Dataset Information

Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers.

ABSTRACT: The aim of this study was to investigate the sensitivity and specificity of endogenous glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) as substrates for organic anion transporting polypeptide 1B1 (OATP1B1) in humans. We measured fasting levels of plasma GCDCA-3G and GDCA-3G using liquid chromatography-tandem mass spectrometry in 356 healthy volunteers. The mean plasma levels of both compounds were ~ 50% lower in women than in men (P = 2.25 × 10^-18 and P = 4.73 × 10^-9 ). In a microarray-based genome-wide association study, the SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) variation showed the strongest association with the plasma GCDCA-3G (P = 3.09 × 10^-30 ) and GDCA-3G (P = 1.60 × 10^-17 ) concentrations. The mean plasma concentration of GCDCA-3G was 9.2-fold (P = 8.77 × 10^-31 ) and that of GDCA-3G was 6.4-fold (P = 2.45x10^-13 ) higher in individuals with the SLCO1B1 c.521C/C genotype than in those with the c.521T/T genotype. No other variants showed independent genome-wide significant associations with GCDCA-3G or GDCA-3G. GCDCA-3G was highly efficacious in detecting the SLCO1B1 c.521C/C genotype with an area under the receiver operating characteristic curve of 0.996 (P < 0.0001). The sensitivity (98-99%) and specificity (100%) peaked at a cutoff value of 180 ng/mL for men and 90 ng/mL for women. In a haplotype-based analysis, SLCO1B1*5 and *15 were associated with reduced, and SLCO1B1*1B, *14, and *35 with increased OATP1B1 function. In vitro, both GCDCA-3G and GDCA-3G showed at least 6 times higher uptake by OATP1B1 than OATP1B3 or OATP2B1. These data indicate that the hepatic uptake of GCDCA-3G and GDCA-3G is predominantly mediated by OATP1B1. GCDCA-3G, in particular, is a highly sensitive and specific OATP1B1 biomarker in humans.

SUBMITTER: Neuvonen M

PROVIDER: S-EPMC7983942 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers.

Neuvonen Mikko M Hirvensalo Päivi P Tornio Aleksi A Rago Brian B West Mark M Lazzaro Sarah S Mathialagan Sumathy S Varma Manthena M Cerny Matthew A MA Costales Chester C Ramanathan Ragu R Rodrigues A David AD Niemi Mikko M

Clinical pharmacology and therapeutics 20201018 3

The aim of this study was to investigate the sensitivity and specificity of endogenous glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) as substrates for organic anion transporting polypeptide 1B1 (OATP1B1) in humans. We measured fasting levels of plasma GCDCA-3G and GDCA-3G using liquid chromatography-tandem mass spectrometry in 356 healthy volunteers. The mean plasma levels of both compounds were ~ 50% lower in women than in men (P = 2.25 × 10<sup>-18</sup> ...[more]

PMID: 32961594

Similar Datasets

Project description:The World Health Organization (WHO) 2030 roadmap for schistosomiasis calls for development of highly sensitive and specific diagnostic tools to continue and sustain progress towards elimination. Serological assays are excellent for sensitive detection of primary schistosome infections and for schistosomiasis surveillance in near- and post-elimination settings. To develop accurate assay formats, it is necessary to identify defined antibody targets with low cross-reactivity and potential for standardized production. Here we aim to identify such target(s) with focus on defined schistosome glycan antigens. Target identification was performed by assessing antibody responses in well-characterized cross-sectional and cohort sample sets (n = 366 individuals) on tailor-made antigen microarrays. IgM and IgG binding to candidate diagnostic targets was measured for serum/plasma samples from controlled human schistosome infection models, schistosome-infected travelers, soil-transmitted helminth-infected individuals, and non-infected individuals. We found that antibodies to a schistosome gut-associated glycan, the circulating anodic antigen (CAA), identify schistosome infection with high sensitivity (IgM ≥100%, IgG ≥97%) and specificity (IgM ≥93%, IgG ≥97%) in the test samples. Infection dose affected timing of anti-CAA antibody isotype switch. Furthermore, we demonstrate that other non-specific glycan epitopes in crude schistosome cercarial and egg antigen preparations can contribute to generation of false schistosomiasis positives, which is relevant for current serological assays based on these antigen mixtures. In conclusion, CAA is an excellent single glycan antigen target for development of highly sensitive and specific tools for schistosomiasis serology with use cases for travelers and surveillance in near- and post-elimination settings, as well as emerging transmission zones.ImportanceThe WHO 2030 roadmap deems diagnostics developments for schistosomiasis critically needed. Here we present identification of an antibody target with superior performance compared to traditionally used crude antigens in schistosomiasis serology. Access to unique controlled human infection model samples, traveler samples, and negative controls enabled this discovery, which forms the basis for development of new diagnostic tools urgently needed in travel medicine, surveillance in emerging transmission zones driven by climate change, and in pre- and post-elimination scenarios.

Project description:Alzheimer's disease (AD), a chronic neurodegenerative disease associated with the loss of neurons in the brain, is the most pervasive type of dementia; 47 million people are affected, and the number is expected to increase to more than 131 million by 2050, according to Alzheimer's Disease International. Both early diagnosis and continuous monitoring are crucial for early intervention, symptomatic treatment, monitoring of the efficacy of intervention and improved patient function. Beta-amyloid peptide, tau, and phosphorylated tau are useful for screening and diagnosis; meanwhile, simultaneous assessment of multiple biomarkers is of paramount importance for accurate disease diagnosis. Methods: Herein, we report a direct, inexpensive and ultrasensitive aptamer-based multiplex assay for the quantification of trace amounts of AD biomarkers in both human serum and cerebrospinal fluid (CSF) samples. In this newly developed assay, molecular recognition of an antibody-aptamer pair provides high specificity in target detection, and the use of a DNA amplification strategy affords high sensitivity, allowing quantification of AD biomarkers in both biological fluids in 1.5 h with only a diminutive amount of the sample consumed. A tailor-made turn-on fluorophore, namely, SPOH, was employed to label the antibody-aptamer hybrids and provide a strong fluorescence signal, which was then detected with a total internal reflection fluorescence microscopy electron-multiplying charge-coupled device (TIRFM-EMCCD) imaging system. The simultaneous detection of biomarkers was achieved by a direct shape-coded method in which the nanoplatforms can be distinguished from one another by their morphologies. Results: This assay demonstrated a lower detection limit (in the femtomolar range) for AD biomarkers than the previously reported antibody-antibody method. Conclusion: The developed assay holds tremendous clinical potential for early diagnosis of AD and monitoring of its progression.

Dataset Information

Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers.

Publications

Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets