Human Orosomucoid (ORM1) Subtyping: Further Population Genetic Data and Reports on the Feasibility to Type Aged Blood Samples and Stains

Dülmer, Marlies; Reker, Gabriele; Nguyen, Thuy Trang; Henke, Lotte; Henke, Jürgen

doi:10.1520/jfs16159j

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…The relative frequencies of alpha-1 glycoprotein acid phenotypes found here are close to those previously described in healthy subjects or in HIV-infected patients (5,8). We did not find ORM1*F2 on this population, but this variant is present only at a low allelic frequency (9,19). As already described in healthy subjects, alpha-1 glycoprotein acid plasma concentrations were not found to differ between the 3 phenotypes (18).…”

Section: Discussionsupporting

confidence: 90%

Influence of Alpha-1 Glycoprotein Acid Concentrations and Variants on Atazanavir Pharmacokinetics in HIV-Infected Patients Included in the ANRS 107 Trial

Barrail-Tran

Mentré

Cosson

et al. 2010

Antimicrob Agents Chemother

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Atazanavir is an HIV-1 protease inhibitor with high protein binding in human plasma. The objectives were first to determine the in vitro binding characteristics of atazanavir and second to evaluate whether plasma protein binding to albumin and alpha-1 glycoprotein acid (AAG) influences the pharmacokinetics of atazanavir in HIV-infected patients. For the in vitro study, atazanavir protein binding characteristics were determined in AAG-and albumin-containing purified solutions. Atazanavir was found to bind AAG on a high-affinity saturable site (association constant, 4.61 ؋ 10 5 liters/mol) and albumin on a low-affinity nonsaturable site. For the in vivo study, blood samples from 51 patients included in trial ANRS 107-Puzzle 2 were drawn prior to drug intake at week 6. For 10 patients included in the pharmacokinetic substudy, five additional blood samples were collected during one dosing interval at week 6. Atazanavir concentrations were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Albumin concentrations, AAG concentrations, and phenotypes were also measured in these patients. Concentrations of atazanavir were modeled using a population approach. A one-compartment model with first-order absorption and elimination best described atazanavir pharmacokinetics. Atazanavir pharmacokinetic parameters and their interindividual variabilities were as follows: absorption rate constant (k a ), 0.73 h ؊1 (139.3%); apparent clearance (CL/F), 13.3 liters/h (26.7%); and apparent volume of distribution (V/F), 79.7 liters (27.0%). Atazanavir CL/F decreased significantly when alanine aminotransferase and/or AAG levels increased (P < 0.01). The ORM1*S phenotype also significantly increased atazanavir V/F (P < 0.05). These in vivo results indicate that atazanavir pharmacokinetics is moderately influenced by its protein binding, especially to AAG, without expected clinical consequences.

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Section: Discussionsupporting

confidence: 90%

Influence of Alpha-1 Glycoprotein Acid Concentrations and Variants on Atazanavir Pharmacokinetics in HIV-Infected Patients Included in the ANRS 107 Trial

Barrail-Tran

Mentré

Cosson

et al. 2010

Antimicrob Agents Chemother

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“…In Method C, desialylated samples were alkylated with iodoacetamide and subjected to isoelectric focusing in the presence of 8M urea. The banding patterns were visualized by immunoprinting and immunoblotting (Yuasa et al 1993;Rocha et al 1993;Dülmer et al 1998). …”

Section: Isoelectric Focusing and Immunodetectionmentioning

confidence: 99%

Characterization of genomic rearrangements of the α1-acid glycoprotein/orosomucoid gene in Ghanaians

et al. 2001

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In this study, the structure of the α 1 -acid glycoprotein (AGP), or orosomucoid (ORM), gene was investigated in a Ghanaian mother and her child, who shared an unusual variant, ORM1 S2(C), found by isoelectric focusing. Three remarkable changes of nucleotide sequence were observed:(1) The two ORM1 alleles, ORM1*S and ORM1*S2(C), had the AGP2 gene-specific sequence at one and three regions, respectively, in exon 5 to intron 5. The variant allele originating from ORM1*S was characterized by a G-to-A transition, resulting in an amino acid change from valine to methionine, which is also detected in ORM1 F2, a form that is common in Europeans. (2) The AGP2 gene of the child, inherited from the father, was duplicated, as revealed by long-range polymerase chain reaction. (3) Three new mutations were observed in two exons of the AGP2 genes of the mother and child. All of these novel genomic rearrangements, which were not observed in Japanese subjects, may have arisen through point mutation, gene conversion, and unequal crossover events. It is likely that the rearrangement of the AGP gene has often occurred in Africans.

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“…ORM phenotyping was performed by three IEF techniques: IEF of desialyzed samples in the presence and absence of detergent (Yuasa et al 1993) and of alkylated samples in the presence of urea (Rocha et al 1993;Dülmer et al 1998). In some experiments a carrier ampholyte with a broad pH range of 3.5-9.5 (Pharmacia, Uppsala, Sweden) was also used.…”

Section: Methodsmentioning

confidence: 99%

Molecular analysis of the human orosomucoid gene ORM1*Q0 köln responsible for incompatibility in a German paternity case

Nakamura

Yuasa

Umetsu

et al. 2000

International Journal of Legal Medicine

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In a German paternity test, an alleged father was excluded only by reverse homozygosity of ORM1 phenotypes (mother ORM1 S, child ORM1 S and alleged father ORM1 F1) out of the 28 classical and DNA markers investigated. Without the ORM1 system the biostatistical probability of paternity was calculated to exceed 99.999%. The intensity of the immunoprinted bands of the ORM1 protein for the child and alleged father after isoelectric focusing appeared to be reduced to about half. To identify a possible null allele, gene-specific amplification followed by single-strand conformation polymorphism and sequencing analyses were carried out. Deletion of one of the two copies of a 4 bp direct repeat sequence (GTCT) in exon 4 of the consensus sequence of ORM1*F1 was observed in the child and alleged father. Thus, the sharing of a rare mutant gene, ORM1*Q0köln, increased the probability of paternity.

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Human Orosomucoid (ORM1) Subtyping: Further Population Genetic Data and Reports on the Feasibility to Type Aged Blood Samples and Stains

Cited by 4 publications

References 17 publications

Influence of Alpha-1 Glycoprotein Acid Concentrations and Variants on Atazanavir Pharmacokinetics in HIV-Infected Patients Included in the ANRS 107 Trial

Influence of Alpha-1 Glycoprotein Acid Concentrations and Variants on Atazanavir Pharmacokinetics in HIV-Infected Patients Included in the ANRS 107 Trial

Characterization of genomic rearrangements of the α1-acid glycoprotein/orosomucoid gene in Ghanaians

Molecular analysis of the human orosomucoid gene ORM1*Q0 köln responsible for incompatibility in a German paternity case

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