LDSC Analysis of UK Biobank IDPs.

Externalizing has been associated with differences in brain structure and function; however, it remains unclear whether these associations reflect shared common-variant genetic influences. Cross-trait linkage disequilibrium score regression was used to estimate genome-wide genetic correlations between externalizing genome-wide association study (GWAS) results and 3,935 brain imaging-derived phenotypes from the UK Biobank BIG40 resource. The imaging phenotypes covered structural magnetic resonance imaging (MRI), diffusion MRI, susceptibility-weighted imaging, resting-state functional MRI, and task-based functional MRI. Results were included in the primary analysis when the imaging phenotype had positive single-nucleotide polymorphism (SNP) heritability, a heritability Z statistic of at least 1.96, a mean GWAS chi-square statistic of at least 1.02, at least 200,000 regression SNPs, and a complete LDSC result without a fatal error. Technical imaging quality-control phenotypes were excluded from biological inference. Individual results were corrected using the Benjamini-Hochberg false discovery rate procedure. Aggregated Cauchy association tests (ACATs) were used to evaluate evidence across all imaging phenotypes and within predefined imaging categories. Statistical power, simultaneous confidence bounds, and alternative quality-control definitions were examined in sensitivity analyses. Of the 3,935 imaging phenotypes, 3,716 produced estimable genetic correlations, 2,980 met the primary LDSC quality-control criteria, and 2,967 were classified as biological imaging phenotypes. No individual phenotype survived false discovery rate correction. The smallest unadjusted P value was 0.0005, and the minimum adjusted q value was 0.486. The distribution of genetic correlations was centered near zero, with a median genetic correlation of 0.0014 and a median absolute genetic correlation of 0.0338. ACAT provided no evidence of an aggregate association across all biological imaging phenotypes (P = 0.302), and no predefined imaging category survived multiple-testing correction. The median minimum detectable genetic correlation at 80% power was 0.216. Bonferroni-adjusted simultaneous confidence intervals were fully contained within the interval [-0.30, 0.30] for 80.0% of phenotypes in the primary analysis and 88.0% under the stringent heritability quality-control definition. Broad and stringent sensitivity analyses produced the same overall conclusions. In this study, no statistically robust evidence of genome-wide genetic correlations between externalizing and individual UK Biobank brain imaging phenotypes was found. Nevertheless, small, localized, mixed-direction, or developmentally specific genetic effects remain possible.

Journal Article↗
PubMed1989

[Ultrastructural evaluation of pulmonary adenocarcinoma. II. Phenotype heterogeneity and classification].

A phenotypical heterogeneity was observed in 45 tumours (45 per cent) from a group of 102 carcinomas with ultrastructural features of exocrine differentiation. Double heterogeneity was found in 36 tumours and a triple one in 8 tumours; a case with quadruple heterogeneity was presented analogy of which has been lacking in literature. A combination of different exocrine phenotypes occurred in 12 tumours, exocrine and endocrine phenotypes combined in 18 tumours, exocrine cells and keratinocytes were found in 21 tumours. The exocrine phenotype was characterized usually (38 times) by secretion granules mostly of a serous type (19 times), cells with microvillous specialization without granules represented (15 times) a lower level of the exocrine phenotypical differentiation. A ciliary phenotype which could not produce homogenous population of dividing cells yet occurred (4 times) as a rudimentary accompaniment of an endocrine phenotype. The case of quadruple heterogeneity combined ciliary, serous, endocrine and keratinocytic phenotypes. The WHO histological typing scheme does not offer a proper category for heterogenous adenocarcinomas with one prevailing exocrine phenotype when compared with an analogous group of "combined" small cell carcinomas. Histological typing of such heterogenous adenocarcinomas is to be completed at least by an electron microscopical prevailing cytological characteristic in the same way as in phenotypically homogenous carcinomas. Heterogenous tumours without any phenotypical prevalence may form a group of mixed carcinomas which has been represented so far only by the histological types of adenosquamous and mucoepidermoid carcinoma.

Adenocarcinoma↗
PubMed2025

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically. METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes. RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without. CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Humans↗
PubMed2005

Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women.

The major transporter of vitamin D metabolites in the circulation is the multifunctional plasma protein Gc, also known as group-specific component, Gc globulin, vitamin D-binding protein, or DBP. There are several phenotypes of Gc, and we examined the influence of Gc phenotype and Gc concentration on vitamin D status. By using isoelectric focusing we identified the Gc phenotype of 595 caucasian recent postmenopausal women enrolled into the Danish Osteoporosis Prevention Study (DOPS). We measured plasma concentration of Gc by immunonephelometry (coefficient of variation [CV] < 5%), 25-hydroxy vitamin D (25OHD) by a competitive protein-binding assay (CV 10%), and 1,25-dihydroxy-vitamin D (1,25(OH)(2)D) by a radioimmunoassay (CV 6--14%), and calculated index as the molar ratio of vitamin concentration divided by Gc concentration. Plasma levels of Gc, 25OHD, 25OHD index, and 1,25(OH)(2)D, but not 1,25(OH)(2)D index, differed significantly between women with different Gc phenotype, being highest in Gc1-1, intermediate in Gc1-2, and lowest in Gc2-2. In multiple regression analysis, Gc concentration was an independent predictor of 1,25(OH)(2)D, whereas Gc phenotype was a significant predictor of 25OHD concentration, even after adjustment for the effects of season, sunbathing habits, skin thickness, use of vitamin supplements, smoking, and body mass index (BMI). Plasma parathyroid hormone (PTH) level did not differ between Gc phenotypes. Despite the fact that more than 60% of the women with Gc phenotype Gc2-2 had plasma 25OHD levels of less than 50 nmol/L none of them had plasma PTH higher than reference limits. Bone mineral content (BMC), Bone mineral density (BMD), and bone markers did not differ between Gc phenotypes. In conclusion, plasma 1,25(OH)(2)D, 25OHD, and 25OHD index are related to Gc phenotype, and we speculate that the thresholds for vitamin D sufficiency differ between Gc phenotypes.

Cross-Sectional Studies↗
PubMed2005

Relationship between biological behavior and phenotypic expression in undifferentiated-type gastric carcinomas.

BACKGROUND: It has been proved that some differentiated-type gastric carcinomas have a gastric phenotype. Similarly, it can be conjectured that some undifferentiated-type gastric carcinomas have an intestinal phenotype and that there are biological differences between undifferentiated-type gastric carcinomas with a gastric phenotype and those with an intestinal phenotype. We classified the phenotypes of early undifferentiated-type gastric carcinomas and investigated the relationship between their biological behavior and the phenotypes. METHODS: Sixty lesions of intramucosal undifferentiated-type gastric carcinoma were classified into four phenotypes; gastric type, incomplete-intestinal type, complete-intestinal type, and unclassified type, according to the expression of CD10, MUC2, small-intestinal mucinous antigen (SIMA), human gastric mucin (HGM), or concanavalin A (ConA). RESULTS: The incidence of gastric-type carcinoma, incomplete-intestinal-type carcinoma, and complete-intestinal-type carcinoma was 33% (20 cases), 65% (39 cases), and 2% (1 case), respectively. There was no significant difference in any of the clinicopathological factors examined between the 20 gastric-type carcinomas and the 40 intestinal-type carcinomas, but there were significant differences in the morphological findings. Intestinal-type carcinomas had a glandular structure more frequently than the gastric-type carcinomas. The spreading pattern of gastric-type carcinomas showed a middle-layer type more frequently than the intestinal-type carcinomas. CONCLUSION: Undifferentiated-type gastric carcinomas frequently expressed an intestinal phenotype. There were differences in the growth patterns between undifferentiated-type gastric carcinomas with a gastric phenotype and those with the intestinal phenotype.

Adenocarcinoma↗
PubMed1994

Evidence that apolipoprotein(a) phenotype is a risk factor for coronary artery disease in men < 55 years of age.

Whereas the importance of plasma lipoprotein(a) [Lp(a)] levels as a risk factor for premature coronary artery disease (CAD) is certain, it is not clear if the apolipoprotein(a) [apo(a)] phenotype plays an additional and independent role. To investigate the possible effect of apo(a) phenotype on premature CAD (in patients < 55 years of age), plasma Lp(a) concentrations, the apo(a) phenotypes, and their relation with many recognized CAD risk factors were examined in 96 non-diabetic male patients with angiographically defined CAD and in 83 age-matched male control subjects with no angiographic evidence of CAD. Results demonstrate that patients with premature CAD are characterized by higher Lp(a) levels (24 +/- 21 vs 17 +/- 15 mg/dl, p < 0.01) and a higher frequency of S2 phenotype (32% vs 15%, p < 0.01). Patients with an S2 phenotype exhibited significantly higher plasma Lp(a) concentrations than control subjects with the same isoform (37 +/- 22 vs 22 +/- 17 mg/dl, p < 0.05). A significant correlation was found between apo B and Lp(a) levels in patients with an S2 phenotype. In addition, patients had a low frequency of S1 and S4, and a high frequency of double-band phenotypes of apo(a). Multivariate analysis did not demonstrate an independent role for apo(a) phenotype as a risk factor for premature CAD. In conclusion, CAD patients < 55 years of age have a very different pattern of apo(a) phenotypes than subjects with no angiographic evidence of CAD; this study confirms the hypothesis that apo(a) phenotype may play an additional role in the etiology of premature CAD.

Apolipoproteins↗
PubMed1990

A 36 nucleotide deletion mutation in the coding region of the NS1 gene of an influenza A virus RNA segment 8 specifies a temperature-dependent host range phenotype.

Previously a spontaneous 36 nucleotide deletion in the coding region of NS1 was detected in the NS gene of a reassortant virus (CR43-3) recovered from a dual infection by the influenza A/Ann Arbor/6/60 cold-adapted (ca) mutant and wild-type (wt) influenza A/Alaska/6/77 (H3N2). The hemagglutinin, neuraminidase and NS genes were derived from the wild type virus parent while the other 5 genes were derived from the ca parent. The CR43-3 reassortant virus exhibited: (i) a host range (hr) phenotype, i.e. the reassortant replicated efficiently in avian cells in tissue culture but failed to grow in mammalian (MDCK) cell culture and (ii) an attenuation (att) phenotype, i.e., the reassortant was restricted in replication in the upper and lower respiratory tract of ferrets and hamsters. Since the CR43-3 reassortant possessed 5 genes from the ca parent which are each known to contain one or more mutations, it was not possible to assign the hr and att phenotypes solely to the NS deletion mutant gene. In order to determine the phenotype(s) specified solely by the mutant NS gene, it was transferred into a reassortant virus (143-1) which derived its seven other genes from the homologous wild type A/Alaska/6/77 virus. The deletion mutant NS gene specified only a partial hr phenotype manifested by a reduction in plaque size in MDCK tissue, but not a reduction in plaque number. Thus, the complete hr manifested by the CR43-3 parent virus is specified by the mutant NS1 gene acting in concert with one or more genes derived from the ca virus. The clone 143-1 virus exhibited the ts phenotype and was restricted in plaque formation at 37 degrees C in MDCK cells, a level of temperature sensitivity previously shown with other ts mutants to correlate with significant restriction of viral replication in the lower respiratory tract of hamsters. However, the clone 143-1 virus grew almost as well as the wt virus in the upper and lower respiratory tracts of hamsters and chimpanzees and thus did not possess the att phenotype. The finding that the ts phenotype was not manifest in vivo in animals with a 37 degrees C core temperature indicates that the mutated NS1 gene specifies a host dependent ts phenotype with replication restricted in vitro (MDCK tissue culture) at 37 degrees C but not in vivo in the lungs of hamsters and chimpanzees. ts+ virus was readily recovered from infected hamsters and chimpanzees indicating that the ts phenotype specified by the 36-base deletion was not stable following replication in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Identification of genes involved in the switch between the smooth and rugose phenotypes of Vibrio cholerae.

Vibrio cholerae can switch to a 'rugose' phenotype characterized by an exopolysaccharide (EPS) matrix, wrinkled colony morphology, increased biofilm formation and increased survival under specific conditions. The vps gene cluster responsible for the biosynthesis of the rugose EPS (rEPS) is positively regulated by VpsR. We recently identified media (APW#3) promoting EPS production and the rugose phenotype and found epidemic strains switch at a higher frequency than non-pathogenic strains, suggesting this switch and the rugose phenotype are important in cholera epidemiology. In this study, transposon mutagenesis on a smooth V. cholerae strain was used to identify mutants that were unable to shift to the rugose phenotype under inducing conditions to better understand the molecular basis of the switch. We identified vpsR, galE and vps previously associated with the rugose phenotype, and also identified genes not previously associated with the phenotype, including rfbD and rfbE having roles in LPS (lipopolysaccharide) synthesis and aroB and aroK with roles in aromatic amino acid synthesis. Additionally, a mutation in amiB encoding N-acetylmuramoyl-L-alanine amidase caused defects in the switch, motility and cell morphology. We also found that a gene encoding a novel regulatory protein we termed RocS (regulation of cell signaling) containing a GGDEF and EAL domains and associated with c-di-GMP levels is important for the rugose phenotype, EPS, biofilm formation and motility. We propose that modulation of cyclic dinucleotide (e.g. c-di-GMP) levels might have application in regulating various phenotypes of prokaryotes. Our study shows the molecular complexity of the switch between the smooth and rugose phenotypes of V. cholerae and may be relevant to similar phenotypes in other species.

Biofilms↗
PubMed1997

Distribution of K88 Escherichia coli-adhesive and nonadhesive phenotypes among pigs of four breeds.

Enterotoxigenic Escherichia coli expressing K88 fimbrial adhesins often cause diarrhea in young pigs. However, some pigs are inherently resistant to colibacillosis, because they lack receptors on their epithelial cell brush borders to which the fimbriae bind. Phenotypic diversity with respect to the binding of E. coli expressing K88 of the three variant types (K88ab, K88ac, and K88ad) was reported by Bijlsma et al. (1982), and binding specificities for each phenotype were described: A (adhesive to all three variants), B (adhesive to K88ab and K88ac), C (adhesive to K88ab and K88ad), D (adhesive to K88ad) and E (nonadhesive). Because brush border adhesiveness has been correlated with disease susceptibility, swine K88 adhesive phenotypes are of significance in the control of enteric disease. To determine the prevalence of the various K88 adhesive phenotypes in the swine population in the Midwestern United States, we tested epithelial cell brush borders of 24 purebred pigs from each of four breeds (Chester White, Duroc, Hampshire and Yorkshire) for adhesiveness to each of the K88 variants. Four, 4-week-old pigs (the largest and smallest healthy female littermates from two litters) were collected from each of 24 farms. Brush border vesicles from the pigs were tested for ability to bind E. coli expressing each K88 variant. The five brush border adherence patterns described for phenotypes A-E were observed. In addition, brush borders from some pigs only bound K88ab + bacteria. Nearly three quarters of the pigs whose brush borders tested, were found to be phenotype A (43%) or phenotype E (28%). These were the most common phenotypes in each breed, except Hampshire, in which case phenotypes C (17%) and D (25%) were more common than E (8%). There appeared to be no relationship between the phenotype of a pig and its weight relative to its littermate.

Animals↗
PubMed1998

Apolipoprotein E phenotype determines the effect of alcohol on blood pressure in middle-aged men.

Apolipoprotein E (apoE) has an essential role in lipoprotein metabolism, but recent studies have also revealed other functions associated with it, eg, neurologic and malignant diseases. We studied the association between apoE phenotypes E2/3, E3/3, and E4/3 and blood pressure after adjustment for covariates, as well as the association between phenotypes and adjusted plasma glucose and insulin levels in the standard oral glucose tolerance test in a random middle-aged population-based cohort of 259 men and 267 women. Systolic blood pressure was associated with apoE phenotype in the men with moderate or heavy alcohol consumption (>115 g/week), the mean systolic blood pressure value being 16 mm Hg higher in the E2/3 and 11 mm Hg higher in the E3/3 phenotypes than in the E4/3 phenotype, P = .04. No association was seen in occasional drinkers or teetotalers (lowest tertile <24 g/week), whereas in the middle tertile the association was intermediate. The same association was seen with diastolic blood pressure. In men, there was a significant correlation between systolic blood pressure and alcohol consumption in the E2/3 phenotype (rs = 0.71, P < .01) and in the E3/3 phenotype (rs = 0.25, P < .01), but not in the E4/3 phenotype (rs = 0.03, NS). No association between apoE phenotypes and insulin resistance was observed. In conclusion, in middle-aged men, apoE phenotype significantly influences the blood-pressure-increasing effect of alcohol consumption. This gene environment interaction may have marked implications for the prevention and treatment of hypertension.

Adult↗
PubMed2002

Phenotypic switching in Cryptococcus neoformans.

Cryptococcus neoformans strains exhibit considerable phenotype variability with regards to the capsular polysaccharide, sterol composition of the cell wall, and cell and colony morphology. Phenotypic changes can occur spontaneously during in vitro passage of strains or during chronic infection in vivo and may be associated with differences in virulence. Studies from our laboratory have demonstrated that phenotype variability can be the result of phenotypic switching. Phenotypic switching is defined as a reversible change of an observable colony phenotype that occurs at a frequency above the expected frequency for somatic mutations. This implies that phenotypic switching represents controlled and programmed changes in this pathogenic yeast rather than random mutations. We have shown that a phenotypic switch from a smooth colony phenotype to a mucoid colony phenotype occurs in vitro and in vivo during chronic infection of mice. More importantly we have now demonstrated that the switch is associated with an increase in virulence and a change in the host immune response. Implications of these findings for the pathogenesis of cryptococcosis are discussed.

Cryptococcosis↗
PubMed1997

Screening with monoclonal anti-Fy3 to provide blood for phenotype-matched transfusions for patients with sickle cell disease.

BACKGROUND: In the United States, there is a shortage of blood group phenotype-matched red cells (RBCs) for patients with sickle cell disease (SCD). A protocol designed to supply phenotype-matched RBCs for these patients by combining the recruitment of African American blood donors and automated testing of RBCs for these patients for the presumptive Fy(a-b-) phenotype using monoclonal anti-Fy3 was evaluated. STUDY DESIGN AND METHODS: African American donors were recruited, to increase the likelihood of phenotype matches in the donor population. Samples of RBCs were tested for the presumptive Fy(a-b-) phenotype by using monoclonal anti-Fy3 and an automated blood typing analyzer. RBCs confirmed to be Fy(a-b-) were retyped for selected Rh, MNS, Kell, Duffy, and Kidd blood system antigens. The extended phenotypes were matched with those of 41 SCD patients requiring transfusions. RESULTS: Of 8323 blood donations during the study, approximately 40 percent (3329) were made by African Americans. Approximately 22 percent (737) of African Americans were identified as Fy(a-b-) by this protocol and 12 percent (410) were phenotype matches for the 41 SCD patients. CONCLUSION: Combining the recruitment of African American blood donors and automated phenotyping using monoclonal anti-Fy3 offers a practical, relatively low-cost strategy for supplying phenotype-matched RBCs for SCD patients. This protocol increases the options for addressing the shortage of phenotype-matched RBCs for SCD patients.

Anemia, Sickle Cell↗
PubMed2002

Predicting the effect of transfusing only phenotype-matched RBCs to patients with sickle cell disease: theoretical and practical implications.

BACKGROUND: Transfusing only phenotype-matched RBCs has been recommended to reduce the incidence of alloimmunization to blood group antigens in patients with sickle cell disease (SCD). STUDY DESIGN AND METHODS: The expected benefit of phenotype matching was determined by identifying which of the existing blood group alloantibodies in patients with SCD who received conventional transfusions would not have been formed if they had received only phenotype-matched RBCs. By use of each patient's alloantibodies as a baseline, it was possible to identify specific alloantibodies that would not have been formed if each of five different phenotype-matching protocols had been used. RESULTS: During a 12-year period, 351 patients received transfusions with 8939 units of ABO- and D-matched RBCs. Of these, 102 patients (29.1%) formed at least one blood group alloantibody. An additional 35 patients with SCD with alloantibodies were identified by reviewing clinical records, yielding a total of 137 alloimmunized patients for inclusion in this study. If all transfusions had been selected by limited phenotype matching (C, c, E, e, and K, as well as for ABO and D), all alloantibodies would have been prevented for more than half (53.3%) of the 137 alloimmunized patients. If all transfusions had been matched for C, c, E, e, K, S, Fya, and Jkb, all antibodies would have been prevented for 70.8 percent of the 137 alloimmunized patients. Approximately 13.6 percent of random white blood donors would be expected to match a limited phenotype-matching protocol, whereas only 0.6 percent would match an extended phenotype-matching protocol. CONCLUSION: Limited phenotype matching would have prevented all alloantibodies in 53.3 percent of the patients who formed alloantibodies. This protocol requires RBCs that are readily available. Extended phenotype matching would have prevented alloimmunization in 70.8 percent of patients who formed alloantibodies. However, this would require phenotypes that are 22.7 times less prevalent among random blood donors and is therefore impractical for a long-term strategy.

ABO Blood-Group System↗
PubMed1984

Is there a relationship between genetically determined haptoglobin phenotype and insulin-dependent diabetes mellitus (IDDM)?

The possible relationship between genetically determined haptoglobin phenotype and insulin-dependent diabetes (IDDM), circulating insulin antibodies and the occurrence of microangiopathy was studied in 144 IDDM. There were no differences regarding the distribution of Hp-phenotypes in 144 patients in comparison with a control population (n = 1726). Irrespective of the Hp-phenotype, the degree and severity of diabetic complications (retinopathy and/or nephropathy) significantly increased with the duration of diabetes. There was no relationship between Hp-phenotype and diabetic microangiopathy (retinopathy, nephropathy). No association existed between Hp-phenotype and the percentage of insulin antibody binding. Regardless of the Hp-phenotype, the insulin antibody concentration decreased with increasing duration of diabetes. Insulin binding parameters (maximum binding capacity and equilibrium dissociation constant) were found to vary considerably with the Hp-phenotypes among IDDM. For a given duration of diabetes the equilibrium dissociation constant increased significantly in the range from Hp 1-1, Hp 2-1 to Hp 2-2 phenotype. There was a direct relationship between the logarithm of the equilibrium dissociation constant and the degree of metabolic control, i.e. the lower the dissociation constant the better the metabolic balance. In conclusion, the results do not provide support for a putative relationship between Hp-phenotype and IDDM. However, differences between insulin binding parameters, in dependence on the Hp-phenotype may be of clinical importance.

Adolescent↗
PubMed1995

Maintenance of syncytium-inducing phenotype of HIV type 1 is associated with positively charged residues in the HIV type 1 gp120 V2 domain without fixed positions, elongation, or relocated N-linked glycosylation sites.

The prevalence of HIV-1 sequences of the envelope domains V1V2 and V3 was analyzed by RT-PCR amplification. Two distinct biological phenotypes of HIV-1 have been described: the nonsyncytium-inducing (NSI) phenotype, best characterized by the inability to infect MT-2 cells, and the syncytium-inducing phenotype (SI), with the ability to infect MT-2 cells. Viral phenotype SI has been associated with HIV pathogenesis. The presence of positively charged amino acids at position 306 and 320 in the V3 domain of gp120 has been shown to be required for the support of the SI phenotype. In addition, V2 elongation and relocation of N-glycosylation sites were postulated to herald an NSI to SI phenotype switch. The present study was designed to assess the stability of an elongated V2 region with relocated N-glycosylation sites observed in SI isolates compared to NSI isolates. Eleven isolates with the SI phenotype and 19 isolates with the NSI phenotype were included in the study. Nine of the SI and 1 of the NSI isolates had a positively charged residue at position 306 or 320 (p < 0.001) in the V3 domain as assessed by direct sequencing of the viral RNA. In contrast, elongation and/or relocation of N-glycosylation sites of the V2 variable region were not found to be a consistent genetic feature of the SI phenotype. However, SI isolates had more positively charged amino acid residues in the hypervariable V2 region compared with NSI isolates. In one of the two SI isolates lacking positively charged amino acids at positions 306 or 320 in the V3 loop an elongation of 26 amino acids with 4 additional N-linked glycosylation sites was observed in the V2 region. This is consistent with the theory that elongation of V2 may be transiently required for SI conversion. These results suggest that maintenance of the SI phenotype requires positively charged amino acids in V3 in the majority of the virus population, but not an elongated V2 region with added or relocated N-linked glycosylation sites. Although increased charged residues in the V2 region may contribute.

Amino Acid Sequence↗
PubMed2006

Clustering of metabolic abnormalities in adolescents with the hypertriglyceridemic waist phenotype.

BACKGROUND: It remains unknown whether the hypertriglyceridemic waist (HW) phenotype, an appropriate screening tool in adults, can also be used to screen for metabolic abnormalities in adolescents. OBJECTIVE: We aimed to evaluate metabolic risk factors identified by the HW phenotype in adolescents. DESIGN: Anthropometric and biochemical measurements were assessed in a population-based cross-sectional study of 1413 male and 1623 female Iranian adolescents aged 10-19 y. The HW phenotype was defined as serum triacylglycerol concentrations > or = 110 mg/dL and concurrent waist circumference > or = 90th percentile for age and sex. Elevated fasting glucose (> or = 110 mg/dL), high LDL (> or = 130 mg/dL) and low HDL (< or = 40 mg/dL) cholesterol, hypercholesterolemia (total cholesterol > or = 200 mg/dL), and hypertension (systolic or diastolic blood pressure > or = 95th percentile for age, sex, and height) were considered as risk factors. RESULTS: Adolescents with the HW phenotype had significantly higher prevalences of all metabolic risk factors except elevated fasting glucose than did those without the HW phenotype. After control for potential confounding variables, adolescents with the HW phenotype were significantly more likely to have high LDL cholesterol (odds ratio: 1.8; 95% CI: 1.3, 2.7), low HDL cholesterol (1.6; 1.3, 2.0), hypercholesterolemia (2.9; 2.0, 4.2), and > or = 1 (1.4; 1.1, 1.7) and > or = 2 (2.2; 1.6, 3.0) risk factors than were those without the HW phenotype. The HW phenotype had a significantly higher percentage of correct prediction of metabolic abnormalities than did overweight, elevated triacylglycerol concentration, or enlarged waist circumference. CONCLUSION: This study shows a clustering of metabolic abnormalities in adolescents with the HW phenotype and suggests this phenotype as a simple marker for identifying adolescents at risk of metabolic syndrome and other metabolic abnormalities.

Adolescent↗
PubMed1986

Evidence for growth heterogeneity among foci with different phenotypes in the population of altered hepatocyte foci induced by a single neonatal treatment with carcinogen.

Relationships between phenotypic and growth characteristics of carcinogen-induced altered hepatocyte foci were investigated. Male and female rats were given a single i.p. injection of carcinogen (diethylnitrosamine or benzo[a]pyrene) within 1 day after birth and were exposed to dietary promoter (phenobarbital) beginning at weaning. Groups of these rats were then killed at intervals, and their livers were examined for foci exhibiting various phenotypic markers through the use of serial frozen sectioning techniques, histochemical staining and computer-assisted image analysis. These procedures permitted the identification and sizing of foci with different specific phenotypes (identities of focus markers) within each phenotypic complexity level (number of markers per focus). The data suggest that foci growth rates differ with respect to specific focus phenotypes within complexity levels. This observation complements previous demonstrations of a direct relationship between foci growth rates and levels of phenotypic complexity and indicates that the observed diversity of focus phenotypes reflects true biological diversity within the focus population. Given the prior evidence for (i) the stability of focus phenotypes; (ii) the rapid emergence of phenotypically dissimilar foci following a single carcinogen treatment; and (iii) the production of foci by single initiation events, we suggest that each proliferatively and phenotypically distinct member of the focus population reflects the occurrence of a lesion at a unique genetic locus during initiation.

Animals↗